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Reprinted from M.J. Lewis and R.W. Phelps (1987), A multifunctional on-line brain stimulation system: Investigation of alcohol and aging effects. In M.A. Bozarth (Ed.), Methods of assessing the reinforcing properties of abused drugs (pp. 463-478). New York: Springer-Verlag.
 
Brain Reward System
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Chapter 22

A Multifunctional On-Line Brain Stimulation System:
Investigation of Alcohol and Aging Effects
 

Michael J. Lewis1 and Richard W. Phelps2

1Department of Psychology
Howard University
Washington, District of Columbia 20059
and
2Cortex Corporation
Wellesley, Massachusetts


Abstract
A multifunctional on-line brain stimulation system designed for brain stimulation reward (BSR) research is described. This microcomputer-based system provides programs which permit determination of BSR thresholds, BSR response rates, and brain resistance. Studies using this system torain resistance. Studies using this system to investigate the reinforcing effects of ethanol and the effects of aging on BSR are discussed.

 

Introduction

Brain Stimulation Reward (BSR) has been used to investigate the reinforcing effects of drugs from early after its discovery by Olds and Milner (1954). Olds himself and his collaborators (Olds, 1958; Olds, Killam, & Bach-y-Rita, 1956; Olds, Killam, & Eiduson, 1957) did some of the earliest research examining the effects of several drugs on BSR (e.g., pentobarbital, chlorpromazine, and LSD). Since this early work there has been quite extensive research on the effects of many drugs of abuse on BSR. This work has been thoroughly reviewed at several junctures (e.g., Esposito & Kornetsky, 1978; Miller, 1960; Stein, 1968; Wise, 1978; Wise & Bozarth, 1981). There have been considerably fewer reports on the effects of ethanol (ETOH) on BSR. ETOH is undoubtedly the most abused substance, yet the physiological and neurochemical bases of its reinforcement, as well as other major phenomena, remain a mystery.

There has been relatively little research on the effects of ETOH on BSR. The previous research showed highly variable effects of ETOH. At low doses response rate has been reported to increase (Carlson & Lydic, 1976; Vrtunski, Murray, & Wolin, 1973), whereas with moderate, Murray, & Wolin, 1973), whereas with moderate to high doses only depression of response was found by these authors. These authors examined only lateral hypothalamic (LH) loci. Earlier research (St. Laurent, 1972; St. Laurent & Olds, 1967) found that ETOH only reduced response rate at these sites; however, ETOH could still enhance BSR responding at subcortical telencephalic placements such as the septal area. Still another report (Routtenberg, 1981) indicates that ETOH has no effect on BSR even at high doses if animals were primed (given noncontingent stimulation) sufficiently at the beginning of the BSR session.

It is apparent from the variable effects reported by these few studies that the effects of ETOH on BSR are not clear and require more extensive research. Recent research in our laboratory has examined the effects of ETOH on BSR at LH and ventral tegmental brain sites with the discovery of new effects of ETOH. This research has focused on BSR threshold as well as response rate at these sites and employed a multifunctional, microcomputer-based BSR system. The system has also been employed to examine both opioid agonists and antagonists, psychostimulants, and age-related declines in motivation. This system and the method for determining threshold will be discussed in detail in the first part of this chapter. We will then discuss our research with it on the rewarding effects of ETOH, on the age-related changes in BSR performance, e-related changes in BSR performance, and on the rejuvenating effects of psychostimulants on the performance of aged individuals.

Multifunctional BSR System

Measurement of electrical brain stimulation reward threshold using psychophysical methods presents a significant problem. The subject’s behavior (usually lever pressing) is controlled by the reinforcing stimulation for which the threshold is to be found. Many experimenters have tried to avoid this problem by measuring animal response rate using suprathreshold stimulation and inferring changes in threshold from changes in rate. If a rate measure is used, however, it is not possible to discriminate between the reward-relevant effects of the experimental treatment and its effects on motor responses.

Alternative methods (e.g., Huston & Mills, 1971; Marcus & Kornetsky, 1974; Valenstein & Meyers, 1964) determine threshold with less reliance on rate of response. Huston and Mills (1971) measure BSR threshold with a psychophysical procedure based on the observation that performance under a fixed-ratio (FR) schedule is different from that under a continuous reinforcement (CRF) schedule (Ferster & Skinner, 1957). In this procedure rats lever press for rewarding stimulation on an FR schedule and, concurrently, on a CRF schedule, using a single lever. This combined schedule is fixed at a suprathreshold level, which maintd at a suprathreshold level, which maintains the lever-pressing response at any CRF current intensity.

An animal performing on a simple FR schedule exhibits postreinforcement pauses (PRP; Ferster & Skinner, 1957). As CRF current intensity is increased from zero on a CRF-FR schedule, FR pauses become shorter and eventually disappear. The rat’s performance shifts from that which is characteristic of an FR schedule (many PRPs) to that which is characteristic of a CRF schedule (no PRPs). Decreasing the CRF current intensity causes the pauses to reappear. Threshold is determined by appearance or disappearance of these pauses as the CRF current intensity is varied. Huston and Mills (1971) reported that threshold determination was independent of the size of the FR and of the suprathreshold FR current intensity.

The definition of a PRP has been a problem using this threshold technique. Huston originally defined a PRP as the interval just visually discernible on the cumulative recorder. Cassens and Mills (1973) defined it as an interval greater than 7 seconds, but not more than 3 minutes. Cassens, Shaw, Dudding, and Mills (1975) devised a rate-independent definition; a PRP was defined as an interval greater than the mean CRF interresponse interval (IRI) plus three standard deviations. Thus, a PRP was relative to the CRF IRI. This provided a rate-independent means of determining the PRP and, hence, threshold.

The system we have developed employs the same rate-independent concept for determining thresholds. A fixed number of FR reinforcements are presented at each CRF current level. Threshold is defined as the current level that produces PRP half of the time—a PRP/FR ratio of 0.50. Threshold is determined by evaluating PRP/FR ratios over a CRF current range and then by interpolating the current value at a PRP/FR of 0.50 (see Figure 1).
 

 
Post reinforcement pauses as a function of current intensity
Figure 1: Post reinforcement pauses per fixed-ratio reinforcement (PRP/FR) as a function of current intensity. From Cassens, Dudding, and Mills, 1975.
 

Threshold determination using this system is reliable and independent of an animal’s rate of response. This is essential for many physiological and psychopharmacological BSR experiments. One drawback to previous threshold determinations using this method is the requirement of approximately 2 hours for a single BSR session. Another drawback is that occasionally threshold cannot be determined because of either floor or ceiling effects with the PRP/FR ratio. The PRP/FR ratio can either be 0 or 1.0 for all CRF current/FR ratio. The PRP/FR ratio can either be 0 or 1.0 for all CRF current levels; thus, no threshold determination, the z-pause, has been developed. With this method it is assumed that with virtually every FR there is a PRP of some duration. The mean PRP interval at each CRF current level is compared with the mean IRI (i.e., during CRF responding). This also results in a rate-independent measure of threshold. No floor or ceiling effects result and, thus, threshold can always be determined.

The principal reason for the development of this system is the need for a reliable, more flexible, and inexpensive computerized BSR threshold system that permits faster threshold determination over a variety of experimental situations. The microcomputer-based system we have developed (Phelps & Lewis, 1982) accomplishes these goals.

Components of the BSR System

Constant Current Stimulator

Constant electrical current is required for most BSR threshold methods. Wayner, Peterson, and Florczyk (1972) and Emde and Shipton (1970) described such stimulators. Mills and his collaborators (Cassens et al., 1975) designed a constant-current stimulator based on a modification of a system described by Wayner et al. (1972). Constant current is maintained by voltage varying as a function of brain resistance (impedance) in the circuit. Voltage is monitored by the use of FET instrumentation amplifier in the stimulator. The stimulator functions e stimulator. The stimulator functions as a voltage follower-regulator with continuous feedback. Instantaneous samples of resistance (impedance) to the stimulating current are made and result in voltage adjustment to maintain a constant current intensity. The stimulator which we have developed is of basic design but modified slightly for better current regulation over a broader resistance range. Current regulation was empirically determined through extensive testing of the design over several years (Lewis & Phelps, in preparation). The components of this stimulator and its operation are described in detail in Phelps and Lewis (1982).

Microcomputer

The microcomputer used in the BSR system is a Cromemco Model Z-2D with 48-K bits of random access memory. Computer peripherals include two 5-inch floppy disk drives, a D+7A board with multiple analog and digital input/output channels, an oscilloscope, and a printer terminal.

Software

The software is written in Cromemco 16-K bit, disk-extended BASIC and Z80 assembly language. Programs for equipment calibration, schedule presentation, data storage, and analysis are all in BASIC. Cross-compatible communication between programming languages provides the ease and flexibility of BASIC programming while meeting the real-time demands of the stimulator operation and current monitoring with an assembly language program. Thus, modification of the experimentam. Thus, modification of the experimental paradigm or schedule parameters is easily accomplished as changes in experiment procedures are indicated.

The computer software consists of seven separate programs which permit several types of basic functioning to the system. The primary functions of these programs permit operation of the constant current stimulator, detection of operant responses and their time parameters, training of animals, collection of data, and statistical analysis of data. A detailed discussion of the software and the microcomputer components has been published (Phelps & Lewis, 1982).

BSR Parameter and Methods

The system provides several measures of an animal’s performance. Key measures are used to provide data on three parameters of BSR performance. These are BSR threshold, response rate, and brain impedance.

BSR threshold is calculated using the PRP/FR ratio method described above. In addition, threshold is determined by the two-pause method; this second method defines threshold as the CRF current level that results in a mean PRP 2 standard deviations greater than the mean CRF IRI. This measure is an alternative way of calculating BSR threshold. With both methods the equation of the best fitting line for CRF current is calculated using a least squares regression analysis (see Figure 1). Threshold is determined by interpolating the CRF current that corresponds with a PRP/FR rcurrent that corresponds with a PRP/FR ratio of 0.05 or a z-pause of 2.

BSR response rate is determined by dividing the total number of responses by the time required to complete the predetermined CRF current levels. This measure is an overall measure of response to stimulation both above and below threshold. In addition, response rate is usually measured during the first CRF current level. Since we usually employ a descending series of CRF current intensities, this provides a measure of response to suprathreshold intensities which is comparable to other studies using only response rate.

Brain impedance to the stimulating current is also determined. This parameter reflects differences in electrical potential at the site of stimulation when all other sources of resistance in the circuit are constant. Bipolar platinum electrodes (0.3 mm in diameter) are used to stimulate discrete brain sites, and the impedance measure reflects instantaneous changes in electrical potential across the electrode tips. Brain resistance is sampled several hundred times during each stimulation and an average of these values constitutes our impedance parameter. Measurement of impedance occurs at the beginning of each session and periodically throughout the operant session to a 30 microampere (mA) current. This provides a measure of brain impedance which is common to all animals and thus permits comparison across animals and braints comparison across animals and brain loci. Impedance measures to all of the FR and CRF current intensities are also sampled throughout each session.

Although the physiological basis of our impedance measure is not understood, it appears to be fairly constant between BSR sessions and may provide a good correlate of brain activity during behavior.

Brain Stimulation and Training Procedures

Using standard stereotaxic procedures rats are surgically implanted with one or more electrodes aimed at specific brain sites. Subjects are tested in an operant chamber with a single lever at one end. Above the cage a mercury swivel commutator permits the animal free movement while connected to the stimulation apparatus. Each lever press produces a 0.2 second train of 100 Hz biphasic rectangular pulses of 1.0 millisecond duration (Current intensity varies as previously discussed.). After recovery from surgery each animal is shaped to press a lever for BSR on a continuous reinforcement schedule. The rat then acquires the response on a FR-15 schedule of reinforcement using the method of Huston (1968). This procedure involves decreasing CRF current intensities gradually while maintaining FR current intensities at suprathreshold intensities. This added training requires a longer period of time to train each animal but provides more information about reward behavior and the effects of various pharmacological and other of various pharmacological and other experimental manipulations.

The length of time to complete an operant session is variable depending upon (a) the rate of lever pressing by the animal, (b) the number of CRF current intensities tested, and (c) the need to descend or to both descend and ascend the CRF intensity range. We typically use four CRF intensities. Animals with implants at several positive brain sites (e.g., lateral hypothalamus) typically complete a session in approximately 15 to 20 minutes.

Uses of the BSR System

This system has been used to determine BSR threshold, rate of response, and brain resistance in various brain sites, including the lateral hypothalamus, medial forebrain bundle, and locus coeruleus. Extensive research (Lewis & Phelps, in preparation) using animals implanted with platinum electrodes has shown performance as observed by the three parameters of BSR remains quite constant from day to day over the several weeks required for most of our experiments. Previous research with animals implanted with stainless steel electrodes showed that the threshold and impedance measures were more variable and tended to increase over time. Changing to platinum electrodes eliminated this problem. Histological evidence and microscopic examination of used electrodes indicated that after many testing sessions stainless steel electrode tips were eroded with passage l electrode tips were eroded with passage of electrical current. This was probably the reason for the instability in BSR performance. Such erosion was not observed with platinum electrodes even after quite extensive testing over a period of more than one year.

Effects of ETOH on BSR

The positive reinforcing effects of ethanol (ETOH) undoubtedly play a significant role in its abuse. Consumption of alcoholic beverages produces positive affective states which reward drinking behavior. Laboratory experiments of these effects in animals, however, typically encounter considerable difficulty. Two types of experimental paradigms are commonly employed to investigate the rewarding effects of substances of abuse, self-administration, and BSR. We have chosen the latter paradigm because it is the one which permits a more direct evaluation of behavioral parameters with specific brain mechanisms.

Adult male albino rats were used as subjects. All were implanted with single electrodes aimed at either the lateral hypothalamus (LH) or mesencephalic ventral noradrenergic bundle (VNB). The latter is a site which is within an ascending norepinephrine pathway described by Ungerstedt (1971) and Jacobowitz (1978). It lies posterior to the mesencephalic nuclei which give rise to forebrain dopamine terminal. Training procedures for all animals were as described above. After stable performance was attained, all rats received thmance was attained, all rats received three intraperitoneal injections of saline and ETOH (0.1, 0.25, 0.50, 0.75, and 1.50 g/kg, 30% v/v) 5 to 10 minutes before BSR sessions.

BSR threshold was reduced by the 0.25, 0.5, and 0.75 g/kg ETOH doses at the LH site (see Figure 2). This enhancement of BSR appeared dose dependent over this range. The 1.50 g/kg produced no significant effect on threshold at the lateral hypothalamus, although there was a trend towards a reduction in threshold. Threshold was not affected at the ventral noradrenergic bundle at doses up to 0.75 g/kg. The 1.50 g/kg dose so disrupted performance at the ventral noradrenergic bundle that threshold could not be determined despite frequent priming.

Overall BSR response rate was unchanged at the 0.10., 0.25, and 0.50 g/kg doses at both brain sites (see Figure 3, panel B). It was, however, significantly reduced at the 1.50 doses at both brain loci. The 0.75 dose showed no significant difference from saline baseline, although most VNB animals showed a slight reduction in rate at this dose. Closer inspection of individual data showed that response rate during the first CRF current level was increased by 0.25 and 0.50 doses in many LH animals (see Figure 3, panel A), although statistical significance was not attained. This lack of significance was due to high variability which was generally seen with the response rate measure.
 

 
Effects of ethanol on BSR thresholds

Figure 2: Effects of five doses of ETOH on BSR threshold expressed as the percentage of baseline. Numbers above each bar are absolute threshold values in microamperes. Vertical lines within each bar are the S.E.M. Asterisks indicate significant differences from baseline (p < 0.05).
 

Brain impedance generally declined slightly at all doses of ETOH over values found after saline injection. It failed, however, to show a dose dependent decline. While the meaning of this measure remains unknown and given the considerable research (for a review, see Ingram, 1982) on ETOH effects on cell membranes, it is not unreasonable to speculate that these changes may have to do with alteration of these membranes or their functioning.

ETOH’s lowering of BSR threshold is in disagreement with Carlson and Lydic (1976), who found that doses 0.9 and 1.2 g/kg increased threshold while a dose of 0.6 g/kg did not affect threshold but did slightly increase response rate. While many procedural details seem to differ between their research and ours, the most notable was threshold determination. Their method of determining threshold was simply to deteermination. Their method of determining threshold was simply to determine the current intensity which would support a rate of 15 responses per minute. This procedure is highly rate dependent and is not likely to be sensitive to reinforcing doses of ETOH which may also have depressant effects.

The differential effects of ETOH on BSR between lateral hypothalamus and ventral noradrenergic bundle sites is an interesting finding. These data suggest that ETOH may produce reinforcement via neural activity at specific brain sites. The lateral hypothalamus contains a heterogeneous group of ascending and descending fiber tracks including the monoamines norepinephrine, dopamine, and serotonin. The ventral noradrenergic bundle contains diffuse ascending noradrenergic fibers and other neurotransmitters including ascending and descending serotonergic neurons (Jacobowitz, 1978). In addition, this region contains enkephalin neurons (Uhl, Kuhar, Goodman, & Snyder, 1979).
 

 
Effects of ethanol on BSR response rates
Figure 3: Effects of five doses of ETOH on BSR response rate during the first 300 responses (A) and the entire operant session (B). Values are expressed as the percentage of baseline. Numbers shown above each bar are absolute response rates in responses per minute. Vertie absolute response rates in responses per minute. Vertical lines within each bar are the S.E.M. Asterisks indicate significant differences from baseline (p < 0.05).
 

Previous research (Lewis, 1980; 1981b) in our lab found that the opiate antagonist naloxone increases BSR performance at lateral hypothalamic sites. These data suggest that ETOH and opiates produce their reinforcing effects by different brain systems. This hypothesis is supported by recent data from our lab (Lewis, Andrade, Reynolds, & Phelps, in preparation) which show that naloxone does not affect either the threshold lowering effects of low doses of ETOH on LH BSR or the rate suppressing effects of high doses of ETOH at this site. Our most recent data, while preliminary, show that low doses of ETOH lower BSR threshold at sites in the A10 nucleus of the mesencephalon (which gives rise to limbic and cortical dopamine fibers) and in the medial septal area near the nucleus accumbens, also. Further research with a range of ETOH doses at these sites as well as at other key brain areas (e.g., locus coeruleus and hippocampus) is necessary to determine if the mediation of ETOH reinforcement is site-specific.

Currently, we are investigating the effects of chronic ETOH administration at varying doses. In particular, we want to determine whether the threshold lowering effects of low doses of ETOH and the rate suppressiffects of low doses of ETOH and the rate suppressing effects of high doses of ETOH show tolerance. More importantly, we want to determine whether there is a threshold lowering effect of high doses of ETOH after tolerance develops to its depressant effects. If we and others can, indeed, confirm these findings, we will have made a major step in unraveling a major mystery about ETOH and its abuse.

In conclusion, we feel that these data show that ETOH is similar to other substances of abuse in enhancing BSR performance when given in low to moderate doses. BSR threshold was reduced at the lateral hypothalamic brain sites at low doses. It is interesting to note that ETOH did not reliably increase response rate at these doses. Higher doses suppressed response rate at both sites. It is also interesting that no dose of ETOH lowered BSR threshold or increased response rate in animals self-stimulating at the ventral noradrenergic bundle sites. These data suggest that ETOH effects may best be determined by measuring BSR threshold as the same measure of reward at specific brain sites.

Aging Effects on BSR and Amphetamine Rejuvenation

A number of physiological and biochemical changes occur with aging. While all bodily systems show such changes, those of the central nervous system probably play a particularly important role in behavioral changes occurring during aging. Shrinkage of the brain (Dayan, 1971) and loss of cortihe brain (Dayan, 1971) and loss of cortical cells (Brody, 1976) are among an increasing number of observed changes found in elderly persons (for a review, see Dayan, 1971; Smith & Sethi, 1977). Experimental animals exhibit a similar loss of cells with aging (Ordy, Brizzee, Kaack, & Hansche, 1978). Associated with these are declines in behavior, especially learning (for a review, see Arenberg & Robertson-Tchabo, 1977) and memory (for a review, see Craik, 1977).

Decreased activity, disturbances or alterations of sleep, and reduced sexual behavior (for a review, see Elias & Elias, 1977) have been reported and suggest a possible decrease in motivation. Such a decline may underlie other well-known changes in behavior (e.g., decline in learning and memory). The research from our laboratory (Lewis, 1981a) which is discussed in this section shows that there is a decline in brain stimulation reward (BSR), a potent motivational behavior, in aged rats. Moreover, it was found that amphetamine, a potent psychomotor stimulant, had a rejuvenating effect on BSR behavior in aged rats.

BSR has long been considered a biobehavioral method to investigate motivation. It has been shown to act as a reinforcer for operant behavior in much the same way that food acts as a reinforcer for food-deprived individuals (Olds & Milner, 1954). Furthermore, BSR has been shown to interact with normal motivational systems (e.g., hunger: Margules &aional systems (e.g., hunger: Margules & Olds, 1962 and sex drive: Caggiula & Hoebel, 1966). Moreover, it is widely believed that BSR involves direct stimulation of neural systems controlling normal motivational states (for a review, see Gallistel, 1973). It is, therefore, appropriate to study the relationship of BSR to aging behavioral processes.

Randomly bred male albino rats were implanted with single electrodes and trained as previously discussed. In the first series of experiments, all animals were implanted and trained at approximately 6 months of age. All animals were vigorous responders and showed stable thresholds between 25 and 50 microamperes.

BSR performance declined with age. This is shown in the first two panels of Figure 4. This is most apparent from the fact that threshold at 15 to 20 months could not be determined because the animals failed to complete enough of the current levels. Impedance levels could, however, be determined during the initial responding, and they were higher at 15 to 20 months in comparison to 6 to 8 month levels. Mean response rate of the first CRF current level in two of three sessions at 15 to 20 months declined also over the rate at 7 to 8 months.

The effects of priming, increased CRF and FR current, food deprivation, and reshaping are shown in Figure 3. These individual procedures were all ineffective in increasing the number of FRs completed by the animals at 15 to 20 months.leted by the animals at 15 to 20 months. Combination of these variables did increase significantly the number of FRs completed (see Figure 5); however, this increase was not sufficient to complete all the CRF current intensities of the BSR program which are required for determination of threshold. The combination which generally produced the largest increase in the number of responses was priming and increased current, although individual differences existed as to which of the combinations proved best for a given animal.

Injection of 0.25 to 0.30 mg/kg of amphetamine at 5 to 30 minutes before the BSR session increased responding in all animals (see Figure 5). Priming was sufficient to initiate responding in 3 of 11 rats. Priming and some reshaping to the bar were required for three rats. Five animals responded without either procedure. Using similar procedures during the BSR session, injection of amphetamine 6 to 24 hours before testing did not increase responding (see Figure 5).

Figure 4 (center panel) shows that threshold and impedance levels were higher after amphetamine injection than 6 to 8 month values. Mean response rate of the first CRF current level and overall rate were unchanged. All animals showed (see Figure 4, right panel) an unexpected residual enhancement of BSR in at least two subsequent sessions after the last amphetamine injection. Three of the animals completed the BSR program in five sessions. In all of these ram in five sessions. In all of these tests, priming was given if necessary to initiate responding. Figure 4 shows that threshold levels and impedance in these subsequent tests were elevated over 6 to 8 month values. Response rate at the first CRF current level and overall rate declined slightly, but not significantly in comparison to the rate under amphetamine. Both were unchanged in comparison to 6 to 8 month rates.

Microscopic analysis of the histology showed no indication of sizable necrosis around electrode tips. All animals were found to have the tips of the electrodes terminating in the lateral hypothalamus medial forebrain bundle area. The tissue near the electrode tips appeared no different from that of younger animals which had exhibited high response rates for stimulation at this brain site.
 

 
Changes in BSR parameters during aging
Figure 4: Changes in BSR parameters during aging. Mean threshold values require completion of all CRF intensities within 90 minutes. Mean impedance was measured at 30 mA of current for all animals. Mean response rate was calculated based on the performance during (a) first CRF-FR current intensity (filled circles), (b) entire operant session (), (b) entire operant session (X). BSR sessions during 6 to 8 and 15 to 20 month periods were undrugged operant sessions selected to represent characteristic performance during these periods. Asterisks indicates p < 0.05 in comparison to 6 to 8 month values. Reprinted from Lewis, 1981a. Copyright 1981 by Beech Hill Publishing.
 

An age-related decline in BSR is a phenomenon which we have often observed in our laboratory. Animals with implants in the lateral hypothalamus as well as other brain sites sometimes stop responding. This may occur at any age; however, these animals rarely turn to BSR behavior or respond to priming, reshaping, food deprivation, increased current, some combination of these procedures, or drugs. These procedures were found to be relatively ineffective in restoring BSR produced increments in responding; however, some improvement was seen with a combination of manipulations. The fact that amphetamine reinstated the BSR behavior indicates that the observed decline was probably not a function of some necrosis of tissue under the electrode tip or that the electrode was in some way defective.
 

 
Effects of various manipulations on BSR in 15 to 20 month old rats
Figure 5: Effects of various manipulations upon the mean number of responses during BSR sessions as indicated by the number of FR reinforcements in 15 to 20 month old rats. The "combination" indicates the use of more than one priming, increased current, food deprivation, and reshaping in a BSR session. One asterisk indicates p < 0.05 in comparison to priming, increased current, food deprivation, shaping and amphetamine (6 to 24 hours). Two asterisks together indicate p < 0.05 in comparison to all others. Reprinted from Lewis, 1981a. Copyright 1981 by Beech Hill Publishing.

The enhancement of BSR behavior by amphetamine has often been observed (for a review, see Wauquier, 1976). Cassens and Mills (1973) report that amphetamine lowers BSR threshold using a similar procedure to that employed here. We have confirmed this observation with amphetamine many times in our laboratory in younger rats. Amphetamine has also been reported to improve motivational behavior in elderly patients (Clark & Manikar, 1979). The results of the current study are consistent with these reports.

Amphetamine may have also rejuvenated brain motivational systems in aged rats. This hypothesis seems possible in light of previous research on neurochemical changes associated with aging and biochemical effects of amphetamine. Wd with aging and biochemical effects of amphetamine. While many brain neurotransmitter alterations occur with aging, a major and relatively consistent effect appears to be a decline in the activity of catecholamines, particularly in dopamine areas (for a review, see McGeer & McGeer, 1976). In addition, there is a loss of neurons in the substantia nigra where striatal dopamine tracts originate and shrinkage of tissue in the dopamine-rich striatum with aging (McGeer, McGeer, & Suzuki, 1977). Amphetamine’s effects on brain neurochemical systems is primarily on dopamine and norepinephrine where it is known to release the stored neurotransmitter from the presynaptic neuron and to block the re-uptake into neurons (Glowinski & Axelrod, 1966; for a review, see Cassens & Mills, 1973). The net effect is to potentiate noradrenergic and dopaminergic neurotransmission. Hence, it is conceivable that amphetamine could have enhanced the functioning of declining catecholamine systems in the aged rats.

The importance of catecholamines, dopamine in particular, in BSR has been shown in a large number of reports (for reviews, see German & Bowden, 1974; Wise, 1978). If catecholamines are indeed highly vulnerable to aging, then a decline in BSR behavior is to be expected in old rats. The fact that amphetamine administered shortly before the BSR session but not 6 to 24 hours before the session enhanced performance on the day of injection and on subseq on the day of injection and on subsequent sessions suggests that probable BSR and amphetamine interacted to effect brain motivation systems. Dopamine, an apparent common neurochemical substrate of both BSR and amphetamine, may decline with aging as discussed above but may be rejuvenated by them. This hypothesis is supported by Marshall and Berrios (1979) who found that the age-related decline in swimming behavior in rats was "rejuvenated" by administration of the dopamine-receptor stimulant apomorphine and of the dopamine precursor L-DOPA.

While not conclusive, this longitudinal study indicates that there is an age-related decline in motivation and that this decrease may be due to decline in brain dopamine systems. A replication of this age-related decline in BSR has been completed in a study investigating cocaine’s effects on aged performance. In a different group of randomly bred rats implanted at 6 months of age, an age-related decline in BSR performance was observed. We compared the effects of cocaine, another dopamine agonist, with amphetamine in improving BSR performance in aged rats. Doses of 0.5, 1.0, and 5.0 mg/kg (intraperitoneally) of cocaine or amphetamine were administered to 18 to 20 month old rats who failed to complete BSR operant sessions. Both drugs enhanced BSR performance with all animals completing the operant session at the 1.0 and 5.0 mg/kg doses. Only amphetamine produced this effect at the 0.5 mg/kg dose. BShis effect at the 0.5 mg/kg dose. BSR threshold was found to be significantly higher under these drug doses than the original 6-month values (undrugged animals). These data replicate the results of the first experiment and further implicate dopamine and/or other catecholamines in the enhancement of the BSR.

A cross-sectional study of the effects of aging on BSR has recently been completed. Two groups of F-344 NIA rats 6 to 8 months and 18 to 20 months of age were implanted with bipolar platinum electrodes aimed at the medial forebrain bundle. All animals were then shaped for lateral hypothalamic BSR and trained on the computer-controlled system. Surprisingly, there was no difference on the performances of both age groups. Continued testing involving two to three BSR sessions per week showed a decline in performance (e.g., failure to complete the BSR session and lower initial BSR rate) in the older group at 23 1/2 to 26 months. The younger group showed no decline during this period. Both groups received the same number of operant sessions with current intensities within the same range. These data show an age-related decline in BSR performance in rats implanted and trained at very different ages and complement the previous longitudinal data showing an age-related decline in BSR. Publication of this research is in preparation.

While these data are far from conclusive concerning the role of dopamine and/or norepinephrine on age-relane and/or norepinephrine on age-related changes in BSR performance, they are strongly suggestive, particularly in light of some of the other data we have gathered recently. Dopamine antagonism either by large doses (2.0 mg/kg, intraperitoneally) of the receptor blocker haloperidol or by intracerebral injection of the catecholamine neurotoxin 6-hydroxydopamine produced age-like deficits in BSR performance. Both manipulations produced lower response rate, increased impedance and prevented completion of all CRF current intensities, and thus BSR threshold determination. We have also found that enhancement of serotonin activity by fenfluramine injection fails to enhance BSR performance in aged F-344 rats. Further research on the role of catecholamines in aging is planned using more specific neurotransmitter agonists and other brain sites.

As with the reinforcing effects of ETOH, aging effects on brain motivational mechanisms may be investigated by using BSR. The multifunctional computerized system described in this chapter, we believe, provides a powerful research tool for such studies. The method for determining BSR threshold is quite sensitive and stable. Measurement of it along with the ability to also measure operant response rate and brain impedance provides multiple parameters for understanding brain reward mechanisms and how substances of abuse affect them.

References

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