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Director's Report to the National Advisory Council on Drug Abuse
September, 2001

Research Findings

Behavioral Research

Augmented Levels of Serotonin (5-HT) in the Nucleus Accumbens Decrease Preferences for Cocaine- or Morphine-Associated Environments in Withdrawn Rats

Central serotonergic neurotransmission is known to be increased in nucleus accumbens and other forebrain regions by morphine and cocaine administration. Conversely, it is also known to be depressed during withdrawal from chronic treatment with these drugs. In two recently published studies, Drs. Glenda Harris and Gary Aston-Jones investigated the consequences of experimentally increasing 5-HT transmission by injecting sertaline, (a selective 5-HT reuptake inhibitor), or the 5-HT precursor 5-HTP, directly into the nucleus accumbens. When 5-HT was augmented during acute morphine or cocaine administration, animals showed an increased preference for environments in which they received one of these drugs. This suggested that enhanced serotonergic activity may be important for the learned associations between primary drug reward and exteroceptive stimuli. Dependent animals continue to show a preference for environments previously paired with drug even during a withdrawal period. These investigators found that increasing 5-HT in the nucleus accumbens during withdrawal strongly attenuated the animal's usual preferences for a drug-associated environment. The 5-HT increase also reduced abstinence-induced anxiety as measured by a defensive burying behavior in which rats use their bedding to bury a probe that delivers a mild shock. These findings suggest that increases in accumbal 5-HT levels may reduce cravings elicited by incentive-motivational stimuli in drug-paired environments. Alternatively, increased 5-HT during the withdrawal state may facilitate extinction - that is, the active process whereby animals learn that these environments are no longer associated with positive drug reward. These studies suggest that drugs that augment 5-HT levels may be useful in reducing the desire for morphine or cocaine during withdrawal, and also for ameliorating subjective withdrawal symptoms (e.g., anxiety) that linger long after somatic withdrawal symptoms have dissipated. Harris, G.C, and Aston-Jones, G. Augmented Accumbal Serotonin Levels Decrease the Preference for a Morphine Associated Environment During Withdrawal. Neuropsycho-pharmacology, 24, pp. 75-85, 2001; Harris, G.C., Altomare, K. and Aston-Jones, G. Preference for a Cocaine-Associated Environment is Attenuated by Augmented Accumbal Serotonin in Cocaine Withdrawn Rats. Psychopharmacology, 156(1), pp. 14-22, published online May 9, 2001.

Environmental Enrichment Affects i.v. Self-Administration of d-Amphetamine in an Animal Model

Dr. Mike Bardo at the University of Kentucky is investigating the effects in rats of both environmental enrichment and social enrichment on the reinforcing properties of psychostimulant drugs. In this study, environmental enrichment, EC, is operationally defined as rats in group housing with daily handling and frequently changed novel objects. Social enrichment, SC, is operationally defined as rats in group housing only. He reports EC and SC rats self-administer less d-amphetamine than animals reared in isolated environments (IC=singly housed, with no handling), but only when offered low doses of the drug (0.03 mg/kg/infusion). In fact, when the higher dose of 0.1 mg/kg per infusion was made available, the researchers found no group differences. In addition, using a progressive ratio schedule, the investigators found that EC rats were less willing to 'work' for the drug, (i.e., make responses on an operant lever), than their IC counterparts. The observation that environmental enrichment seems to act as a protective factor for acquiring self-administration of d-amphetamine is interesting in light of previous observations that psychostimulant-induced sensitization is attenuated in EC animals. Collectively, these findings suggest that, under some conditions, environmental enrichment can reduce the motivation to respond for a psychostimulant reinforcer and furthermore may alter the neural substrate for chronic neuroadaptive processes that underlie sensitization. Thus, environmental enrichment may serve as a protective factor for reducing amphetamine self-administration, and may possibly attenuate the rewarding effects of the drug. Bardo, M.T., Klebaur, J.E., Valone, J.M. and Deaton, C. Psychopharmacology, 155, pp. 278-284, 2001.

Behavioral Requirements Following Drug Ingestion Determine the Reinforcing Effects of Cocaine

Animal and human studies have been unable to completely explain drug reinforcement via the inherent pharmacological properties of the drug or via characteristics of the user. That is, whether or not a drug functions as a reinforcer can be determined by environmental factors such as previous experience with the drug, type of drug, drug dose and response requirements for obtaining the drug. Dr. Roland Griffiths and his collaborators sought to determine whether the reinforcing effects of oral cocaine could be influenced by the behavioral requirements following drug ingestion. Nine adult volunteers with histories of cocaine abuse were trained to discriminate under double-blind conditions between orally administered cocaine (100 mg/70 kg) and placebo capsules. Following the acquisition of discrimination, volunteers could choose to receive either cocaine or placebo prior to performing one of two behavioral activities - a vigilance activity or a relaxation activity. The investigators found that volunteers consistently chose cocaine over placebo with the vigilance activity, and placebo over cocaine with the relaxation condition. Thus, cocaine functioned as a positive reinforcer in the vigilance context, but as a negative reinforcer (i.e., cocaine was avoided) in the relaxation context. These results demonstrate that the behavioral requirements following drug ingestion can be a determinant of whether or not oral cocaine functions as a reinforcer in volunteers with histories of drug abuse and illustrate the malleability of human drug self-administration. These results are also consistent with anecdotal reports that people use stimulant drugs to meet physically or mentally challenging behavioral requirements. Jones, H.E., Garrett, B.E. and Griffiths, R.R. Reinforcing Effects of Oral Cocaine: Contextual Determinants. Psychopharmacology, 154, pp. 143-152, 2001.

Chronic Morphine Enhances the Suppressive Effects of Cocaine on Saccharin Intake

Pairings of a toxic substance (such as LiCl) with a (generally preferred) gustatory cue like saccharin, produce a subsequent aversion to the taste of this flavor. Likewise, when a psychoactive drug such as cocaine, morphine or amphetamine is paired with saccharin, saccharin is subsequently avoided. This phenomenon is known as conditioned taste aversion (CTA). Dr. Patricia Sue Grigson hypothesizes that CTAs that develop to drugs of abuse can be explained by "anticipatory contrast" - thus, avoidance of the flavor results because the soon-to-be-experienced positive drug effects outweigh the appetitive motivation to drink the palatable solution. In other words, the palatable solution becomes devalued by comparison with the rewarding properties of the drug. Dr. Grigson recently reported that a history of morphine treatment augments the CTA that develops via pairing with the drug cocaine, but not with the toxin LiCl, in Sprague-Dawley rats. In particular, she found that 75 mg of subcutaneous morphine per day for 5 days enhanced the saccharin suppressing effects of cocaine, but not of LiCl. These data support the anticipatory contrast hypothesis in that rats appear to avoid tastes conditioned to drugs of abuse because they are anticipating the rewarding properties of the drug, not because of the aversive properties of the drugs (as is the case with toxins such as LiCl). Moreover, these are the first data to show that chronic drug treatment can cross-sensitize CTAs that develop to drugs of abuse, resembling cross-sensitization seen with other behaviors (e.g., psychostimulant-induced hyperlocomotion) after repeated drug administration. Grigson, P.S., Wheeler, R.A., Wheeler, D.S., and Ballard, S.M. Chronic Morphine Treatment Exaggerates the Suppressive Effects of Sucrose and Cocaine, but Not Lithium Chloride, on Saccharin Intake in Sprague-Dawley Rats. Behavioral Neuroscience, 115, pp. 403-416, 2001.

A Single Cocaine Injection Induces LTP-Like Synaptic Changes in Dopamine Neurons of the VTA

Previous studies have implicated increased excitatory input to the midbrain dopamine neurons as a mechanism involved in behavioral sensitization, which is thought to be important for the development of addiction to drugs of abuse. This recent study from the laboratories of Dr. Robert Malenka at Stanford and Dr. Antonello Bonci at the Gallo Research Center, UCSF, showed in both mice and rats that a single injection of cocaine could induce long-term increases in excitatory post synaptic currents in the ventral tegmental area. The increased synaptic currents were measurable for at least 5 days, but not longer than 10 days, and the effect was specific for AMPA-mediated excitatory currents in the dopamine neurons. No effect was observed on hippocampal neurons or on GABAergic neurons in the VTA, although these cells also receive glutamatergic input. The potentiated synaptic currents had many similarities to long-term potentiation (LTP), which is a prominent form of synaptic plasticity involved in learning and memory processes in many areas of the brain. Thus, a single dose of cocaine apparently "usurped" a cellular mechanism involved in a normally adaptive learning process. This rapid and long-lasting change in synaptic transmission in the VTA may help explain cocaine's ability to take control of incentive-motivational systems to produce compulsive drug seeking behavior. The observed synaptic potentiation may also be important for understanding relapse, where a single exposure to cocaine after a period of abstinence can induce renewed drug-seeking behavior. Ungless, M.A., Whistler, J.L., Malenka, R.C., and Bonci, A. Single Cocaine Exposure in vivo Induces Long-Term Potentiation in Dopamine Neurons. Nature, 411, pp. 583-587, 2001.

Estrogen Plays a Role in the Acquisition of i.v. Cocaine Self-Administration in Female Rats

Prior research by Drs. Wendy Lynch and Marilyn Carroll of the University of Minnesota showed that female rats acquire i.v. self-administration of cocaine faster than male rats. To assess the role that estrogen might play in this sex difference, these researchers compared i.v. self-administration in female rats for whom estrogen was blocked, either chemically or surgically, with female rats for whom estrogen was not blocked. Four groups of female rats were studied: ovariectomized (OVX) females treated either with estradiol benzoate (OVX-EB) or vehicle (OVX-VEH), and sham-operated (SH) females treated either with the estrogen blocker tamoxifen (SH-TAM) or vehicle (SH-VEH). In the two groups of female rats for which estrogen was not blocked, the SH-VEH and OVX-EB groups, the percentage of females who acquired cocaine self-administration according to the study criterion (a mean of 100 self-administered infusions over five consecutive 6-hr sessions) was 80% and 70%, respectively. In the two groups in which estrogen was either surgically or chemically blocked, the OVX-VEH and the SH-TAM groups, only 30% and 50%, respectively, met the study criterion for cocaine self-administration. In their prior work, these researchers found that 30% of the intact males met acquisition criterion, which is the same percentage as found for the OVX-VEH females in the present study. Taken together, these studies indicate that estrogen plays a role in the acquisition of i.v. cocaine self-administration among females and also in gender differences seen in the acquisition of i.v. cocaine self-administration. Lynch, W.J., Roth, M.E., Mickelberg, J.L. and Carroll, M.E. Role of Estrogen in the Acquisition of Intravenously Self-Administered Cocaine in Female Rats. Pharmacology, Biochemistry and Behavior, 68, pp. 641-646, 2001.

d-Amphetamine Increases Choice of Cigarette Smoking over Monetary Reinforcement

Dr. Steve Higgins and his colleagues at the University of Vermont report their finding that oral d-amphetamine (0, 7.5 mg/kg, 15 mg/kg) increases ad lib cigarette smoking from 2.8 to 3.8 cigarettes per 3-hr session. This finding is consistent with previously published reports of a relationship between psychostimulant use and cigarette smoking. In a separate study, Dr. Higgins and his colleagues sought to determine whether this relationship is due to non-specific activating effects of psychostimulants or to an increase in the reinforcing effects of cigarette smoking. Ninety minutes after ingesting oral d-amphetamine (0, 7.5, 15 mg/kg) in a 3-hr session, subjects were given 20 opportunities to choose among cigarette smoking (two puffs per choice), money (25 cents per choice), or neither. The authors report that d-amphetamine dose-dependently increased smoking choices from 4.2 to 5.7 cigarettes. While this and other studies have shown d-amphetamine and other psychostimulants increase the frequency of smoking, these findings are the first to provide evidence that d-amphetamine may produce an increase in the reinforcing effectiveness of cigarette smoking. Tidey, J.W., O'Neill, S.C and Higgins, S.T. d-Amphetamine Increases Choice of Cigarette Smoking Over Monetary Reinforcement. Psychopharmacology, 153, pp. 85-92, 2000.

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