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Reprinted from D.C.S. Roberts and K.A. Zito (1987), Interpretation of lesion effects on stimulant self-administration. In M.A. Bozarth (Ed.), Methods of assessing the reinforcing properties of abused drugs (pp. 87-103). New York: Springer-Verlag.
 
Brain Reward System
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Chapter 4

Interpretation of Lesion Effects on Stimulant Self-Administration
 

D. C. S. Roberts and K. A. Zito*

Department of Psychology
Carleton University
Ottawa, Ontario, Canada K1S 5B6


Abstract
A number of studies have employed the lesion approach to understand the neural mechanisms which underlie drug self-administration behavior. In general, two strategies have been used. One method examines the effect of lesions on acquisition of the self-administration response. Changes in drug reward are inferred by comparing differences in the acquisition rates between lesioned and control animals. Alternately, some have used a within subject design and analyzed the effects of lesions on previously established self-administration behavior. To date, only simple schedules of reward (i.e., fixed ratio or continuous reinforcement) have been used in conjunction with the lesion technique. The difficulty in interpreting changes in drug intake or rate of acquisition is discussed with reference to stimulant self-administration data generated in several laboratories. The importance of characterizing the extent and specificity of the lesion and of choosing the most appropriate postlesion test period is also emphasized.

 

Introduction

How do drugs of abuse act on the brain to produce their reinforcing effects? This is one of the most interesting and perhaps one of the most difficult questions in the field of neuropsychopharmacology. It is complicated for two reasons. First, most abused drugs have many effects unrelated to reward which are produced at sites throughout the nervous system. The task is to separate these irrelevant responses from those actions in the specific loci responsible for reward. One method which has enjoyed some success has been to lesion different neural systems in an attempt to selectively block the drug reward. This approach requires either the evaluation of drug reward before and after the lesion or the comparison of lesioned with nonlesioned control animals. Such comparisons imply that reward strength can be quantified and that any change in reinforcement may be detected and measured. This is the second complication. There appears to be a lack of consensus on how to measure reward strength. While the concept of reinforcement seems straightforward, methods for quantifying reward remain contentious.
 

*Present address for K.A. Zito: Department of Anatomy, University of Toronto, Toronto, Ontario, Canada M5S 1A8.

 Over the past few decades several different approaches have been used to assess the reinforcing properties of abused drugs. These methods involve brain stimulation, drug discrimination, conditioned reinforcement, conditioned place preference, and intravenous or intracerebral self-administration. Some applications of these approaches are represented in this volume. Although each of these techniques has added to our knowledge of reinforcement, ultimately the characterization of the neural substrates of reward will depend on convergent evidence from all these procedures rather than from one idealized strategy.

This chapter will focus on the self-administration technique as a method to evaluate the effects of lesions on the rewarding effects of psychomotor stimulants. Self-administration studies have proven valuable for evaluating the abuse potential of new drugs. Such studies have shown that drugs that are typically abused by humans are also self-administered by laboratory animals. It should be noted that although such a demonstration may indicate whether a drug is rewarding or not, it does not necessarily measure reinforcement magnitude. Attempts at evaluating the degree of reward strength, therefore, typically require more complex tasks or complicated schedules of reinforcement.

Several potential measures have been offered in the self-administration literature to quantify stimulant reinforcement. For example, the "cost" of the drug in terms of energy or amount of behavior elicited for an infusion has been proposed as one method to measure drug reward. In such studies a progressive-ratio is typically employed and the number of responses required to produce a reinforcement (until the animal eventually fails to respond) is used as a dependent measure. The value where responding falls below a specific criterion is defined as the break point of responding (for an example of this technique the reader is referred to Bedford, Bailey, & Wilson, 1978; Brady, Griffiths, Hienz, Ator, Lukas, & Lamb, this volume; Griffiths, Bradford, & Brady, 1979; Griffiths, Brady, & Snell, 1978; Griffiths, Findley, Gutcher, & Robinson, 1975; Hoffmeister, 1979; Yanagita, 1973, this volume; Yokel, this volume). The break point of responding has been shown to vary systematically with several motivational conditions (e.g., degree of food deprivation, concentration or volume of liquid reinforcer) and has therefore been argued to provide an index of the relative strength of a reinforcer (Hodos, 1961; Hodos & Kalman, 1963).

Drug cost may also be manipulated by employing an electric shock to suppress drug self-administration (Grove & Schuster, 1974; Smith & Davis, 1974). With this method response suppression produced by concurrent shock may be overcome by progressively increasing the dose of the drug (Johanson, 1977). This technique should, therefore, make possible the determination of drug reward strength by measuring the amount of shock animals are willing to tolerate concomitantly with the drug injection. This method, unfortunately, could be confounded by possible analgesic or anxiolytic effects produced by the drug under study.

Concurrent schedules have also been used to evaluate the relative reinforcing properties of various reinforcement relationships. With this technique two equally valued variable interval schedules are made available on two separate operants. The relative response rates produced at each lever are apparently indicative of reinforcement magnitude. This approach has been applied to intravenous self-administration procedures to compare the response rates produced at each lever for two doses of the same drug (Iglauer, Llewellyn & Woods, 1976; Iglauer & Woods, 1974). This method does not lend itself to lesion work, however, because we are most interested in comparing pre- versus post-lesion self-administration behavior. The technique may be useful if a change in relative value between one drug affected by lesion (e.g., cocaine) to another not affected by the lesion (e.g., apomorphine) could be detected, although we are unaware of any studies that have used matching of two different drugs instead of two doses of the same drug.

None of these rather difficult methodologies have so far been used in conjunction with lesion techniques. Future studies may well require these procedures; however, for a number of reasons the studies to date have restricted themselves to simple schedules of drug reward. The continuous reinforcement schedule (CRF), in which each response produces an intravenous injection, is the most basic variation of the self-administration procedure. Intuitively, it makes sense to employ the most elementary approach available (i.e., the most fundamental schedule of drug reward) prior to superimposing other factors which may complicate the analysis unnecessarily (e.g., concurrent shock, more complicated schedules of reinforcement).

Additionally, chronic lesions, whether neurotoxic, radiofrequency, or electrolytic, all require extensive postoperative testing to observe long-term degenerative or compensatory physiological changes. The inclusion of complicated schedules of reinforcement, which may require many days of training before establishment of stable baseline performances, increases the probability of extending the experiment beyond the limits of the intravenous implant. Therefore, due to the technical difficulties inherent in the self-administration technique itself, unnecessary time-consuming procedures should be kept at a minimum. There exists a delicate balance between including those factors which are absolutely essential to the experiment and omitting those which may be unnecessary.

Lastly, aversively motivated behaviors and those maintained by partial reinforcement schedules may make unnecessary response demands on subjects. The more complicated the behavioral response or the more motorically demanding, the more susceptible the behavior is to disruption from secondary effects (e.g., motor impairment). For this reason a simple, stable, on-going behavior is desirable because it eliminates unnecessary masking of effects that may be attributable to the effect of lesions. In general, therefore, most studies have typically employed a CRF schedule, relying on rate and pattern of self-administration. It should be noted that most researchers would agree that rate of self-administration does not measure drug reward, although it does provide a useful starting point for investigating lesion effects.

This chapter discusses both the relative merits and shortcomings of the self-administration technique as a method of assessing the effects of lesions on psychomotor stimulant reward. Particular attention will be drawn to the difficulties in interpreting results obtained with the self-administration technique as well as various control procedures that must be included in the design to rule out nonspecific lesion effects. Experiments which have examined the effects of lesions to monoaminergic systems on stimulant self-administration will be reviewed as a vehicle to explain the conclusions which can be drawn concerning the neuroanatomical and/or neurochemical basis of stimulant reward.

Self-Administration Behavior

When provided with the opportunity, laboratory animals will acquire and maintain a lever response to receive a stimulant injection in a pattern very similar to human stimulant abuse (Kramer, Fischman, & Littlefield, 1967). When given unlimited access, all species of laboratory animals show a cyclic pattern of intake (e.g., Deneau, Yanagita, & Seevers, 1969; Johanson, Balster, & Bonese, 1976) with periods of abstinence alternating with periods of high drug intake ("binges"). Daily drug intake, therefore, varies considerably. By contrast, when access to the drug is restricted (e.g., 4 hours/day), a highly reliable and stable rate of responding is observed. Animals will self-administer very close to the same amount of drug each day for many weeks.

Although the mechanisms governing rate of self-administration are not fully understood, response rate typically has been used as the dependent variable. Animals apparently attempt to maintain a constant level of drug effect by increasing drug intake when drug impact is reduced and by decreasing intake when drug impact is increased (see Yokel, this volume). Typically, at the beginning of each session several injections are taken in quick succession after which responding becomes regularly spaced with little variation in the time between infusions (Pickens, 1968; Pickens & Thompson, 1968). Animals may exhibit variability in the rate of drug intake among animals, although the pattern is quite regular from day to day within a single subject. In instances where stimulant reinforcement is totally removed or suppressed, animals will display extinction-like behavior, initially increasing their rate followed by a total cessation of responding (Roberts, Koob, Klonoff, & Fibiger, 1980; Yokel & Wise, 1975, 1976). Thus the self-administration technique is particularly useful because it produces a stable behavior that can be quantified and qualified both preoperatively as a baseline behavior and postoperatively as a dependent measure of the effects of various forms of neuroanatomical disruption.

Although there are many variations of the self-administration technique, considering the procedure more generally, a limited number of ways for investigating the neurobiology of stimulant reward become evident. One approach is to examine the acquisition of the self-administration response (e.g., LeMoal, Stinus, & Simon, 1979; Lyness, Friedle, & Moore, 1980; Singer, Wallace, & Hall, 1982). A second is to examine the effects of particular lesions on the maintenance of self-administration behavior. Possibly the most basic approach requires that subjects acquire a stable self-administration response for the drug prior to surgery, then following surgery animals are again given the opportunity to self-administer. This methodology permits the comparison or pre- and post-operative behavior within a single subject and minimizes the effects of individual differences in rate and pattern of self-administration behavior that are likely to be found among subjects.

Effects of 6-Hydroxydopamine Lesions
on Cocaine Self-Administration

We have investigated the effects of 6-hydroxydopamine (6-OHDA) induced lesions on cocaine self-administration in a variety of neuroanatomical regions over the past several years, and we have found that this behavior appears to be extremely resistant to such lesions.

For example, injections of 6-OHDA into the dorsal tegmental bundle, the major ascending noradrenergic (NA) fiber system, do not significantly influence the rate or pattern of cocaine self-administration (see Figure 1, injection site 1). This seems remarkable since this treatment reduces NA content of the hippocampus and cortex to 4% of control levels and in the hypothalamus to 28% (Roberts, Corcoran, & Fibiger, 1977). These lesions do not, however, significantly affect dopamine levels. Inasmuch as near total depletion of telencephalic NA has no effect in the rate of cocaine self-administration, it appears that NA does not play an important role in this behavior. This conclusion is in agreement with pharmacological evidence reviewed by Yokel (this volume).
 

 
Dorsal noradrenergic bundle and mesolimbic dopamine system
Figure 1: Sagittal projection of the ascending dorsal noradrenergic bundle and the mesolimbic dopaminergic system depicting four lesion sites (upper panel). The lower panel displays a coronal section of the rat brain depicting three 6-hydroxydopamine injection sites into dopaminergic terminal fields that have been tested for their effects on cocaine self-administration. Coronal view corresponds to section A 8920. Reproduced with permission from Konig and Klippel, 1970.
 

We have also noted that responding for cocaine infusions is particularly resistant to 6-OHDA lesions in a variety of dopamine-rich areas. Figure 1 (lower panel) displays a coronal section of the rat brain depicting three 6-OHDA injection sites into dopaminergic terminal fields that have been tested for their effects on cocaine self-administration. Only one of these injection sites produces a significant effect on this behavior. The lower circle represents the target for nucleus accumbens injections. The upper, medial circle represents an infusion site which should control for damage caused by leakage of the neurotoxin up the side of the injection needle or into the lateral ventricle. The lateral site was designed to investigate the effect of dopamine depletion of the caudate nucleus.

Neither of the two dorsally placed injections affected either the rate or pattern of cocaine self-administration (Roberts & Koob, unpublished observations). In contrast to the lack of effect produced by these lesions and those to the ascending NA fibers, bilateral 6-OHDA injections into dopaminergic terminal fields in the nucleus accumbens or the DA cell bodies which project to the accumbens (see Figure 1, upper panel, sites 2 and 4) produced a significant alteration in both rate and pattern of responding for cocaine.
 

 
Event records following 6-OHDA lesions
Figure 2: Event records of cocaine self-administration in two rats before and after 6-OHDA infusions into the nucleus accumbens. Each line represents one daily 3-hour session. A: An example of one rat (No. 60) which did not resume cocaine self-administration. B: An example of a rat (No. 62) which gradually recovered baseline self-administration rate. Reprinted with permission from Roberts, Koob, Klonoff, and Fibiger, 1980. Copyright 1980 by Ankho International, Inc.
 

Figure 2 displays the effects of such injections on cocaine self-injection for 18 days postlesion. These data illustrate several interesting aspects and problems. First, we see an abrupt cessation of responding, with animals typically taking only 1 or 2 injections on the days immediately following surgery. Second, over a period of several days some animals (e.g., Figure 2, right panel) begin to resume their intake, indicating that the drug continues to have rewarding properties. And third, the rate at which they begin to self-administer is less than prelesion rates. This final observation raises the question about the lesion causing an increase or a decrease in the reward strength of cocaine. The following sections address each of these issues.

Motor Deficits

The simplest explanation for the failure of the animals to respond for cocaine on the day following the lesion is that nonspecific effects of the lesion exist unrelated to reward. Inasmuch as the integrity of central dopaminergic neurons is known to be important in the motor aspect of operant responding (Clavier & Fibiger, 1977; Fibiger, Carter, & Phillips, 1976), it is

reasonable to assume that the animals may have been incapable of responding. To examine this possibility, animals were trained to lever press for food on a variable ratio 2.5 schedule of reinforcement and, after their responding had stabilized, stereotaxically injected 6-OHDA into the nucleus accumbens. Although operant responding for food was observably depressed especially on the first day after the lesion, animals were capable of making an average of 55 responses on the food lever in 15 minutes (Roberts et al., 1977). This is far in excess of the responses necessary to self-administer the drug.

These results indicate that animals subjected to 6-OHDA lesions of the nucleus accumbens are probably capable of responding; however, the data do not rule out the possibility that the induced lesion caused a malaise which would inhibit self-administration of any drug. If nucleus accumbens lesions were to disrupt the self-administration of all agents, this would argue that the observed effect was due to a nonspecific mechanism. We have tested this possibility in a separate experiment by examining the effects of the lesion on the pattern of self-administration of two drugs (cocaine and apomorphine; Roberts et al., 1977).

Apomorphine, which has been shown to be reliably self-injected (Baxter, Gluckman & Scerni, 1976; Baxter, Gluckman, Stein, & Scerni, 1974), was chosen as an alternate drug because it is known to be a direct-acting dopamine agonist. Cocaine is thought to act as an indirect agonist: that is, it potentiates the action of dopamine by blocking synaptic reuptake and, therefore, requires intact presynaptic terminals to have an effect. Infusions of 6-OHDA into the nucleus accumbens cause preferential degeneration of the presynaptic catecholamine element but spare the postsynaptic target cell. This treatment should therefore disrupt cocaine self-administration but should leave apomorphine self-administration unaffected. However, if the lesion is shown to disrupt the self-administration of both drugs, then one would have to conclude that the effect was nonspecific.

With this procedure baseline intake for both apomorphine (0.06 mg/kg/injection) and cocaine (0.75 mg/kg/injection) was initially established. Each animal was given access to cocaine for several days (4 hours/day) until daily intake stabilized; then the animals were switched to several days of apomorphine self-administration. The cocaine baseline was again checked prior to surgery.

Following 6-OHDA lesions of the nucleus accumbens, responding for cocaine is disrupted; however, animals displayed a regular response pattern for apomorphine. This double drug baseline procedure helps demonstrate that animals can and will respond and that there are no trivial reasons (e.g., cannula problems) for the effect on cocaine self-administration. Infusions of 6-OHDA into the ventral tegmental area (VTA: the origin of the DA innervation of the nucleus accumbens) also disrupt cocaine self-administration, and the two-drug control procedure has also been used in these experiments to show that animals will continue to respond for apomorphine (Roberts & Koob, 1982).

The apomorphine self-administration results demonstrate that 6-OHDA/accumbens-lesioned animals are capable of responding but will not self-inject cocaine on the first few days following 6-OHDA lesions of the nucleus accumbens. Eventually, however, the animals begin to show signs of a regular self-administration pattern. This recovery begins with a slow self-administration rate which can approach prelesion drug intake. The interpretation of these data is problematic.

Interpretation of Rate Changes

A decrease in the unit dose of cocaine has been shown to produce an increase in response rate (Pickens & Thompson, 1968; Yokel, this volume). Accordingly, an increase in responding may indicate a decrease in reward value. This argument has been used to interpret the increases in stimulant intake observed following neuroleptic pretreatment (de Wit & Wise, 1977; Yokel & Wise, 1975, 1976). Apparently, a partial blockade of dopamine receptors induced by neuroleptics produces a reduction in drug impact, an effect analogous to lowering the drug dose.

If the dopamine terminals in the nucleus accumbens are essential to the rewarding effects of stimulant drugs and if many of these terminals are destroyed by the 6-OHDA treatment, then should we not expect that animals display an increase in self-administration rate rather than a decrease? Why should lesions of the accumbens cause a decrease in rate while neuroleptics cause an increase? Could not the suppressed response rates observed in lesioned animals be interpreted as a potentiation of the drug effect?

The answers to these questions must lie in the assumption that rate of self-administration is in a state of equilibrium, being controlled not only by the rewarding effects of the drug but also by aversive (toxic) properties and other limiting factors (e.g., stereotypy, competing response patterns). We might assume that the animal increases its intake (and therefore its blood or brain levels) to the point where the aversive effects outweigh the rewarding effects. A hypothetical relationship between positive and aversive components at various drug levels is depicted in Figure 3a. Of course the curves could have a variety of shapes, but the figure is simply intended to illustrate that at lower blood levels the predominant effect of the drug may be rewarding, while at higher blood levels the predominant effect could be aversive. Increases or decreases in the injection dose would not alter this relationship; therefore, the animal behaviorally compensates for changes in dose to maintain almost exactly the same optimal drug level.

In the case of response rate increases following neuroleptic treatment, there is an important difference. Animals increase their overall drug intake (not simply their response rate), which presumably causes a substantial increase in the amount of drug in the system. This could imply that blockade of dopaminergic receptors affects not only the positive but also the aversive actions. This relationship is depicted in Figure 3b. The slope of both the rewarding and aversive curves is reduced. If all these effects are mediated by dopamine, then neuroleptic pretreatment should attenuate all aspects of the drug injection, which would indeed by equivalent to reducing the dose.
 

 
Hypothetical relationship between positive and aversive components
Figure 3: Hypothetical relationships between positive and aversive components at various drug levels illustrating that at low drug levels the rewarding effects outweigh the aversive effects while at higher drug levels the reverse is true. For further discussion see text.
 

Conversely, lesions to specific nuclei may attenuate individual actions of the drug and potentially affect either the rewarding effects or the aversive effects specifically. By altering the balance between the rewarding and punishing effects, changes in rate in either direction may be expected. Figure 3c illustrates an example of a specific attenuation of the rewarding effects with no change in the aversive effects. Note that the range in which the rewarding effects of the drug predominate is much smaller. The upper bound is greatly reduced which demands a lower rate of intake. In the case of lesions, therefore, a lower rate of intake is not paradoxical and may reflect a specific attenuation of the rewarding effects.

Recovery of Self-Administration

As noted earlier, lesioned animals will frequently recover their self-administration rate, often stabilizing at prelesion levels. We have attempted to relate this recovery to the extent of the 6-OHDA-induced depletions and have found that the greater the dopamine loss in the nucleus accumbens the longer the animal takes to recover. Animals that sustain the greatest degree of dopamine loss (greater than 90%) often fail to recover at all. These data emphasize the importance of achieving complete lesions of the system of interest. Many compensatory changes can reverse the effects of the lesions such as supersensitivity, increased turnover of transmitter in the remaining terminals, regrowth, and compensation by other systems. Thorough depletions are essential, particularly since it has been shown in other systems that partial lesions can either fail to block the drug response or even in some cases potentiate it.

Towards this end the neurotoxic action of intracerebral infusions of 6-OHDA may be potentiated by administering the monoamine oxidase inhibitor pargyline. This treatment inhibits the metabolism of 6-OHDA and allows for more thorough depletion of noradrenergic or dopaminergic systems (Kostrzewa & Jacobowitz, 1974). Some degree of specificity may also be achieved by lesioning individual fiber pathways at the point of greatest separation between other catecholamine systems (e.g., dorsal NA bundle, see Figure 1). This is not possible with the DA system due to the considerable intermixing of NA and DA fibers as they ascend. However, NA fibers can be spared from the toxic effects of 6-OHDA by pretreatment with desipramine (DMI), thereby permitting a specific lesion to dopaminergic systems (Roberts, Zis, & Fibiger, 1975).
 

 
Event records following 6-OHDA lesions
Figure 4: Event records of cocaine self-administration after 6-OHDA infusions into the nucleus accumbens or saline substitution. Each line represents one daily 3-hour session. Downward pen deflections indicate drug injections. A: Example of cessation of responding for cocaine 5 days after 6-OHDA treatment. On postlesion Day 9, regular responding is evident for apomorphine. On Days 10 and 20, cocaine was substituted for apomorphine, which produced an initial burst of responding followed by cessation. B: Another example of extinction of cocaine self-administration 5 days after 6-OHDA treatment. Apomorphine self-administration is shown on Days 13, 14, 16 and 17. Reprinted with permission from Roberts, Koob, Klonoff, and Fibiger, 1980. Copyright 1980 by Ankho International, Inc.
 

We have used these pharmacological tools to investigate the effects of more complete and specific depletions of DA from the nucleus accumbens. Because DMI and pargyline could have residual pharmacological effects for several days, animals were not tested until the fifth day post lesion. This strategy produced quite different results from those previously observed. That is, in the first day of testing an extinction-like pattern of responding was observed. Animals displayed bursts of responding followed by occasional "sampling" of the lever (see Figure 4). This is in contrast to the complete failure of animals to respond more than one or two times when tested the day following the lesion (cf. Figure 2).

One explanation for these effects is that until the 6-OHDA-induced degeneration is complete, cocaine may have a pharmacological action on the degenerating terminals. In fact, it has been shown that the blockade of amphetamine and cocaine-induced locomotor activity following 6-OHDA accumbens lesions follows a pattern very similar to that observed in the self-administration studies. Unless a severe depletion of DA is achieved, no blockade of the drug-induced locomotor response is observed (Joyce & Roberts, unpublished observations). Furthermore, the blockade of the locomotor response is not permanent but recovers in many animals just as does the self-administration behavior (Kelly, Saviour, & Iversen, 1975). Interestingly, when tested immediately following 6-OHDA injections, stimulants can elicit vigorous and bizarre behaviors (Creese & Iversen, 1975). This may explain the suppressed self-administration for cocaine immediately after the lesion, if this interaction of drug with degenerating terminals is aversive.

The results observed in both the self-administration and locomotor activity studies are probably interpretable if one considers that at least two mechanisms take place following a lesion--degeneration and recovery. It is difficult to assess the time course for each of these neuroanatomical/neurochemical changes or the degree to which they may interact. It appears that any results observed in the first few days after the lesion are confounded by neuronal degeneration, and that alterations in a drug response may be due to an interaction with a degenerating system rather than on one which has been destroyed.

On the other hand, if the animals are not tested until several weeks after the lesions, compensatory mechanisms may mask the "true" lesion effect. If one assumes that degenerative effects are limited to the first few days and that the influence of compensatory mechanisms is minimal for two weeks, then testing during this middle period best reflects the treatment effect. Of course there may be no appropriate testing period if the lesions are incomplete because recovery processes may already be influencing the results as degeneration proceeds.

Acquisition of Self-Administration

Another approach that has been used to investigate stimulant reward has been to examine the acquisition curve of animals learning to self-administer the drug. If it is assumed that animals will only acquire the self-administration response when the drug injection is rewarding, then failure to acquire the task following lesions of specific neural pathways supposedly reflects an attenuation or blockade of the reinforcing properties of the drug. A reduction of the rewarding effects should, therefore, retard the acquisition of self-administration behavior. Conversely, the stronger the reward, the faster the acquisition; therefore, faster acquisition may reflect a potentiation of the reinforcing effects. Examples of both accelerated and retarded acquisition of stimulant self-administration employing a variety of lesion techniques may be found in the literature.

5,7-Dihydroxytryptamine (5,7-DHT)

Lyness et al. (1980) have shown that animals injected with 5,7-DHT in the lateral cerebral ventricles self-injected more amphetamine from the first day of training and their intake stabilized at a higher level. Interestingly, the number of sessions required before the lesioned animals stabilized did not differ from controls, indicating that acquisition was not in fact enhanced. The locus of this effect is uncertain. Since 5,7-DHT injections into the nucleus accumbens exaggerate the hyperactive response to amphetamine (Pycock et al., 1978), Lyness et al. (1980) tested the possibility that serotonin depletion from this nucleus may mediate the effect. Injection of 5,7-DHT into the accumbens had no effect on the acquisition of amphetamine self-administration. Therefore, the involvement of serotonin in the acquisition of stimulant self-administration is as yet undefined.

Radiofrequency Lesions

A similar strategy, but a different lesion technique, was used by LeMoal et al. (1979). They reported that radiofrequency lesions to the mesolimbic DA cell bodies of the ventral tegmental area (VTA) result in an improved acquisition of (+)-amphetamine self-administered by rats. Following a one month recovery period from the lesion, animals were catheterized and allowed to self-administer amphetamine every other day for a 12-hour session. Lever pressing for amphetamine evolved dramatically with an extreme sensitivity to the drug and with enhanced acquisition of the operant response (see Figure 5a). The authors have suggested that this acquisition paradigm may be particularly useful for revealing pre-existing vulnerability to amphetamine and "psychopathology which leads to addiction" (p. 158).

These results, however, are inconsistent with literature which suggests that DA is the critical neurotransmitter involved in stimulant reinforcement. If mesolimbic DA is necessary for the rewarding value of amphetamine, then destruction of these perikarya should have resulted in a slower rate of acquisition of amphetamine self-administration or in a total failure to acquire the response.

One possible explanation for these findings may be the inability to have performed a complete lesion of the mesolimbic-cortical DA projection with the radiofrequency method, unlike the total destruction of DA terminals that may be obtained employing 6-OHDA. In studies employing the 6-OHDA lesion technique, destruction of DA terminals results in a failure to acquire self-infusion of amphetamine (Lyness et al., 1979). Experimentally naive rats pretreated with 6-OHDA in the nucleus accumbens did not acquire self-administration behavior despite only a 95% depletion of accumbens DA; this is true even when they are allowed access for the drug for up to 19 days (see Figure 5B). It is also possible that the one month recovery period allowed by LeMoal et al. (1979) in combination with damage to other nondopaminergic systems could also account for the apparent discrepancy.
 

 
Effects of lesions on amphetamine self-administration
Figure 5A: (+)Amphetamine self-administration (0.75 mg/kg (+)amphetamine per 100 administrations) in rats after radiofrequency lesions of the dopaminergic meso-cortico-limbic (A10) cell group lying in the ventral mesencephalic tegmentum (VMT) surrounding the interpeduncular nucleus (lesioned against controls: *p < 0.00l, Student’s t-test). a, Operant session; b, first (+)amphetamine session; c, second (+)amphetamine session; d, saline; open bars, Controls; n = 20; hatched bars, VMT-A10 lesioned; n = 27. Reprinted with permission from LeMoal, Stinus, and Simon, 1979. Copyright 1979 by MacMillan Journals Ltd. 

Figure 5B: Effect of 6-OHDA-induced lesions of DA nerve terminals in nucleus accumbens on the acquisition of d-amphetamine self-administration. Self-administration studies were started 14 days after the bilateral injection of vehicle (open circles) or 6-OHDA (filled circles) into the nucleus accumbens of rats (four rats in each group). Each symbol represents the mean number of self-injections of d-amphetamine (0.125 mg/kg/injection; FR-1) made during 19 consecutive daily 16-hour sessions. Adapted from Lyness, Friedle, and Moore, 1979. Copyright 1979 by Ankho International, Inc.

 

The results from these and other studies which employ the acquisition technique inevitably pose the question of what an animal must learn during self-administration acquisition. It must be that animals not only learn that pressing a lever produces an injection but also that responding too often will produce toxic effects. Animals sometimes self-administer lethal doses during the first training session and some lesions appear to increase the likelihood that an animal will take a toxic overdose. Therefore, does the amount of drug taken on the first day necessarily reflect anything useful? Possibly not, although it does appear that a high intake on the first day does predict a higher level of drug intake once the animal has stabilized its pattern of intake. Conversely, a low level may indicate a low stabilization rate or a lesser likelihood that an animal will acquire the behavior. However, neither of these outcomes are predictive of the amount of time an animal will require before intake stabilization. It may be that the rate of acquisition measures something different from the ultimate level of stable intake.

Conclusions and Recommendations

In general, then, the self-administration procedure has proven a particularly useful technique to the extent that it produces a stable behavior that can be quantified and qualified both preoperatively as a baseline behavior and postoperatively as a dependent measure of the effects of various lesions. Its use, however, should be approached with some degree of caution. The relative value of any behavioral task is dependent upon the types of questions being posed by the experimenter. For example, the processes involved in acquisition may not be the same as those responsible for the maintenance of the behavior.

Although one of the more attractive features of self-administration behavior is its apparent simplicity, the mechanisms which govern it are exceedingly complex. It would be preferable to view the behavior as a combination or sequence of responses and cognitive events, perhaps mediated by distinct neurochemical systems, which interact to produce the self-administration response. Accordingly, when a disruption in the response is observed, it could be due to the absence of a single neurobiological event or perhaps a breakdown in a complex patterns of events. We should expect that many systems may be critical and should, therefore, be cautious in our interpretations when a disruption is observed. Many systems may also be redundant. Therefore, a failure to disrupt the response or a recovery of the response may indicate compensation of other constituents.

With appropriate lesioning techniques the self-administration procedure is a valuable research tool in the analysis of drug reward. However, there are three important factors which will determine its worth. Firstly, the choice of the lesioning procedure is critical. Electrolytic or radiofrequency lesions seem inappropriate for questions involving specific transmitter systems. With regard to neurotoxins, their value is directly proportional to their specificity in destroying only identifiable classes of cells. Regardless of the nature of the lesion, the importance of allotting sufficient time for recovery cannot be overemphasized. Incomplete lesions can produce bizarre effects due to long-term regeneration or supersensitivity of damaged systems. Complete degeneration of cell bodies, axon terminals, etc. is essential if the behavioral data is to be of any use.

Secondly, the behavioral data cannot be interpreted unless the lesion is adequately characterized. In the case of 6-OHDA and 5,7-DHT, this requires biochemical data to determine the extent of the lesion. It would seem appropriate to investigate also the pattern of cell or terminal field damage through histochemical methods. For other neurotoxins such as ibotenic or kainic acid lesions, complete histology is essential.

Lastly, the behavioral effect must be characterized. It is an important question whether a lesion-induced disruption of self-administration for one drug is specific to that drug or is a more general phenomenon. Dose-response curves may be worthwhile but they may not always be possible to generate if the behavior is changing following the lesion or if the animal fails to self-administer at all. In all cases it is preferable to test subjects as long as is practical for recovery in order that the behavioral effect produced by the lesion can be fully characterized. This is feasible particularly if the experimental design is not unnecessarily complicated.

Acknowledgments

Supported by the Medical Research Council (Grant MA7374) and the Natural Sciences and Engineering Research Council (Grant A7471) of Canada.

References

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