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Tests Involving Pressing for Intracranial
as an Early Procedure for Screening Likelihood
of Addiction* of Opioids and Other Drugs
Larry D. Reid
Department of Psychology
Rensselaer Polytechnic Institute
Troy, New York 12181
|On the basis that the medial forebrain bundle system of the anterior brain stem is a major component of the system whose activity is positive affect, it is submitted that any drug that would increase activity in that system has a high risk of becoming the focus of an addiction. When an increasee focus of an addiction. When an increase in activity of that system is a contingency of an act (such as imbibing, inhaling, snorting, or injecting), then that act will occur more and more frequently (i.e., positive reinforcement occurs) and this is a basis for an addiction. The potential for a drug to increase activity in the system is often manifested by measuring the lever pressing of rats for a fixed intensity of electrical stimulation of the system. Drugs, therefore, can be screened for their addiction likelihood by observing their effects on pressing for brain stimulation.|
Thirty years ago the first complete report (Olds & Milner, 1954)
of positive reinforcement from direct electrical stimulation of the
was published. We are still a little stunned by that revelation. We
and are imbued with the idea that the brain is marvelously complicated.
We are also faced with mounting evidence that it is even more
then we imagined (Snyder, 1980, for example, predicted over 200
will be discovered). Our own experience tells us that pleasure and
processes are varied and subtle. Yet, a gross manipulation by way of
with a macroelectrode can produce positive affect, and when there is a
contingency, this can be reward or positive reinforcement. All that is
necessary or positive reinforcement. All that is
necessary is to step down the house current to a level that does not
neural tissue and to direct it, in brief spurts, to any number of sites
in the brain and positive affect is initiated. Furthermore, it seems
in all vertebrates (from samples as diverse as goldfish to human
an effect can be elicited by brain stimulation that maintains behavior
for that stimulation (Heath, 1964; Olds, 1962).
|*The term "abuse liability" is extraordinarily confusing, particularly in the context of this chapter. Discussing all of the problems with the term is beyond the scope of this chapter. It will be sufficient to say here, first, we are concerned with addiction liability. Second, the word liability has two meanings: likelihood and debt. In this context, and perhaps the entire book, it seems that we are attempting to assess addiction likelihood rather than addiction debt or abuse (albeit a likely consequence of addiction). Consequently, my topic is the use of procedures involving ICS in establishing likelihood of addiction. In accordance with modern theory of addiction, particularly opioid addiction (Smith & Lane, 1983), an addiction likelihood, in turn, is strongly related to the potential for a drug to be positively reinforcing.|
When the possibility of positive intracranial reinforcement (ICR) was first announced, it was met, not surprisingly, with inordinate skepticism. That skepticism was extant even though the pioneering work of Hess had shown that intracranial stimulation (ICS) elicited a number of motivational and emotional sequences in freely moving animals. Since Olds used in his initial studies small experimental spaces with large manipulanda, it was suggested, for example, that the rats were not voluntarily pressing to get ICS but that they were merely being thrown on the manipulanda by ICS-elicited forced movements. Rats eventually ran mazes, crossed electrified grids, worked a variety of devices, and solved complex discrimination problems for ICS. So, it is no mere automatism that leads rats to work for ICS (Olds, 1962).
To observe ICR, subjects (usually rats) are fixed with chronically indwelling electrodes. The surgical procedures have become standard and electrodes and holders for electrodes are commercially available. In brief, all preparations involve putting wires into the brain so that electric current can stimulate a small amount of neural tissue making that tissue supra-active with respect to the rest of the brain in the freely moving subject.
The standard experimental space is a box similar to the one popularized by Skinner and colleagues. The rat is placed into a box that has a bar or lever extending through one wall. With depressionending through one wall. With depression of the lever, events can be programmed, such as delivery of food, water or ICS. Using such an experimental procedure, an extensive body of knowledge has been developed as variables, (e.g., degree of food deprivation and rate of food-delivery relative to lever-pressing) were manipulated. The effects of making ICS a contingency of lever-pressing, therefore, can be understood in the context of this extensive information.
At a site of ICS, intense or prolonged current flowing in one direction destroys neural tissue. The typical ICS, then, is low intensity current with alternating polarity. Even if, however, the current is set so as to not damage tissue, ICS is unambiguously positive only when it is of brief duration. So, the standard experimental arrangement is to put a rat in a box and program it so that a lever-press yields a train of pulsate current with alternating polarity of low intensity lasting 0.5 seconds or less (i.e., train duration = 0.5 seconds).
With ICS set at safe values and brief train durations, sites of ICS were varied while observing the subjects’ responsiveness. With some sites rats do not learn to press for ICS. Using other experimental arrangements, it is possible to show that rats will work to avoid getting some ICS that was not positive. ICS, in a standard form, is either positive, neutral, or aversive in affective tone.
Sites of positive ICR differ. Once pressing tes of positive ICR
differ. Once pressing has been established, the
differences are made obvious by changing intensity or duration of ICS.
Also, for some sites rats more readily accept experimenter-imposed,
occurring trains of ICS whereas at other sites they will respond to
the imposed ICS. Sites are classed a "pure positive" when the rat works
to initiate ICS and does little to escape it when imposed and
when it both initiates and escapes the ICS (Olds, 1962). This
is highly dependent on the ICS used in testing. The ICS at all sites
be made too intense, too frequent, or too prolonged for optimal
by the subject.
|Figure 1: The typical arrangement for observing intracranial reinforcement.|
We infer that the medial forebrain bundle (MFB) as it extends from the ventral midbrain through the lateral hypothalamus and lateral preoptic areas is particularly relevant to reinforcement processes because MFB ICS is often unambiguously positive. Rats emit many presses for hours each day for MFB ICS. With MFB sites the minimum intensity for eliciting pressing is low. Rats press tes the minimum intensity for eliciting pressing is low. Rats press for MFB ICS across an extensive range of features of the ICS itself (intensity, train duration, frequency of pulses, et cetera). And, rats do not escape imposition of MFB ICS across many variations of its imposition.
One general feature of the behavior emitted for ICS is that the rats work more for greater intensity (more accurately, microcoulombs) of ICS (Keesey, 1964; McIntire & Wright, 1965). For many MFB sites the relationship between rate of pressing and intensity of current is linear up to the point of neural damage. For other sites the function reaches an asymptote so that further increases in intensity produce no further increases in pressing or may even produce a decrease. Observations make it apparent why some rates of pressing may decrease at higher intensities; the higher intensity may elicit seizures or forced movements interfering with pressing.
It appears to be necessary to activate a rather large group of neurons and fibers to elicit ICR. The threshold for perception of ICS (i.e., intensity sufficient for a rat to use it as a conditional stimulus) is less than the intensity that will sustain a minimal rate of pressing. After the threshold for ICR is achieved, it seems that the recruitment of more and more activity in relevant tissue yields more and more intense positive affect which is manifested in greater rates of pressing. When eventually an intensity is reached that entually an intensity is reached that elicits activity leading to seizures or other side effects, the affective quality is diluted or the ability to press is hindered.
With the initial studies there were a number of observations indicating that ICR had some peculiar features. In contrast to the behavior of rats working for small bits of food, for example, it was concluded that when a delay was programmed between trains of ICS, operant behavior deteriorated. These peculiarities of ICR, compared to behavior following conventional reinforcement, became known as the anomalies of ICR and were provided in lists to support various theories (Deutsch & Howarth, 1963; Kimble, 1961).
Research on ICR involved an inspection of reputed anomalies (e.g., Reid, 1967). This research was a test, despite some limitations, of the general idea that certain ICS was indeed initiating activity ordinarily initiated by conventional reinforcers. Although it is impossible to prove an identity, the more the two kinds of reinforcers control behavior in the same way, the more confidence one has that they have considerable neural features in common. There is, of course, the obvious difference that one process follows ICS and one follows events such as eating or drinking. Also, with eating and drinking there is the eventual consequence of a full stomach that has no obvious match with ICR. Keeping these differences in mind, it seemed that if ICS was initiating, it seemed that if ICS was initiating the processes of reinforcement, then ICS should control behavior in nearly the same way as conventional reinforcers.
The first finding of the systematic inspection of the anomalies was that some were not apparent when ICR was from MFB stimulation. For example, on the basis of observations of cats, it was concluded that cats did not show good signs of ICR and, therefore, ICS was not activating a universal reinforcement system present in different species. We (Schnitzer, Reid, & Porter, 1965) merely placed electrodes so that the MFB was stimulated and found that cats worked very hard for ICS.
Also, direct comparisons were made between behavior maintained by food and water and that maintained by ICR. Prior to these experiments, the comparisons were made indirectly by comparing the behavior of rats working for ICR to the generalizations derived from studying rats working for conventional rewards. When rats press for food, the lever press activates a dispenser that delivers food in a dish usually slightly to the side of the lever. When rats pressed for ICS, the ICR was delivered with the depression of the lever. We (Reid & Porter, 1965) then arranged test conditions so that the lever press merely made it possible to get ICS at the dish that usually received food (i.e., the rat broke a photobeam across the dish to receive ICS). Under these comparable conditions of ways of delivering the tconditions of ways of delivering the two kinds of reinforcers and when the ICS was of the MFB, the behaviors maintained by ICS and by conventional reinforcers were indistinguishable in topography (e.g., Gibson, Reid, Sakai, & Porter, 1965).
Rats have been shown to work on periodic schedules of delivery of ICS, to show no peculiarities of extinction (Gibson et al., 1965), and to press without decrement even when intervals between opportunities to press are great (Hunsicker & Reid, 1974; Wasden, Reid, & Porter, 1965). The anomalies of ICR are related to two features: the site of ICS and the comparisons of performance after unequal tasks (Reid, 1967). The site of ICS is a major consideration. There are no gross anomalies of ICR with certain sites of ICS, namely those of the MFB.
Rats do show anomalies when tissue related to positive affect is activated concurrently with other tissue. This can be due to a slightly misplaced electrode or to features of the ICS such as high intensity, prolonged durations, or very brief surges in current that accompany generation of ICS by some stimulators. They perform like rats getting bitter food or food accompanied by low level foot shock. They show vacillation, performance decrements, rapid extinction, et cetera.
By observing when anomalies were and were not present, the features of the system became more defined. When ICS was exclusive to the MFB, anomalies were less apparent or weFB, anomalies were less apparent or were absent. Arrangements for the clearest cases of ICR supported the idea that activity of the MFB system was, indeed, an important element of the behavior of positive reinforcement.
More recent anatomical study of ICR has both expanded the borders of the MFB system and made more precise the cells and fibers of the system. It has become clear that among the critical tissues are dopaminergic neurons and processes (Wise, 1983). The MFB and adjacent tissue are places where dopaminergic fibers are reasonably densely packed (Jacobowitz & Palkovits, 1974), and ICR is achieved when ICS activates these dopaminergic elements (Wise, 1983).
There are other lines of converging evidence to support a conclusion that the MFB system with its components of dopaminergic cells and fibers is critical to positive affective processes. For example, reward and positive reinforcement procedures fail when the MFB system is debilitated (Wise, 1982a). Experiments showing that the rewards of prototypic addictive drugs have localized, critical effects within the MFB system are, of course, particularly germane (Bozarth, 1983; Wise, 1983). These lines of research have received extensive review and discussion (e.g., Wise, 1980; 1982b; 1983) and this is not the place to repeat them. What is controversial is whether or not the MFB system of dopaminergic elements is part of the brain’s only system for expressi brain’s only system for expression of positive affect and the consequent events of positive reinforcement.
As the basic information of ICR accumulated, other events happened to produce an interest in the effects of psychotropic drugs on ICR. Most importantly, there was further confirmation of the idea that many, if not all, addictive drugs were taken for their positively reinforcing aspects (Deneau, Yanagita, & Seevers, 1969; Schuster & Thompson, 1969; Thompson & Schuster, 1964; Weeks, 1962).
If drugs of addiction are taken for their positively reinforcing effects and if the MFB system is the only system of positive affect, as retina, optic nerves and geniculate are exclusive to vision, then drugs of addiction must act, either directly or indirectly, on the MFB system. The problem of measuring addiction likelihood then becomes one of measuring drug-induced increases in that functional activity. The MFB system need not be, however, the only system of positive affect for measures of drug effects on the MFB system to be useful. The MFB system need only be a major part of the brain’s apparatus for positive affect. A test drug that would increase MFB’s functional activity would have high addiction likelihood. Along the same lines the ability of a drug to elicit positive affect need not be the only reason for a drug to be taken recreationally. All that is necessary is that the ability to elicit positivey is that the ability to elicit positive affect be a major component of the addiction syndrome.
I doubt if anyone will challenge the conclusion that the MFB system is a major component of the brain’s apparatus for positive affect. (They may challenge the use of the term positive affect; however, they may substitute their favorite synonym without taking away from the conclusion.) I doubt if anyone will challenge in the 1980s that a drug’s ability to be positively reinforcing is a major component of a drug’s ability to become the focus of an addiction. Given this consensus, it follows that a drug increasing the functional activity of the MFB system is also a drug having high addiction likelihood. If the MFB system is not the only system of positive affect or if other factors besides the ability to elicit positive affect contribute to addiction likelihood, tests of functional activity of the MFB system may fail to index a drug’s addiction likelihood. Although there is a consensus concerning the primary conclusions, such a consensus does not translate directly into tests of addiction likelihood. Many problematic theoretical and practical issues remain, some of which, but surely not all, are discussed here. The result is the recommendation of a test, involving drug-induced changes in pressing for ICS by rats, as an initial screening procedure for likelihood of addiction.
No one is satisfied with our current knowledge of the brain’s appour current knowledge of the brain’s apparatus of positive reinforcement. Little is known, for example, about the afferent patterns of activity that, in ordinary circumstances, set activity in the MFB system. Our lack of knowledge of the brain’s apparatus for reinforcement limits all approaches to assessing addiction likelihood. This obvious point is stated because it seems to be a covert criticism of methods using ICS. Perhaps the limitations to our knowledge are merely more focused when considering ICR. This is an advantage rather than a disadvantage.
Although one may develop techniques for measuring the MFB’s functional activity in preparations other than those involving behaving subjects (e.g., electrical recording; Nelsen & Kornetsky, 1972), measuring the behavior of subjects is likely to provide a more complete assessment of the relevant functional activity. This also follows from the realization that the MFB system itself is defined behaviorally as well as anatomically.
Two features of responsiveness for MFB ICS seem to index changes in functional activity: measures of threshold for elicitation of ICR and measures of work expended for a fixed intensity of ICS. For either of these indices of MFB activity to be a valid assessment of addiction likelihood, known addictive drugs must have common, systematic effects.
Initial results with the effects of addictive agents on pressing for ICS were confusing. Morphine essing for ICS were confusing. Morphine decreased pressing but amphetamine, cocaine, and barbiturates increased it (Crow, 1970; Olds & Travis, 1960; Reid, Gibson, Gledhill, & Porter, 1964; Stein, 1962). Then, Adams, Lorens, and Mitchell (1972) reported that morphine was capable of increasing pressing. With reports verifying and extending that observation (Bush, Bush, Miller, & Reid, 1976; Holtzman, 1976; Koob, Spector, & Meyerhoff, 1975; Lorens & Mitchell, 1973; Marcus & Kornetsky, 1974; Pert, 1975), the idea was supported that drugs taken frequently for their recreational features by people share two properties. At some doses, these agents are self-administered by laboratory subjects and they facilitated responsiveness for rewarding ICS (Bozarth, 1978; Esposito & Kornetsky, 1978; Reid & Bozarth, 1978).
There were a number of questions concerning morphine’s (the prototypic addictive agent) ability to increase pressing for ICS: (a) Was the increase a rebound from initial suppression of pressing? (b) Did the increase reflect morphine’s ability to suppress aversive concomitants that could easily accompany ICS? (c) Did the facilitated pressing reflect some increment in positive affect or merely some increased propensity to be active? Each of these questions was addressed experimentally.
With large daily doses of morphine (e.g., 10 or 15 mg/kg/day), the period of facilitation moves forward and the initiaacilitation moves forward and the initial depression of press rates wanes. Figure 2 depicts the effects of smaller doses of morphine on pressing for ICS. It is apparent that the effects of morphine, compared to baseline, are characterized by a triple interaction of dose by time after dosing by days of daily dosing (see Figure 3). A further factor is the rate of pressing at baseline. When press rates at baseline are low, the relative increment in pressing can be great. When press rates at baseline are high, there are ceiling effects.
The facilitated pressing is paralleled by a decrease in the lower threshold for ICR, a topic reviewed extensively by Esposito and Kornetsky (1978; Esposito, Porrino, & Seeger, this volume). Morphine shifts the rate of pressing to intensity of ICS function to the left (Esposito & Kornetsky, 1977). Such findings provide an important confirmation for the idea that morphine is increasing the effectiveness of the ICS.
The issue of tolerance to the facilitation effect has received
attention (Esposito & Kornetsky, 1978). It is clear that the
in responsiveness to ICS shows nothing approaching complete tolerance
& Kornetsky, 1977). As daily dosing continues, there is clearly
to the initial suppression (Adams et al., 1972; Bush et al., 1976).
|Figure 2: The effects of small doses of morphine on pressing for hypothalamic ICS.|
There are a few remaining issues concerning tolerance of the facilitation effect. Quantifying the maximum extent of the facilitation is extraordinarily difficult, because the period of peak facilitation may differ with each dose. We do have enough comparisons to conclude that, in general, facilitation does not diminish much, if any, with repeated doses. In fact, peak effect may become larger with repeated doses.
Along the same lines we do not have enough data to judge whether the period of enhanced positive affect due to morphine actually becomes briefer with repeated doses. There are reasons to suppose it does. With repeated injections the period of facilitated pressing moves forward closer and closer to the time of injections. Withdrawal symptoms do emerge and the events of withdrawal do diminish pressing (Bush et al., 1976). So, with the advent of withdrawal and the movement of the period of facilitation forward, the net result may be that the period of positive affect is shorter.
The data with respect to tolerance provide the first good indication
that morphine’s ability to induce analgesia and positive affect phine’s
ability to induce analgesia and positive affect are separable.
|Figure 3: An attempt to depict the triple interaction of the effects of morphine, a standard large dose, on pressing for ICS. Reprinted with permission from Bozarth, 1978.|
|Figure 4: Comparison of time-effect relationship for analgesia and pressing for ICS induced by a single administration of morphine (10 mg/kg). The analgesia data are adapted from Hipps, Eveland, Meyer, Sherman, and Cicero, 1976, and Kayan, Woods, and Mitchell, 1971. The ICR data are extrapolated from Adams, Lorens, and Mitchell, 1972, and Bush, Bush, Miller, and Reid, 1976. Reprinted with permission from Bozarth, 1978. Also, the time course of analgesia and positive affect (as indexed by pressing for ICS) are not the same (see Figure 4). There are also other kinds of evidence (to be summarized later) to indicate separation of morphine’s potential forevidence (to be summarized later) to indicate separation of morphine’s potential for analgesia and positive affect. So, morphine probably does not facilitate responding for ICS because it reduces some aversive concomitant of ICS that may accompany it.|
A direct test (Farber & Reid, 1976) of morphine’s ability to affect positive affect independent of its analgesic properties was done by assessing morphine’s ability to modify responding for positive ICS that was accompanied by a clearly aversive stimulus. Rats were fixed with two electrodes, one for stimulation of MFB and one for ICS that rats would escape. During one phase of testing, rats had only positive ICS as a contingency. During another phase rats had positive ICS followed immediately by aversive ICS as a single contingency of a lever press. Without drugs the programming of the aversive ICS reduced pressing compared to when only positive ICS was a contingency.
For 20 days rats pressed for positive ICS alone and for combinations of positive and aversive ICS following an injection of morphine. Morphine increased pressing for positive ICS as expected. After a few doses of morphine, morphine did not facilitate pressing for the combination of positive and aversive ICS. If morphine acted by way of diminishing aversiveness, just the opposite would be predicted.
From dose-response data and from data measuring pressing after self-administrated doses orasuring pressing after self-administrated doses or after equivalent small doses (Collaer, Magnuson, & Reid, 1977; Gerber, Bozarth, & Wise, 1981; also, see Bermudez-Rattoni, Cruz-Morales, & Reid, 1983), it is concluded that the facilitated pressing is not a rebound from any initial suppression that may accompany larger doses. This conclusion is compatible with the idea that morphine-induced facilitation of pressing is due to morphine’s ability to enhance activity in the MFB system. To confirm this notion an independent test of morphine’s capability to produce positive affect was developed.
It was reasoned that if morphine was producing positive affect at the time it facilitated pressing for ICS, then that increment in positive affect should be manifested in some feature of the rat’s behavior. If the rat experienced that positive affect in a distinctive place, there is a good possibility that the stimuli of that place would be associated (classically conditioned) to the positive affect and would come to have a positive valence. When given a choice between the place of the drug experience and another place, the subject would choose the place where it had experienced the drug.
Following this reasoning, rats were placed into one side of an alley while under the influence of morphine and, subsequently, were given the choice of being in that side or the other side (Rossi & Reid, 1976). The rats were confined to one side of the allets were confined to one side of the alley for conditioning at different times after injection of a large dose of morphine. Among the times chosen was the time that morphine readily facilitated pressing for ICS and times before and after morphine-facilitated pressing. The subjects receiving putative conditioning during the time when morphine facilitated pressing for ICS clearly spent more time on the side of the drug experience compared to rats given saline and treated the same way. Rats receiving putative conditioning at times when morphine did not produce clear signs of facilitated pressing did not show a conditioned preference for a side of the alley.
The test of morphine’s ability to establish a preference for the place of a drug experience has come to be called the conditional place preference test (CPP test; Bozarth, this volume; van der Kooy, this volume). The test gave an independent verification that rats were experiencing something (positive affect) that established a preference for a place under the same dosing that facilitated pressing for ICS. Under dosing conditions that facilitate pressing for ICS, a CPP is established, the threshold for initiation of ICR is reduced, and the facilitation is difficult to explain by resorting to explanations other than those involving changing affective-reinforcing properties of ICS. Further, doses comparable to those that are self-administered produce facilitated pressing without an apparefacilitated pressing without an apparent interval of suppressed pressing. So, the conclusion is that morphine’s ability to be positively reinforcing is manifested in a number of indices of the rat’s behavior, including facilitating pressing for ICS.
Tests of Addiction Likelihood
It is one thing to come to the conclusion that a measure of responsiveness to ICS could be an index of addiction likelihood and another thing to devise a reliable, valid, practical test that, indeed, measures or reflects a functional change in reactivity of the MFB system. There are a large number of variables that can be manipulated within the context of assessing a drug’s effect on responsiveness to ICS. There are the features of the ICS itself (such as waveform, intensity, train duration, pulse duration, frequency of pulses). There are the variables associated with the subject’s performance, for example, difficulty of the task or high versus low rate-dependency tasks. There are, of course, subject variables such as species, gender, age, and drug and testing history. These and other procedural variables (e.g., drug doses) can be combined into a totally overwhelming set of combinations. It is safe to say that no drug will ever be assessed (even in one kind of rat) across all of the potential combinations of procedural variables. The task, then, is to select procedural variables rationally rather th procedural variables rationally rather than arbitrarily. The rational choice from among this multitude of variables will be discussed in terms of each of the broad categories mentioned starting with the choice of subject.
One definite consideration is the ease and productivity of testing (Liebman, 1983). Any devised system has to be justified on the basis of its ability to screen a large number of drugs, because the medicinal chemists can and are devising more drugs (and, perhaps, food additives) than can be assessed behaviorally even with our most productive procedures. As we shall see, it is on the grounds of practicality that measures of responsiveness to ICR recommend themselves.
The best predictor of a drug’s addiction likelihood for an individual is knowledge concerning how the drug has been responded to by others. If a drug is taken repeatedly for its apparent recreational qualities by a large number of people, then the prediction is made, with some surety, that the drug is likely to be addicting for others. The whole purpose of procedures described in this book, however, is to avoid making the prediction in that way. At this stage, I do not believe anyone has serious objections to concluding that rats show enough of the features of the addiction syndrome seen with human beings to be adequate subjects for screening drugs for their addiction likelihood (e.g., see Collins, Weediction likelihood (e.g., see Collins, Weeks, Cooper, Good, & Russell, 1984; and the drug discrimination data summarized in Woolverton & Schuster, 1983). Since addictions occur with both genders and across all ages, the choice of rats’ gender and age will evidently be of little consequence. The typical, healthy, young adult, male rat has a number of practical features, such as those of price, ease of handling, and ready availability, that recommend its use. Given these considerations, the problem generates into how to use rats to predict addiction likelihood.
In this context the interest is in testing drug effects rather than ICS effects. So, the problem is to select optimal features of ICS. The choices among ICS variables and among the tasks chosen to index responsiveness to ICS are discussed thoroughly by Liebman (1983). Since Liebman’s goal was a discussion of techniques for doing research on the basis of ICR and mine is the more restrictive goal of screening drugs for addiction likelihood, this chapter may be considered an addendum to Liebman’s excellent review.
Site of ICS
On the grounds that the MFB system is a major component of the brain’s apparatus for positive affect and may even be the only critical part (All other sites of reinforcing ICS may lead to activity that feeds through the MFB or that is part of the field of MFB activity.), the sites of choiced of MFB activity.), the sites of choice are those referred to as the MFB. Aiming an electrode tip to stimulate the anatomically defined MFB of the lateral, posterior hypothalamus has the advantage of aiming the tip toward a relatively large area. If the electrode tip should deviate from MFB itself and be in adjacent areas of the zona incerta or Forel’s fields, it is of little consequence. These sites also sustain pressing for ICS without inordinate side effects and have been shown to be appropriately responsive to prototypic addictive agents. These sites also involve the fibers from the ventral tegmental-substantia nigra areas (the meso-limbic dopaminergic system) judged to be particularly relevant to the positive features of conventional rewards and abused drugs (Wise, 1983). This large area, fortunately, allows a high ratio of rats that press for ICS to those fixed with electrodes, a nice practical feature.
Although the size of the electrode’s stimulating tip (the uninsulated portion of the indwelling wire) has not been systematically evaluated, it is known that a relatively large area of tissue needs to be stimulated to achieve ICR. An area of ICS which is too large, however, increases the possibility of stimulating tissue that is outside of the MFB system for reinforcement thereby producing side effects. Along the same lines bipolar electrodes provide a more discreet focus of stimulation than unipolar electrodes (Valenstein &n unipolar electrodes (Valenstein & Beer, 1961). The recommendation, then, is to use the smallest, commercially available, bipolar macroelectrode.
The waveform must have the feature of alternating polarity to prevent neural damage. This has been achieved by using 60 Hz sine waves or by using biphasic square waves. Stimulators made by controlling house current are usually adequate and inexpensive. When devising a stimulator, care must be taken to avoid ground loops (such as those involving oscilloscopes) that can provide very brief but high intensity surges in current.
Duration of Train of ICS
Rats will press one lever to start a train of ICS and then press another to terminate it (Bower & Miller, 1958). There has been considerable research directed toward answering the question why do rats terminate initially positive ICS (see Liebman, 1983, for a review). Among the things to consider is that prolonged durations of ICS, even at low intensities, will destroy neural tissue (Becker & Reid, 1977). The evidence indicates that some feature of prolonged ICS yields aversiveness (Liebman, 1983). All places of positive ICS have extensive connections. Prolonged ICS must, therefore, eventually produce considerable "irrelevant" activity away from the site of ICS. That this other activity and its effects are not positive is, of course, very likely.
A drug-induced increase in the accepted duration of ICS is likely to reflect modification of the side effects. Wauquier, Gilbert, Clincke, and Franson (1983) concluded "There is no reason to sustain that keeping on the stimulation for long times, suggests that the rewarding effect becomes larger, but rather that rats are able to sustain prolonged stimulation which they normally escape because of the building up of aversiveness" (p. 161). It follows that if one wants to measure changes in positivity, only short durations of ICS should be used.
Rats work very well for low intensity ICS of 0.25 seconds, although self-selected durations are usually greater than 0.25 seconds. Since longer durations are apt to also produce aversive side effects, there is no reason to complicate measures of drug-induced changes in responsiveness for ICS by using longer trains of ICS.
Rats escape from places where frequent trains of ICS are delivered as they do prolonged trains. Although task variables are discussed subsequently, it is apparent that any task involving rats working for long durations of ICS or measuring their acceptance of frequently occurring ICS can measure both the positivity of the ICS and the aversiveness of side effects. Since the desire is to measure only changes in positivity, these tasks are inappropriate. If high intensities are used, then brief durations are even more critical. So, the recommendation is the use of low intene recommendation is the use of low intensity ICS of 0.25 seconds (60 Hz sine waves).
Intensity of ICS
Using ICS of 60 Hz sine waves of 0.25 seconds, pressing for MFB ICS can be easily trained with intensities less than 50 microamperes. With MFB ICS lower thresholds for ICR are less than 15 microamperes. It is only after the introduction of higher intensities or longer durations (seconds rather than fractions of second) that lower thresholds climb beyond that limit. Press rates can be maintained after small lesions at the electrode tip with the use of higher intensities, but this increases the possibility of side effects. When one observes inverted U-shaped pressing-intensity functions, it is a reasonable assumption that the down turn in rates at the high intensities is due to the elicitation of unwanted side effects; hence, these intensities are to be avoided. Some investigators never seem to see low threshold levels, probably because the first intensity used produces a lesion. So, routine testing for a drug’s effect on responding for ICS should use low intensity ICS.
The goal is to use some feature of rats’ responsiveness to brief MFB ICS to index drug-induced changes in the functional activity of the MFB. A number of ways have been used. One way is to measure the lower threshold for the elicitation of ICR (see Esposito, Porrino, & Seeger, this volume). Another way is to meSeeger, this volume). Another way is to measure the work a rat will engage to get a fixed ICS (i.e., all features of ICS remain the same across testing).
If a drug induces more work for a fixed ICS, the conclusion is that the drug has increased some feature of the activity initiated by the ICS making the ICS more potent. A standard way of indexing work among rats is lever pressing. The question comes down to whether drug-induced changes in lever pressing for a fixed ICS is, indeed, a reliable and practical method for assessing germane functional activity, and, if not, are there viable alternatives.
The issue is not with the reliability of the index of modification in press rates. The arrangement of rats pressing for ICS is relatively easy; consequently, many rats can be tested and the reliability of any resulting drug-induced modification in pressing is assessed by asking, in conventional ways and by using conventional standards, is the change in pressing statistically significant.
The potential confound between reward and performance is the major issue associated with the validity of conclusions made following drug-induced changes in lever pressing. When lever-pressing rates are decreased, it could be because the ICS is less effective or because the rat is debilitated. The procedures one has to engage to prove that decreases in behavioral output are due to decreased reward rather than alternative factors are too laborious for ternative factors are too laborious for a standard screen of likelihood of addiction. There are, of course, research issues that demand such attention. Wise (1982a), for example, reviews the elaborate series of studies he and his colleagues have engaged to show that pharmacological blockage of dopaminergic systems reduces potential for reward as well as, or rather than, inducing motoric limitations. This work was necessary for development of a theory of the neurochemistry of affect but cannot be done as a routine screen for addiction likelihood.
When a test drug decreases pressing for ICS, no conclusion about its addiction likelihood can be reached. Morphine at some doses and chlorpromazine at many doses both decrease pressing and are different in addiction likelihood. Of course, morphine at other doses and times after dosing increases pressing. So, when a decrease in pressing is seen with a test drug, such a decrease calls for more tests with more doses. If the test involves rats working in sessions of an hour or more, a reasonable sample of behavior following drug administration can be taken. When a wide range of doses are used, particularly within the range of doses that do not produce obvious debility and are reputed to have therapeutic value, then there is a good opportunity to see any increases in pressing that may occur.
When a test drug produces no period of increased pressing across a wide range of doses, the conclusion o wide range of doses, the conclusion of low potential for addiction is supported. Such a result, however, is not sufficient by itself to conclude with confidence that the test drug has low addiction likelihood, and it calls for other kinds of tests that are not so dependent on performance. The CPP test is recommended (Hunter & Reid, 1983).
The question might be raised that if one must test a drug eventually with the CPP test, then why not just use that test in the first place. The CPP test involves the arbitrary selection of length of the conditioning period and of the time after dosing of the conditioning period. On the grounds of the principle of delay of reinforcement gradient, it is clear that among the times to be tested is the time shortly after drug administration. This, however, provides only some guidance in selecting periods for conditioning and leaves an inordinate array of choices. A drug, for example, eliciting brief positive affect followed by aversiveness is one that will be difficult to assess in the CPP test. The conditioning period will have to be chosen, before the facts, to exclude the period of negative affect.
When a drug produces an increment in pressing for fixed (but selected) ICS, the conclusion is drawn that the drug has a likelihood of becoming the focus of an addiction. A drug could, however, increase pressing for reasons other than enhancing the potency of ICS. The probable reasons for an incremCS. The probable reasons for an increment in pressing, besides the one associated with increased positive affect, fall into two categories: (a) increased arousal and (b) diminished side effects. There has also been critical commentary concerning press rates, themselves, as a measure. Each of these is discussed, in turn, beginning with the last criticism.
The criticism of the measure of rate of lever pressing is based evidently (on the basis of citations given) on the possibility that a rat may choose ICS of one site over that of another and that the chosen site, on occasion, will be pressed for less than the other site (Valenstein, 1964). That A is preferred to B by one assessment technique, however, says very little about whether or not B plus one is greater than B. Since morphine, for example, will likely increase pressing for A-ICS as well as B-ICS, it is irrelevant that A-ICS is preferred, under some circumstances, to B-ICS. There are some potential difficulties in interpreting drug-induced increments in pressing, but these difficulties have little to do with the results of some preference testing.
That rates of pressing do not predict everything is surely a truism. Individuals work very hard, on occasion, for a less preferred reward. There are surely circumstances when a measure of work and a measure of choice lead to concordant conclusions. With careful experimental conlusions. With careful experimental control these two measures can often be made concordant. The fact that they may not be perfectly concordant across tests involving different procedures, however, does not detract from the reliability or the validity of either measure.
To avoid the complications associated with the conclusion that a drug may decrease side effects rather than increase reward potential, the features of the test should be arranged to minimize side effects. As mentioned above, this is done by using low intensity, brief ICS. One should also eliminate rats for which ICS clearly elicits side effects.
As a further procedural variable, it may be desirable to use a variable interval schedule of ICS delivery. If the mean interval is only a few seconds, it is easy to train rats and obtain a steady rate of pressing that is maintained for long testing sessions. This choice of task also has the advantage that the maximum number of ICS, for a session, can be fixed. This eliminates the possibility of side effects occurring with too frequent ICS. The recommendation, then, is to use a lever-pressing task with brief, low intensity ICS delivered on a brief variable interval schedule.
Anticonvulsant drugs produce an increase in pressing for ICS (Reid, Gibson, Gledhill, & Porter, 1964). Evidently, an anticonvulsant drug can act to reduce some side effects of ICS by reducing the spread of activity leaving a more focused effect. tivity leaving a more focused effect. In general, we expect drugs eliciting positivity to produce their greatest effect at low intensity. When they do not, alternative explanations seem more reasonable. Once again, the recommendation is to use ICS that is unlikely to elicit side effects such as seizures--low intensity, brief ICS of the MFB (Bogacz, Laurent, & Olds, 1965). If there are still questions concerning whether an increment in pressing is due to anticonvulsant activity, the drug can be tested with the CPP test. After tests with pressing for ICS, the doses and times after dosing are specified.
With the task of pressing for a fixed intensity of ICS, it has been suggested that there is an interpretational problem concerning whether the drug may be merely increasing nonspecific arousal (called incentive by Liebman, 1983) or whether the increases are due to increased reward potential. The screening of drugs for addiction likelihood is not such an issue, provided some care is taken in choosing the task. When there is a small lever in a relatively large box, as in standard experimental spaces, drugs such as morphine and amphetamine (at doses that would increase other measures of activity) do not increase lever pressing when the lever depression yields no ICS.
There is, of course, the possibility of arousal interacting with ICS-elicited processes to produce an increase in pressing. It makes little difference, however, whethekes little difference, however, whether a drug-induced increase is due to the interaction or due to only increasing reward potential. A drug doing either has a risk of addiction likelihood. An advantage of the task of pressing for ICS is that it allows for the interaction to be made manifest. A drug, for example, that would increase the basal activity of the MFB system associated with the natural rewards of eating and sexuality is apt to be taken often. Also, in many cases, it may be impossible to separate arousal from reward; rewards by their nature are arousing and have other incentive qualities (Iversen, 1983).
There has been considerable discussion (Liebman, 1983) of using simplified operants (such as nose poking) rather than lever pressing as the task. The reasoning is that simplified tasks are less likely to be disrupted by side effects of ICS or drugs. When a drug reduces any operant, more testing is demanded. There seems to be no inordinate advantage to using simplified operants (Liebman, 1983). Some of the suggested tasks are so novel that considerable research would have to be done to provide an adequate basis for interpreting results (Liebman, 1983).
One can use pressing for ICS to measure thresholds by varying the intensity of ICS and by determining the lowest intensity maintaining pressing. The intensity that produces half of maximum press rates can also be determined. Such testing, however, involves using shortenedsting, however, involves using shortened sessions or an inordinate number of sessions or rats. An advantage of using pressing for a single intensity is that it can easily sample a drug effect across time. Prolonged testing with a range of doses is apt to index any facilitation that may occur. If an increment in pressing is observed, then further testing for threshold will add meaningful data.
There are threshold tracking procedures that allow a continuous sampling of threshold across an extended period. In one situation, two levers are available. Each press of one lever provides ICS and sets the intensity for the next ICS at a lower value. Depression of the other lever resets the intensity to the highest level on the first lever. Rats do press the ICS lever until some low value is reached, then press the reset lever, and again press the ICS lever (Stein & Ray, 1960). The intensity of reset is then monitored with and without drug. The procedure is valuable and was used effectively to show heroin’s ability to lower threshold (Bozarth, Gerber, & Wise, 1980). Judgments from this test should be concordant, in most instances, with tests involving pressing for a fixed ICS. Since pressing for a fixed ICS is simpler and since there are unknown complications with threshold tracking (such as the effects of test drug on tendency to perseverate in unrewarding tasks), it seems that there is no marked superiority of this threshold-tracking uperiority of this threshold-tracking procedure to those measuring pressing for fixed ICS.
An inspection of some of the myriad variables that may affect the decision of whether or not a drug increases activity in the MFB system leads to the recommendation of using a test involving (a) rats, (b) brief, low intensity MFB ICS, and (c) a lever-pressing task with a short variable interval schedule of delivery of ICS. A drug-induced increment in pressing, under such circumstances, leads to the judgment of risk of addiction. A decrease or no change in pressing leads to the judgment of little or no risk, but that judgment has to be qualified and tested further.
The following procedures are recommended as an economical way of screening novel drugs for addiction likelihood. Among the first tests should be the drug’s effects on pressing for ICS. Such tests should follow the procedural guides given and should involve lengthy testing sessions beginning just after drug administration. A wide range of doses should be tested including, of course, a range of reputed therapeutic doses. Because of the test’sc doses. Because of the test’s economics, this is manageable. If a drug increases pressing for a fixed MFB ICS, the judgment is made that it has a risk of becoming the focus of an addiction. To verify that likelihood, other tests can be performed such as a self-administration test or CPP test. The data from the tests with ICS, however, provide guides, which are difficult to derive in other ways, for selection of doses and other procedural variables to use in these other tests.
A drug producing no increment in pressing for ICS has an unknown addiction likelihood. With doses that interfere with ability to bar press, the next test of choice is probably the CPP test, a test that is not dependent upon an animal’s ability to move with coordination. Any dose and time aftery dose and time after dosing that may appear to be eliciting increments in pressing for ICS, but do not produce large effects, should be assessed in the CPP test.
I submit that measures of responsiveness to ICS are highly sensitive. The CPP test is limited by the necessity to choose before the facts the period of drug-elicited positive affect. The self-administration test is limited by a number of features including its lack of productivity and the necessity to choose doses before the fact. If productivity of self-administration tests is enhanced by using animals already trained to self-administer drugs, mixed agonist-antagonists may produce withdrawal sickness that masks the potential for positive affect (Hunter & Reid, 1983). Measures of responsivenesss of responsiveness to ICS, because of their relative ease, can use drug-naive (or nearly drug-naive) subjects with many doses and with measures extending considerably beyond the time after injection. This feature allows the test to index potential for positive affect across a considerable range of variables of drug. With pressing for a low intensity, brief ICS, a very small increment in current can produce marked increases in pressing. Because the test can be sensitive to small increments in elicitation of positive affect and can index such small increments with a variety of doses and times after dosing, the screen is very sensitive. Tests with ICS, for example, would have predicted the likelihood of addictions to commonly used benzodiazepines (Kamei, Yoshinobu, & Schimizu, 1974; Lorens & Sainati, 1978; M. Olds, 1966; 1970).
A highly sensitive test may not be desirable from the view of a manufacturer of drugs. A drug with therapeutic potential for widely occurring disorders such as minor pain, hypertension, obesity, or anxiety and having a low but reliable ability to elicit positive affect with few deleterious side effects (including few withdrawal signs merely because it is not metabolized rapidly) will, if marketed, produce high sales and profits. The use of a highly sensitive test, or group of tests, for likelihood of addiction can surely lead to limiting sales. This is not the place to discuss the isss is not the place to discuss the issues of management of risk, only the measurement of risk. If the most sensitive tests are not used, however, measurement of risk is bypassed and management of risk is impossible.
Pleasure and Specificity of Effects of ICS and Drugs
I started with the premise that the MFB system is a major component of the brain’s apparatus for pleasure in order to discuss the procedural variables of a test for addiction likelihood. Considerations of those procedural variables, in turn, bring to focus a number of issues concerning the specificity of both ICS and drugs with respect to their ability to induce positive affect or pleasure.
As stated, the MFB system is defined behaviorally as well as anatomically. The MFB system is the system involving elements of or near the MFB, the stimulation of which yields the most unambiguous instances of positive reinforcement. It does not follow from this working definition, however, that the MFB system is homogenous with respect to neurochemical coding or with respect to kinds of pleasure. Smith, Co, and Lane (1984), for example, postulate two reinforcement systems in brain with a variety of relevant neurotransmitters. Interestingly, ICS of the lateral hypothalamic MFB could easily set up relevant activity in both postulated systems (Yardin, Guarini, & Gallistel, 1983). Nevertheless, the advances to be made involve ftheless, the advances to be made involve further specification of the relevant tissue and chemical coding. Recent studies lead to the possibility of remarkable specificity of certain opioids for inducing pleasurable affect.
Because all parts of the brain are connected, supra-activity in one part must eventually lead to activity in other parts. This basic feature puts a definite upper limit on the pleasure that can be derived by activating the central circuits, including pharmacological activation. Eventually, specific activity, if intense, has to "spill over" into circuits mediating other events, including negative affect, thereby diluting any elicited pleasure. There also could be activity elicited in the cardiovascular system, gut, muscle, or glands whose activity, in turn, could produce negative feedback (Sakai, Reid, & Porter, 1965). It is for this basic reason that brief duration, moderate intensity ICS is recommended above.
By definition, pleasure is not ambiguous and there can never be too much pleasure (Young, 1967). Experiences involving pleasure can be ambiguous and there surely can be too much of the circumstances initially eliciting pleasure. There are limitations to the achievement of pleasure. The very system (the reward system or pleasure systems) is self-limiting, because it is part of the larger system (brain). Since a number of sites of ICS sustain inordinately high rates of pressing for prolonged times and sin of pressing for prolonged times and since the rate-of-pressing to intensity-of-ICS function is linear up to the point of damaging the tissue at the electrode’s tip, it seems that the pleasure system’s capacity is great.
It is equally clear, however, that driving the system with prolonged trains of ICS, or driving the system with frequent trains, leads to events that rats avoid. Although stimuli that ordinarily are aversive will apparently dampen the positive affect of a fixed ICS (Buckwalter, Gibson, Reid, & Porter, 1967) and although there is probably a gross reciprocal relationship between the systems of pleasure and pain (Miller, Reid, & Porter, 1967), there is no reason to believe that every positive ICS elicits a negative event or dampens the possibility for pleasure of the next ICS, as suggested by Solomon and Corbit (1974). The situation seems much simpler. The limitations to pleasure are related to the system’s capacity to be active without engendering supra-normal activity in other systems (manifested by seizures, by forced movements, by high autonomic efferent activity, by preference for brief trains of ICS, et cetera in self-stimulating rats). The limitations to pleasure are due to "spill over."
Since toxic and other side effects are more probable with increasing doses of drugs and since a dose is eventually reached that will produce sickness, coma, or death, large doses of any putative euphorigen will elicits of any putative euphorigen will elicit ambiguous effects. It is not surprising, therefore, that large doses of many drugs having some claim to being euphorigens can be used as an unconditioned stimulus for a conditioned aversion to tastes serving as a conditional stimulus (Riley & Baril, 1976). It is also easy to predict that it will be possible to establish conditioned place aversions with drugs having euphorigenic capabilities using the procedures of the CPP test.
The limitation to the development of "pure" euphorigenic drugs (drugs that, until large doses are given, produce unambiguous states) is the specificity of the brain’s chemical coding for pleasure. If drug X interacts with chemical system M and if chemical system M has as itsi>M has as its only function the transmission of information that is positive affect, then drug X is apt to be a pure euphorigen. If, however, chemical M is part of the information processing of a number of systems, then a drug mimicking the actions of M will produce increments in positive affect and other effects. Since we are finding, for example, that the endogenous opioid systems are extensive and subserve many functions, a drug mimicking the activity of all endogenous opioids has little chance of being a pure euphorigen. Stated another way, if there is an exclusive chemical code in brain for pleasure (or a type of pleasure), then there is a possibility for the development of a pure euphorigen. If a number of pleasures arember of pleasures are mediated by a single neurochemical system and if this neurochemical code is exclusive to pleasure systems, then there is a possibility of devising not only a pure euphorigen but also one of extraordinary potency. As related later, there is a possibility for considerable specificity with respect to the brain’s opioid systems.
There is an implication to this line of thinking that is at variance with conventional wisdom. In as much as side effects are a major limitation to addiction likelihood and in as much as withdrawal symptoms are side effects, it follows that presence of withdrawal (and of tolerance) is a major limitation to addiction likelihood. From this view heroin is used despite the eventuality of withdrawal, not because of the eventuality ofof the eventuality of withdrawal. Heroin’s long-term, dire consequences, in terms of withdrawal, function as only a weak controller of behavior, as remote consequences do for almost any act (Casper & Reid, 1975; Miller, Reid, & Porter, 1967). A compound that will be self-administered by animals and that is free from the side effects of withdrawal could have, I submit, a greater addiction likelihood than a similar compound readily producing discernible withdrawal symptoms. Along these lines cocaine is apparently more popular than heroin.
It also follows from this line of thinking that a high propensity for withdrawal is as likely to predict limitations on recreational drug use as it is to predict sustained drug use. Also, calling tests of withdrawalg tests of withdrawal potential "a test for dependence" is flawed on the same grounds. Nothing is gained by renaming tests for withdrawal symptoms "tests for physical dependence liability." Actually, considerable precision is lost.
We now know that three genes produce large peptides whose cleavage can yield up to 18 smaller peptides whose actions are similar to one or more actions of morphine and whose effects are antagonized by naloxone. The location of some of the cells producing these endogenous opioid peptides (EOPs) is concentrated in subcortical forebrain and there are widespread connections throughout brain. EOPs interact with specialized receptors in neuronal membranes. There is probably more than one kind of opioid receptor of opioid receptor (opioceptor).
The knowledge that the brain has extensive EOP systems provides the basis for a more complete understanding of the actions of morphine, heroin, and related opioids, including their ability to engender signs of positive affect. Morphine has many actions, only some of which are related to its addictive potential. Relatedly, only some parts of the extensive EOP systems are related to positive affect. Only a few of the EOPs have been screened in tests similar to those recommended for assessing addiction likelihood. We can anticipate that future research will delineate the parts of the EOP system that provide information processing relevant to modulation of positive affect, including specification of the EOPs and opioceptors that and opioceptors that are involved. All of the methodological issues discussed in this chapter (and, indeed, in this book) are relevant.
As mentioned, there is a possibility for considerable specification of opioids’ effects, and this is more likely given that there are many EOPs and opioceptors. There is, however, another topic to be discussed before considering the specificity of opioids--the topic of naloxone’s effects on responding for ICS. Naloxone is the prototypic antagonist at the opioceptor. Since naloxone is reputed to have, at doses most often used, no agonist action at opioceptors and no actions at other receptors, the effects of naloxone would, therefore, reveal the functions of the EOPs (Goldstein, 1978). Belluzzi and Stein (1977) reported that administrationd that administration of naloxone led to substantial reductions in pressing for ICS in rats having had no other drugs. They inferred from their observations that EOPs were major transmitters of reward processes.
Our attempts to replicate Belluzzi and Stein (1977), as well as other attempts (e.g., Lorens & Sainati, 1978; van der Kooy, LePiane, & Phillips, 1977) did not succeed. In some of our tests (Bozarth & Reid, 1977), naloxone, by itself, appeared to have no reliable effects. We then explored with Drs. Stein and Belluzzi the reasons for the apparently conflicting results. We were then using rats pressing at high rates for optimal intensities and short, periodic testing sessions (3 to 5 minutes), while they had ratswhile they had rats pressing at low to moderate rates for intensities just above threshold and for longer (30 to 45 minutes) testing sessions. We then started using longer testing sessions and saw slight, but statistically significant, decreases in pressing (Stapleton, Merriman, Coogle, Gelbard, & Reid, 1979).
As mentioned, drug-induced reductions in pressing are difficult to interpret. Before more facts are gathered, however, there is no reason to suppose that naloxone would change a rat’s capacity to press. Naloxone may modify rats’ responsiveness in other testing situations (e.g., Amir, Solomon, & Amit, 1979); presumably, however, that is due to naloxone modifying motivational and emotional variables (Reid & Siviy, 1982) and not dueiy, 1982) and not due to naloxone interfering with rats’ ability to move with full vigor and coordination. The decreases in pressing for ICS are in situations where the likelihood of seizures and of other interfering side effects is low (i.e., the decreases are seen with low intensity, brief ICS). Also, naloxone does not appear to induce convulsions until extremely high doses are given (Breuker, Dingledine, & Iversen, 1976; Pearl, Aceto, & Harris, 1968). Nevertheless, interpretational problems remain and testing with other procedures is, as we shall see, helpful.
Reliable reductions in pressing rates for ICS under naloxone have been reported for sites within the periaqueductal gray area, area of the lateral hypothalamus (MFB, zona incerta, Forel’s fields), accumbens nucleus, substantias nucleus, substantia nigra-ventral tegmental area, locus coeruleus area, nucleus paratenialis of the thalamus, amygdala, and prefrontal cortex (Belluzzi & Stein, 1977; Bermudez-Rattoni, Cruz-Morales, & Reid, 1983; Cruz-Morales & Reid, 1980; Franklin & Robertson, 1982; Stapleton, 1979; Stein, 1978). There is variability in the extent of reductions across rats with similar placements. Some rats (sites) show very small reductions (about 5% reductions) after large doses, whereas others show much more substantial reductions (upwards to 60%) with a modal reduction of about 20% (Stapleton, 1979). Differences in baseline rates of pressing can probably account for some of this variance. There has not been adequate study of the exact densityf the exact density of opioceptors and the extent of naloxone’s effects. There have been few sites tested that have few or no EOP processes. There is no apparent correlation between sites producing analgesia and the extent of the naloxone effect on pressing for ICS (Franklin & Robertson, 1982; Stapleton, 1979).
There is the interesting report of Glick, Weaver, and Meibach (1982) that does specify a relationship between site of ICS and the extent of a naloxone effect. They reported that naloxone’s effects are lateralized (i.e., naloxone reduces pressing on the side of the hypothalamus with lower threshold for reward and increases pressing on the side with higher threshold). Thresholds, in this case, were determined by pressing rates in 4-minuteg rates in 4-minute sessions with varying intensities of ICS. Given that a 4-minute session is not optimal for seeing a naloxone effect, any potential reductions to be seen with the side of higher threshold may have been missed. Nevertheless, the conclusion is still valid that one side of the hypothalamus may be more sensitive than the other.
Although a full range of doses of naloxone have not been tested with every site, there have been rather extensive testing with lateral hypothalamic sites. Naloxone reliably reduces pressing in doses of 1.25 mg/kg or greater. Within the range of 1 to 60 mg/kg, there are greater reductions with greater doses (references given above). We have recently collected more dose-response data with naloxone and pressing for lateral hypothalamic ICS. We find thatmic ICS. We find that doses of 0.1 mg/kg produce about a 30% reduction in pressing, doses of 1.0 mg/kg produce very small or no reduction in pressing, doses greater than 1.25 mg/kg produce about 30% reductions. It seems from the extant results that the dose-response curve is not uniform. This observation has implications for assessing the role of the various EOPs in mediating positive affect.
The naloxone effect on pressing for hypothalamic ICS is not apparent when the testing session is 3 minutes or shorter, is apparent when the session is 5 minutes, and presumably is even more apparent in sessions approaching an hour (Belluzzi & Stein, 1977; Stapleton, 1979). The situation is similar to naloxone’s effects on reducing intake of waterucing intake of water and food. In water-deprived rats presented water, naloxone does not reduce latency to begin drinking (Cooper & Holtzman, 1983; Siviy, Calcagnetti, & Reid, 1982). It is as if naloxone blocked an action involved in maintaining drinking as it approached the point of satiety. Naloxone has similar effects on eating.
Pressing for ICS is notable because it seemingly does not show quick satiation. In rats with constant access to ICS, however, the median burst of responding is 2.9 minutes with 20 to 60 of these episodes occurring nightly (Katz, 1980). If naloxone reduced each episode a small amount, then the result would be no apparent reduction with short sessions and an effect with longer sessions.with longer sessions.
Naloxone does not lead to abolition of responding; it reduces responding rather uniformly across a session (Stapleton, 1979). The resulting pattern is not one of extinction but is more similar to the effect of reducing intensity of ICS a small increment. The conclusion is that the circuitry of EOPs is not critical to elicitation of ICS-produced reward but functions synergistically with other more critical neurotransmitters (Stapleton et al., 1979).
Using a discrete trial procedure, Perry, Esposito, and Kornetsky (1981) did not observe that naloxone lowered the threshold for ICR. Such testing just does not allow for a sample of behavior for which naloxone is likely to have an effect. It is similar to circumstances of drinking (Siviy etof drinking (Siviy et al., 1982). If one only observes drinking prior to the approach of satiation under naloxone, then no naloxone effect is apparent.
The reductions following naloxone can be interpreted as a decrease with respect to performance (Franklin & Robertson, 1982) or as a decrease in reward potential (Belluzzi & Stein, 1977; Stapleton et al., 1979). The resolution is to do further testing. Mucha and Iversen (1985) have tested for naloxone’s effects in the CPP test. They found that naloxone produced no signs of a preference and actually led rats to spend less time in the place of the drug experience. These results need to be interpreted in the light of Pilcher, Jones, and Browne’s (1982) finding that naloxone’sing that naloxone’s ability to condition a taste aversion varied with the circadian cycle. Nevertheless, naloxone’s effects are likely due to reduction in affective tone rather than ability to press.
The results with naloxone present an interesting case study demonstrating the limitations of any one procedure and the value of multiple kinds of tests. The reductions in pressing needed to be assessed further to segregate performance from reward. The pressing for ICS in more lengthy test sessions, however, did reveal an interesting drug effect: Naloxone effects were apparent only after the rats had pressed for a number of ICS. The temporal locus of the naloxone effect provides the basis for understanding why the discreteng why the discrete trial testing procedures for threshold yielded a conclusion of no effect of naloxone. The effects of large doses of naloxone on responding for ICS, water, and food do support the idea that one or more of the EOPs are involved with reward processes.
Many addictive agents may increase activity with respect to EOPs; they could mimic one or more EOPs at the receptor or could lead to a release of EOPs. Since naloxone by itself reduces pressing for ICS and establishes an aversion in the CPP test, naloxone cannot be used to assess the involvement of EOP systems in the reward potential of other drugs. If a test drug produces an increment in pressing for ICS and then if naloxone is given thereby reducing pressing, the reduction may be due only to naloxone’s effectsto naloxone’s effects (or an interaction involving naloxone’s effects). Other ways must be devised to assess the involvement of opioceptors and EOPs in the reward potential of drugs such as diazepam and ethanol. Along these lines it has been shown that morphine produces an increment in pressing for ICS by way of its interaction with a specific opioceptor. Weibel and Wolf (1979) have shown that only one enantiomer of the basic morphine molecule will increase pressing for ICS.
The effects of naloxone are relatively nonspecific with respect to kinds of opioreceptor; in fact, naloxone’s ability to antagonize an action of an agent is the defining characteristic for the action and the agent to be classed as opioid. So, naloxone is not the drug of choice for delineatinghoice for delineating the specificity in the actions of opioids. Other antagonists and mixed agonists-antagonists, however, do seem to show marked specificity.
Naltrexone is very similar to naloxone in structure and in action but is more resistant to degradation. An unpublished study (Merriman & Reid) revealed, however, that naltrexone’s effects were more variable than naloxone’s. Under naltrexone some rats’ press rates were not reliably modified, some were depressed, and some even increased. This finding is similar to that recently reported by Katz (1981).
WIN 44,441 antagonizes the analgesia of some opioids and acts as an antagonist in various bioassays (Ward, Pierson, & Michne, 1983). WIN 44,441 antagonized the depressive actions of large doses of morphine in doses of morphine in rats pressing for ICS. WIN 44,441, by itself, leads to reliable increases in pressing (Bermudez-Rattoni et al., 1983).
Diprenorphine is a remarkably potent antagonist for many of morphine and other opioid’s effects. We confirmed that doses and times after dosing to be used, subsequently, completely antagonize the analgesia produced by fentanyl (a short acting but powerful opioid analgesic). Using doses that antagonize analgesia (and many other effects of morphine), it was found that diprenorphine facilitated pressing for MFB ICS with doses in the range of 1 to 5 mg/kg (Hunter & Reid, 1983; Pollerberg, Costa, Sherman, Herz, & Reid, 1983).
In summary, naloxone at doses above 1.25 mg/kg decreases pressing. Naltrexone’s effects are variable. WIN 44,441 stereoselectively and dose-relatedly increases pressing. Diprenorphine increases pressing and is capable of producing a CPP (Beaman, Hunter, & Reid, 1984). Nalorphine, a compound that has antagonist actions with respect to precipitating withdrawal but also produces analgesia, increases pressing. Other mixed agonist-antagonists and agonists can facilitate pressing for ICS, but their analgesic potency does not correlate well with ability to facilitate pressing for ICS (Bozarth, 1978; Sandberg & Segal, 1978). The ability to facilitate pressing for ICS is unrelated to ability to induce analgesia. In fact, two compounds that clearly antIn fact, two compounds that clearly antagonize opioid analgesia (WIN 44,441 and diprenorphine) produce strong facilitation in pressing.
The case for the separation of opioid analgesia and opioids’ ability to elicit signs of positive affect is very strong. There is tolerance with respect to analgesia but not with respect to facilitation in responsiveness to ICS (Bush et al., 1976; Esposito & Kornetsky, 1978). The time course of analgesia and increments in pressing following morphine differ (see Figure 4). Morphine increases pressing for positive ICS alone but not (after a few doses) positive and negative ICS given as single contingency for pressing (Farber & Reid, 1976). Morphine is not self-administered intracranially at some sites clearly related to analgesia but is at other sites (Bozarth, 1983). Antagonists of analgesia facilitate pressing for ICS (Bermudez-Rattoni et al., 1983; Pollerberg et al., 1983). These observations are all compatible with the idea that opioid analgesia and an opioid’s ability to elicit positive affect are not two facets of the same process.
Some of the more recently developed measures of drug-induced positive affect in the laboratory (i.e., responsiveness to ICS, the CPP test, and intracranial self-administration) have led to the conclusion that opioid analgesia, tolerance, withdrawal symptoms, and catatonia are separable, both anatomically and functionally, from opioids’ capability of inducingly, from opioids’ capability of inducing positive affect. As long as most tests for opioids’ specific actions were in preparations that obviated measures of positive affect (e.g., bioassays involving muscle strips, spinal dogs, binding properties of opioids in brain homogenates), there was no reason to devise systems having a specific category for positive affect.
Now that we have measures of opioids’ ability to elicit positive affect, classificatory systems of opioid’s specific actions can be modified to take into account that facet of the collective actions of nonspecific opioids such as morphine. Any new classificatory system should be built taking into account what is now known about the EOP systems and the idea of multiple kinds of opioceptors. It has been suggested that a particular opioreceptorarticular opioreceptor type might be exclusive to the system of opioid-induced positive affect (Pollerberg et al., 1983). Such a receptor may be particularly responsive to the agonist properties of diprenorphine. Such a possibility leads to the idea that agents can be devised having remarkable specificity with respect to eliciting positive affect.
We have barely begun to assess the implications of the possibility of specificity of chemical coding for pleasure and the inherent possibility of developing euphorigens having few other effects. Measures of addiction likelihood can be used to devise new, subtle, potent euphorigens. One question is whether measures of addiction likelihood will be widely used to manufacture and to market new addictive agents or used to prevent such potentiallyvent such potentially profitable marketing.
Some of the early work reviewed here was supported by grants from the National Institute on Drug Abuse and subsequent work by a grant from the Health Research Council of the State of New York. I thank the students currently working with me for their work and general encouragement--Carol Beaman, Laura Dunn, Chris Hubbell, and, particularly, George A. Hunter. Jean Bestle and Betty Osganian provided clerical support and helped in many ways, and I appreciate their efforts.
This is the year of retirement of my major professor, Prof. Paul B. Porter. I sincerely wish that I had something more eloquent than this chapter to honor the occasion of his retirement. I have learned, by having students of my own, that professors have only limited effects on the eventual work of their students. So, Paul cannot be held accountable for any foolishness contained here. With that caveat, I dedicate this chapter to the occasion of Prof. Porter’s retirement.
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