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Director's Report to the National Advisory Council on Drug Abuse
May, 2002


Research Findings

Behavioral Research

Role of the Rostral and Caudal Basolateral Amygdala on the Maintenance and Reinstatement of Cocaine-Seeking Behavior in Rats

Associative learning mechanisms within the basolateral amygdala have been hypothesized to control the salience of cues associated with cocaine self-administration and thereby induce drug-seeking behavior. Recent research by Dr. Kantak and her associates employs a second-order operant schedule to investigate whether sites in the rostral-(BLA) and caudal-(cBLA) would provide a critical neuroanatomical substrate for drug seeking and drug taking behavior during the maintenance and reinstatement of self-administration. The use of this second-order schedule allows for drug intake to be measured independently of drug-seeking so that the neuroanatomical basis of drug seeking may be dissociated from that of drug taking. In the second order schedule, rats were trained to self-administer 1 mg/kg of cocaine under an FI 5-min (FR5:S) second-order schedule of drug delivery, where every fifth lever press (FR5) during the 5-min fixed interval (FI 5-min) resulted in the delivery of a 2-sec brief light stimulus located above the lever. Cocaine delivery was contingent on the completion of an FR5 after the FI had elapsed. The stimulus light remained on for the duration of the drug infusion as well as for the 20 sec following infusion. Thus, the light was associated with cocaine delivery. Following a period of extinction and abstinence, reinstatement of responding by the stimulus light alone and by the light + drug prime were examined. Results indicated that lidocaine inactivation of both structures attenuated the reinstatement induced by light + drug prime. In contrast, lidocaine inactivation of only the rBLA blocked reinstatement induced by light alone. Similarly, during cocaine maintenance sessions, inactivation of rBLA did not modify drug seeking, whereas inactivation of the cBLA during maintenance sessions reduced drug-seeking behavior. By contrast, drug taking was not altered under maintenance or reinstatement conditions. Thus, the rBLA and cBLA appear to selectively and dissociably regulate drug-seeking behavior under conditions of cocaine abstinence, as well as maintenance. These findings suggest that the BLA may be more functionally heterogeneous than commonly thought for regulating drug-seeking behavior. Kantak, K.M., Black, Y., Valencia, E., Green-Jordan, K., and Eichenbaum, H.B. Dissociable Effects of Lidocaine Inactivation of the Rostral and Caudal Basolateral Amygdala on the Maintenance and Reinstatement of Cocaine-Seeking Behavior in Rats. Journal of Neuroscience, 22 (3), 1126-1136, 2002.

Prenatal Exposure to Cocaine Decreases the Survival and Growth of Neurons Involved in Attentional Processes

Problems of attention can arise in the young children of individuals who use cocaine during pregnancy. Dr. Diane Snow and her collaborators at the University of Kentucky are using a clinically relevant rodent model of prenatal cocaine exposure to investigate dysfunction in noradrenergic neurons of the locus coeruleus (LC), an area that has been associated with attentional deficits in previous studies. Dr. Snow is using a unique approach in which she measures cell survival and neurite outgrowth in LC neurons cultured from fetal rat brains. With this technique, she can compare the consequences of in vivo prenatal exposure, which could result from either direct or indirect effects on the cells of interest, with the direct effects of cocaine applied in vitro to neurons cultured from fetuses of untreated dams. Another virtue of this approach is that it permits the delineation of critical periods of drug exposure during prenatal development. In her first study, Dr. Snow found that both in vivo and in vitro cocaine exposure decreased neuron survival, the number of cells that extended neurites, the number of neurites elaborated per neuron and total neurite length. The two treatments produced consistent results, which suggests that prenatal exposure may alter the growth potential of LC neurons via direct effects on these cells. Snow, D.M., Smith, J.D., Booze R.M., Welch, M.A., and Mactutus, C.F. Cocaine Decreases Cell Survival and Inhibits Neurite Extension of Rat Locus Coeruleus Neurons. Neurotoxicology and Teratology, 23, pp. 225-234, 2001.

Discovery of a Novel Family of Neuropeptides that Contribute to Switching Between Behavioral Patterns

One characteristic of drug addiction is compulsive seeking and taking of a drug. We have some understanding of the neural circuitry involved in switching between behavioral actions, but only a rudimentary understanding of how dysregulation of this circuitry leads to compulsive behaviors. Recent findings suggest that various classes of peptides are involved in the control of behaviors such as feeding, maternal behavior, and drug ingestion. Dr. Ferdinand Vilim is using a model invertebrate system, the feeding behavior of Aplysia, to discover new neuropeptides and investigate their role in the modulation, coordination, and pattern selection of neural circuits. The advantage of this system is that the neural circuitry underlying the behaviors is well defined at the single neuron level, and new techniques for measuring peptides at the single cell level have been pioneered in Aplysia, because their neurons are very large. Dr. Vilim and his colleagues recently reported their discovery of a novel family of neuropeptides they call enterins, which are present in both the gut and central nervous system of Aplysia. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) they were able to characterize the precursor processing and determine post-translational modifications of the multiple enterins. Using electrophysiological techniques, they showed that enterins are likely to be involved in switching between ingestive and egestive motor programs. While it remains to be seen whether enterins are found in the mammalian nervous system, this study demonstrates the potential of using invertebrate model systems for the discovery and characterization of new neuroactive molecules. Since the biological functions of such molecules are often evolutionarily conserved, studies in Aplysia can provide new targets and methods for future drug abuse studies. Furukawa Y., Nakamaru K., Wakayama H., Fujisawa Y., Minakata H., Ohta S., Morishita F., Matsushima O., Li L., Romanova E., Sweedler J.V., Park J.H., Romero A., Cropper E.C., Dembrow N.C., Jing J., Weiss K.R., and Vilim F.S. The Enterins: A Novel Family of Neuropeptides Isolated from the Enteric Nervous System and CNS of Aplysia. Journal of Neuroscience, 21, pp. 8247-8261, 2001.

Prior or Concurrent Exposure to Environmental Novelty Decreases Drug Self-Administration in Rats

When natural rewards such as food or sucrose are provided during the availability of drug self-administration, these consummatory rewards attenuate the intake of both psychostimulant drugs and opiates. Dr. Michael Bardo and his colleagues recently conducted a series of investigations to determine if nonconsummatory rewards would also act as alternative reinforcers when provided along with d-amphetamine (amp). Rats were trained to self-administer amp and when response rates were stable they were provided with novel objects in the self-administration environment. The investigators report an attenuation of responding for drug each time novel objects were introduced. In a second study, they sought to determine if pre-exposure to this form of alternative reward might attenuate the acquisition of self-administration. In this study, one group of animals was given an opportunity to explore novel objects for 15 min prior to each drug self-administration session during acquisition and this group was compared to handled-only animals. Exposure to the novel objects delayed acquisition of amp self-administration, but once the behavior was acquired there was no difference between the two groups. These observations suggest that environmental novelty, which activates the same central dopaminergic pathways as drugs of abuse such as amp, may attenuate the vulnerability to acquire self-administration. However, these effects appear to be transient. Klebaur, J.E., Phillips, S.B., Kelly, T.H., and Bardo, M.T. Exposure to Novel Environmental Stimuli Decreases Amphetamine Self-Administration in Rats. Exp Clin Psychopharm., 9, pp. 372-379, 2001.

Amotivational Effects of Acute Smoked Marijuana in Human Drug Abusers

It has been suggested that marijuana (mj) abuse is associated with an "amotivational" syndrome characterized by apathy, lethargy and a general loss of productivity. NIDA-funded investigators Don Cherek and Scott Lane have been testing mj abusers in the laboratory setting, using operant conditioning techniques to assess responding for monetary reinforcers. In their procedure, subjects respond under progressive ratio (PR) schedules to receive varied amounts of monetary reward. The investigators first demonstrated that under non-drug conditions, greater progressive ratio segments were completed, greater responses made per minute and more monetary rewards earned, with increasing values of available monetary rewards. The authors argue that these response indices assess motivation, since they rose in a direct relationship to increasing value of the reinforcer. They then used this procedure to demonstrate that decreases in responding, under unchanging reinforcement conditions, can index decreases in motivation. In this second study, they treated mj abusing subjects with three different doses of smoked mj or placebo. They found decreases on all three response measures, that were related in a dose-dependent fashion to the dose of mj smoked just prior to testing. In a second phase of this acute mj study, increasing the monetary value of the reward was found to attenuate mj induced reductions in the size of the largest PR completed (i.e., number of responses the subject is willing to make to receive a monetary reward). Thus, to the extent that reductions in PR size reflect decreased motivation for monetary rewards under the effects of acute mj, this effect can be overcome by increasing reinforcing value of the reward. The authors argue that the PR procedure appears to be a sensitive technique for detecting motivational changes in human drug abusers and suggest that it might be useful for assessing residual effects in chronic mj smokers. Cherek, D.R., Lane, S.D., and Dougherty, D.M. Possible Amotivational Effects Following Marijuana Smoking Under Laboratory Conditions. Exp Clin Psychopharmacol, 10, pp. 26-38, 2002.

Neurotoxicity Induced by Repeated MDMA Treatment Does Not Affect Performance on Repeated Acquisition Tests of Cognitive Performance

Abuse of the drug "ecstasy" (3,4-methylenedioxy-methamphetamine) has shown alarming trends on several epidemiological indices of drug abuse in this country. This trend is of great concern because both preclinical neurobiological data and findings from human neuroimaging studies reveal that this drug induces neurotoxicity in central serotonergic (5-HT) transmitter systems. Studies in human abusers also suggest that chronic MDMA administration produces functional deficits on memory tasks, and possibly on measures of higher order cognition. The challenge has been to model some of these functional deficits in preclinical studies and ascertain whether or not they can be linked to toxic effects in central neurotransmission. Recent studies by Dr. Peter Winsauer and colleagues employed a repeated acquisition learning paradigm in squirrel monkeys to assess the effects of a neurotoxic MDMA regimen on working memory. Animals were trained on the task until they demonstrated stable performance and then tested with drugs that stimulate 5-HT release. After dose-response determinations were made for the effects of these drugs on response rate and errors made on the task, half of the animals were treated with 2.5 mg/kg MDMA twice per day for four days. Dose response determinations were repeated under effects of two 5-HT releasers, mCPP and fenfluramine. The MDMA treatment was then repeated in the same monkeys, only for this second regimen animals received 5 mg/kg twice per day for four days. Again, MDMA-treated and non-treated controls were retested under effects of the two 5-HT releasing drugs. While these drugs decreased response rates on the task, in a dose-dependent fashion, they produced no effect on response accuracy (i.e., correct responses to different stimulus ‘signals'). Most notably, MDMA treated rates performed no differently from untreated controls when assessed under non-challenge conditions (without mCPP or fenfluramine), and there were no differences in the effects of these 5-HT releasing drugs within animals at pre- and post- MDMA time points. The failure to observe a functional effect of repeated MDMA treatment is surprising, given that post-mortem measures showed severe reductions of [3H]citalopram-labled SERT and significant reductions of 5-HT and its metabolites over multiple brain regions. It is possible that compensatory changes in other neurotransmitter systems sustain the integrity of the cognitive processes assessed by this task, that residual 5-HT is adequate for mediating this behavioral effect, or that well-learned cognitive tasks may be difficult to disrupt with repeated MDMA treatment. Winsauer,P.J., McCann, U.D., Yuan, J., Delatte, M.S., Stevenson, M.W., Ricaurte, G.A. and Moerschbaecher, J.M.. Effects of Fenfluramine, m-CPP and Triazolam on Repeated-acquisition in Squirrel Monkeys before and after Neurotoxic MDMA Administration. Psychopharmacology, 159, pp. 388-396, 2002.

The Effects of Smoked Cocaine during the Follicular and Luteal Phases of the Menstrual Cycle in Women

Dr. Suzette Evans and colleagues of the New York State Psychiatric Institute and the College of Physicians and Surgeons of Columbia University have found that phase of the menstrual cycle is a determinant of cocaine craving as well as of the subjective response to smoked cocaine. Eleven females research volunteers who were currently using cocaine were recruited for participation in this study. Their mean amount spent per week on cocaine was $397 and their average use was 3-4 days per week. Each subject was tested in both the luteal and the follicular phase and in each phase subjects received four cocaine sessions in which they could smoke up to six doses of cocaine (either 0, 6, 12, for 25 mg cocaine base) at 14-min intervals. Under placebo conditions, resting heart rate, reports of dysphoria (e.g, ratings of "depressed," "irritable," "miserable"), and cocaine craving were greater during the luteal phase than in the follicular. Following cocaine administration, luteal phase dysphoric ratings were dose-dependently improved. Cocaine craving was greater during the luteal phase than during the follicular under 3mg and 25 mg, but not after 12 mg at which time craving was higher in the follicular phase. Cocaine-produced ratings of mood states (alert, friendly, self-confident, social, talkative), positive drug effects (good drug effect, high, stimulated), and drug quality ratings were generally greater during the follicular phase than the luteal phase. Heart rate increase was also greater during the follicular phase. Plasma cocaine levels increased with increasing cocaine dose, but did not differ in the follicular and luteal phases. The differential subjective effects of cocaine in the luteal and follicular phases as well as the cocaine-produced amelioration of mild luteal phase dysphoria observed in this study warrant investigation of the mechanisms underlying these effects as well as an exploration of treatment implications of these findings. Evans, S.M., Haney, M, and Foltin, R.W. The Effects of Smoked Cocaine during the Follicular and Luteal Phases of the Menstrual Cycle in Women. Psychopharmacology, 159, pp. 397-406, 2002.

Social Factors Can Ameliorate Vulnerability to Drug Abuse in Cynomolgus Monkeys

In an investigation of the relationship between social rank and cocaine self-administration, Dr. Mike Nader and colleagues at Wake Forest School of Medicine report in Nature Neuroscience that cocaine functions as a reinforcer for subordinate, but not dominant monkeys. For the first 18 months of the study, monkeys were individually housed and then were housed socially in groups of four. Following the emergence of a dominance hierarchy, the monkeys were given the opportunity to acquire cocaine self-administration. In subordinate monkeys, cocaine self-administration was an inverted U-shaped function of dose, whereas in dominant monkeys, responding for cocaine did not exceed responding for saline at any of the study doses. The investigators also assessed D2 receptor binding via PET imaging before the monkeys were individually housed and again after they were group housed. When individually housed, D2 receptor binding levels did not differ between the monkeys that eventually became dominant and those that became subordinate. Following group housing, however, D2 receptor binding increased in the dominant monkeys, but not the subordinate monkeys. The investigators suggest that switching from individual housing to social housing "normalized" dopamine functioning in the dominant monkeys, but not in the subordinate monkeys. Thus, low D2 binding in the basal ganglia of socially housed monkeys appears to be associated with a greater vulnerability to acquire drug self-administration with cocaine. Morgan, D., Grant, K.A., Gage, H.D., Mach, R.H., Kaplan, J.R., Prioleau, O., Nader, S.H., Buchheimer, N., Ehrenkaufer and Nader, M.A. Social Dominance in Monkeys: Dopamine D2 Receptors and Cocaine Self-Administration. Nature Neuroscience, 5(2), pp. 169-174, Feb 2002.

Wheel Running Attenuates the Antinociceptive Properties of Morphine and Its Metabolite, Morphine-6-Glucuronide, in Rats

Prior studies conducted by Dr. Robin Kanarek of Tufts University, (in conjunction with contributions from other research programs) have established that chronic running in an activity wheel is associated with a reduction in the pain-relieving actions of opioid drugs in laboratory animals. Dr. Kanarek has suggested that this effect results from cross-tolerance between the endogenous opioid peptides released during exercise and exogenously administered opioid agonists. Alternatively, given that exercise affects opioid metabolism, the effect could result from altered opioid metabolism. Dr. Kanarek and her colleague, Wendy Foulds Mathes, tested these alternative explanations by examining the effect of chronic exercise on the pain-relieving effects of the morphine metabolite, morphine-6-glucuronide (M6G). M6G itself is not further metabolized, and it also is capable of producing profound antinociception. She found that, like morphine, the antinociceptive response to M6G also was attenuated by chronic wheel running, thus lending support to the hypothesis that there is cross-tolerance between chronic exercise and exogenously administered opioids. Mathers, W.F. and Kanarek, R.B. Wheel Running Attenuates the Antinociceptive Properties of Morphine and Its Metabolite, Morphine-6-Glucuronide, in Rats. Physiology & Behavior, 74, pp. 245-251, 2001.

Chronic Sucrose Intake Enhances Nicotine-Induced Antinociception in Female But Not Male Long-Evans Rats

Previous work has shown that in rats and mice, chronic consumption of palatable foods and fluids enhances the antinociceptive effects of morphine and other opioid agonists. Dr. Robin Kanarek and her colleague, Silvia Mandilo, of Tufts University have now shown that this effect extends to nicotine-induced antinociception. They found that nicotine administration produced dose-related increases in antiociception, but only in female subjects. Other animal studies have also shown sex differences in response to nicotine, e.g, females exhibit a greater antinociceptive effect of centrally-administered nicotine, a greater effect of nicotine on food intake and body weight, and greater motivation to self-administer nicotine. In the present study, the authors speculate that the sucrose enhancement of nicotine-induced antinociception in females, but not males, could be due to the fact that because female rats are smaller than males, their percent daily calories obtained from sucrose was greater. This study, along with prior research demonstrating sucrose enhancement of opioid-induced antinociception, highlights the need for additional research on the role of diet in effects of psychoactive drugs as well as highlights the importance of examining the role of gender in these effects. Mandilo, S. and Kanarek, R.B. Chronic Sucrose Intake Enhances Nicotine-Induced Antinociception in Female but not Male Long-Evans Rats. Pharmacology, Biochemistry and Behavior, 68, pp. 211-219, 2001.

Ketaconazole Suppresses Food Restriction-Induced Increases in Heroin Self-Administration in Rats: Sex Differences

In animal laboratory studies, augmentation of drug self-administration by food restriction is well established, although the mechanism for this effect is not well understood. Given that food restriction produces an increase in corticosterone, it has been hypothesized that food deprivation is a stressor and thus acts as other stressors to elevate drug self-administration. This hypothesis was tested in a recent study by Dr. Marilyn Carroll and colleagues at the University of Minnesota who sought to determine whether ketaconazole, a corticosterone synthesis blocker, would suppress the increase in heroin self-administration produced by food restriction. In both male and female rats, heroin self-administration was increased approximately two-fold by food restriction. Under conditions of food satiation, ketaconazole had no effect on heroin self-administration in either males or females. Under conditions of food restriction, ketaconazole suppressed the food-restriction increase in heroin self-administration in females, but not males. This outcome in females lends support to the hypothesis that stress mediates the effects of food restriction on increased drug self-administration, and also has implications for the development for medications to be used in opiate abuse. Carroll, M.E., Campbell, U.C., and Heideman, P. Ketaconazole Suppresses Food Restriction-Induced Increases in Heroin Self-Administration in Rats: Sex Differences. Experimental and Clinical Psychopharmacology, 9, pp. 307-316, 2001.

Sex Differences in the Effects of Baclofen on the Acquisition of Intravenous Cocaine Self-Administration in Rats

Previous work by Dr. Marilyn Carroll and colleagues at the University of Minnesota has shown that female rats acquire i.v. cocaine self-administration faster than male rats and that a larger percentage of female than male rats acquire cocaine self-administration. These researchers now report that baclofen differentially affects acquisition of i.v. cocaine self-administration in male and female rats. Prior animal studies have shown the GABA agonist, baclofen, to be effective in reducing both the maintenance of i.v. cocaine self-administration as well as the reinstatement of i.v. cocaine self-administration following extinction. Dr. Carroll and her colleagues have now extended baclofen's effects to the acquisition phase of i.v. cocaine self-administration. They found that baclofen not only reduced the rate of acquistion of i.v. cocaine self-administration, but it also reduced the percentage of subjects that acquired i.v. cocaine self-administration. For both outcomes, the reduction was greater in females than males. Whereas 77.7% of the males met criterion for acquisition of cocaine self-administration under baclofen, only 15.4% of the females met criterion. These data join a growing body of behavioral research with animals indicating sex differences in drug effects. Campbell, U.C., Morgan, A.D., and Carroll, M.E. Sex Differences in the Effects of Baclofen on the Acquisition of Intravenous Cocaine Self-administration in Rats. Drug and Alcohol Dependence, 66, pp. 61-69, 2002.

Chronic Cocaine Increases Perseverative Responding and Impairs Reversal Learning in Monkeys

Several lines of evidence support the hypothesis that compulsive drug seeking and drug taking behavior are attributable, in part, to dysfunctions in the neural systems mediating incentive motivation and behavioral regulation (e.g., the striatum, amygdala and ventral frontal cortex). Specifically, impairments of frontal lobe function have been thought to release well-learned conditioned responses, resulting in compulsive drug seeking and taking that characterize addictive behavior patterns. Few studies, however, have directly investigated the long-term consequences of prolonged exposure to addictive drugs on frontal cortex cognitive function in non-human primates. The present experiments investigated the effects of acute and chronic administration of cocaine on the acquisition and reversal of object discriminations in male and female Vervet monkeys to test the hypothesis that cocaine affects performance of tasks that depend upon the functions of the orbitofrontal cortex and amygdala. It was hypothesized that cocaine would impair reversal learning without affecting the acquisition of novel discriminations. In the first experiment, an acute dose of cocaine (1 mg/kg) impaired reversal of a previously acquired object discrimination, but did not affect learning of a novel discrimination. Moreover, an analysis of the errors made indicated that cocaine did not increase perseverative responding, but rather produced disorganized behavior during reversal learning. In the second experiment, monkeys were treated repeatedly with cocaine (2 or 4 mg/kg) or saline once daily for 14 days. At nine and 30 days after the last drug treatment, acquisition and reversal of a novel discrimination were assessed under drug free conditions. On both tests, reversal learning was impaired, but there was no effect of drug treatment on acquisition. Moreover, the pattern of errors indicated that reversal learning was impaired as a result of perseverative responding. These data suggest that monkeys treated repeatedly with cocaine exhibit interference from previously conditioned stimulus-reward contingencies and/or develop an inability to inhibit irrelevant responses in the face of new reinforcement contingencies. The results suggest that long-term cocaine administration may disrupt orbitofrontal efferents to the striatum, resulting in impaired inhibition of established conditioned responses. Jentsch, J.D., Olausson, P., De La Garza, II, R., and Taylor, J.R. Impairments of Reversal Learning and Response Perseveration after Repeated, Intermittent Cocaine Administrations to Monkeys. Neuropsychopharmacology, 26 (2), pp. 183-190, 2002.

Neurons in Nucleus Accumbens Maintain Firing Patterns Related to Responses for Cocaine more Strongly than those Related to Water Reinforcement during Extinction

Dr. Regina Carelli is studying electrophysiological responses of neurons in the nucleus accumbens (Nas) in rats performing operant behaviors such as lever pressing to receive cocaine or natural rewards. She previously found that some Nas neurons increase their activity just prior to a lever press, and that these cells usually discriminate between type of reinforcer. For example, the vast majority of neurons that show anticipatory responses when the rat presses a lever associated with water reward, do not also increase their firing for a cocaine-associated lever, and vice versa. In two recent studies, Dr. Carelli and her graduate students asked whether Nas neurons maintain such firing patterns during extinction, when lever presses are no longer reinforced with water or cocaine. In experiments with cocaine self-administration, cells showed anticipatory firing during extinction trials at the same level as was recorded during earlier reinforced trials. In contrast, under conditions of water reinforcement, neuronal responses during extinction were greatly attenuated, and they did not return to pre-extinction levels even during reinstatement trials, at least over the short term. These findings are intriguing, but they also pose new questions for future experiments. First, anticipatory responses of Nas neurons have generally been thought to signal the expectation of reward in conditioning experiments, but the maintained firing of cocaine-associated neurons was not correlated with a slower extinction rate in the present experiments. In fact the opposite was true -- during the extinction from cocaine reinforcement, animals pressed about once per minute for about 25 minutes, whereas rats undergoing extinction from water reinforcement continued non-reinforced responding at this rate for about one hour. Thus, it would be of interest to determine if neuroadaptations produced by cocaine exposure uncouple the firing properties of Nas neurons from expectations of reward. Second, differences in Nas activity were not correlated with ease of reinstatement in either experiment -- rats resumed responding after a period of 30 minutes of no lever presses when primed with a cocaine infusion or with water plus a reward-associated auditory signal. Also, it is not known how long cocaine-associated neural responses are maintained and whether they might contribute to reinstatement at much later time points when, perhaps, reinstatement might fail to be produced in animals previously responding for water reinforcement. Carelli, R.M. and Ijames, S.G. Nucleus Accumbens Cell Firing during Maintenance, Extinction, and Reinstatement of Cocaine Self-administration Behavior in Rats. Brain Research, 866, pp. 44-54, 2000; Hollander, J.A., Ijames, S.G., Roop, R.G., and Carelli, R.M. An Examination of Nucleus Accumbens Cell Firing during Extinction and Reinstatement of Water Reinforcement Behavior in Rats. Brain Research, 929, pp. 226-235, 2002.

Environmental and Social Enrichment Protect against Vulnerability to Acquire Amphetamine Self-administration

Environmental enrichment (EC) in a preclinical model consists of placing novel and interesting objects into the housing environment and varying these objects over days. In the laboratory of Dr. Michael Bardo at the University of Kentucky, adolescent rats reared in EC environments are also socially housed. Another group of rats are reared in a social environment (SC) but without the rotating novel objects. Dr. Bardo recently compared rats exposed to these environments, starting at 21 days of age, to animals reared in isolation (IC), on responding for sucrose reinforcement and on the acquisition of self-administration for d-amphetamine (amp). EC has previously been shown to increase dopamine in the same nucleus accumbens (Nas) region that is involved in amphetamine reinforcement. Previous studies have revealed that animals exposed to EC conditions show enhanced locomotor stimulation, conditioned place preference, and DA release in the Nas in response to amp when compared to control rats. In the present study animals were tested for operant responding to receive sucrose at age 45 days and began i.v. self-administration for amp at age 62-63 days. The authors found that both EC and SC animals had higher response rats for the natural sucrose reinforcer on a fixed rate operant schedule, but as the schedule requirements were increased this difference dissipated. When self-administration rates were compared for the three groups there were no differences for responding to receive 0.1 mg/kg/infusion amp, but at 0.03 mg/kg/infusion both EC and SC animals made significantly fewer responses to receive drug. When the groups were compared on a progressive ratio operant schedule, that more precisely assesses magnitude of drug reinforcement, again EC rats self-infused significantly less amp. No differences were noted on an inactive lever on either procedure. These observations suggest that environmental enrichment is capable of reducing reinforcing impact of the psychostimulant d-amphetamine, and may therefore be an environmental variable that can affect vulnerability. It is not clear, however, why these results differ from those previously observed using other procedures to measure sensitivity to amphetamine. As it is possible that this protective effect is dose-dependent (i.e., not seen with higher doses of drug), further parametric analysis of the effect is warranted. Differences between these and previous data may also be attributed to different routes of administration (e.g., i.v. versus oral versus central infusion). Bardo, M.T., Klebaur, J.E., Valone, J.M. and Deaton, C. Environmental Enrichment Decreases Intravenous Self-administration of Amphetamine in Female and Male Rats. Psychopharmacology, 155, pp. 278-284, 2001.


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