Research Findings - Basic Behavioral Research

Combined Inhibition of Dopaminergic and Serotonergic Transporters as a Cocaine Treatment Approach

The dopamine transporter is thought to play a critical role in mediating the reinforcing efficacy and subjective effects of cocaine. It has been known for many years that the affinity of drugs for this transporter is positively correlated with their capacities to maintain self-administration behavior in animals. Dopamine transport inhibitors are now generally considered to demonstrate potential as cocaine treatment medications. Dr. Leonard Howell and his colleagues at the Yerkes National Regional Primate Research Center combined these observations with those of studies showing that inhibitors of the serotonin transporter can mitigate the reinforcing effects of psychomotor stimulants in animals. He and his colleagues examined the effectiveness of combining the selective dopamine transporter inhibitor RTI-336 with either of two serotonin transporter inhibitors, fluoxetine or citalopram, and found that cocaine self-administration was completely suppressed without affecting dopamine transporter occupancy (as measured by PET neuroimaging). Additionally, the reduction in self-administration with the drug combinations was greater than that of the RTI compound alone. Dr. Howell interpreted these findings to indicate that combined inhibition of the dopamine and serotonin transporters merits further study as a cocaine treatment medication. Howell, L.L., Carroll, F.I., Votaw, J.R., Goodman, M.M. and Kimmel, H.L. Effects of Combined Dopamine and Serotonin Transporter Inhibitors on Cocaine Self-Administration in Rhesus Monkeys. Journal of Pharmacology and Experimental Therapeutics, Online Published November 14, 2006.

Brain Reward Systems are Activated by Acute Nicotine and Produce Long-Lasting Increases in Reward Sensitivity

Changes in intracranial self-stimulation (ICSS) thresholds have been used to monitor the effects of drugs of abuse on brain reward systems: the lower the ICCS threshold after drug treatment, the greater the sensitivity to rewarding effects of the drug. NIDA grantee Dr. Athina Markou investigated the short- and long-term actions of nicotine consumption on the sensitivity of brain reward systems. Rats were first trained to lever press to receive ICSS. Two experimental groups were then given 1h or 12h access to intravenous nicotine for 20 consecutive days. ICSS thresholds were assessed before and after each nicotine self-administration session. After nicotine self-administration, ICSS thresholds were lowered (indicating increased sensitivity to reward) for 36 days in both 1h and 12h nicotine self-administration groups. Short-term effects of nicotine on reward thresholds were blocked by DH E, indicating that this effect is mediated by nicotine receptors. It is interesting to note that, unlike cocaine or morphine, access to nicotine did not result in escalation of drug intake, and decreases in reward sensitivity were not attenuated over time. These findings reveal that nicotine produces short- and long-term effects on reward hypersensitivity. Kenny, P.J. and Markou, A. Nicotine Self-administration Acutely Activates Brain Reward Systems and Induces a Long Lasting Increase in Reward Sensitivity. Neuropsychopharmacology, 31, pp. 1203-1211, 2006.

Gestational Nicotine Exposure Changes Basal Neuronal Activity in Areas Associated with Motivated Behavior

Dr. Frances Leslie and colleagues investigated whether nicotine, infused into a pregnant dam during gestation, would affect the neuronal response to acute nicotine during adolescence. One of three challenge doses of nicotine, or saline, was administered during postnatal days 38-40 (i.e., adolescence in the rat), and c-fos mRNA was used as a measure of neuronal activity. Gestational exposure to nicotine did not alter response to acute nicotine challenge during adolescence. The highest dose of acute nicotine challenge, however, did result in a significant increase in c-fos mRNA in the nucleus accumbens, the superior colliculus and the dorsolateral geniculate nucleus. Stress-sensitive areas of the lateral bed nucleus of the stria terminalis and the paraventricular nucleus also showed increased neuronal activity in response to acute nicotine. Two brain areas showed significant increases in c-fos mRNA as a result of gestational treatment, independently of nicotine challenge during adolescence: the infralimbic cortex and the nucleus accumbens core. These regions are important mediators of executive function and inhibitory control. These data suggest that gestational nicotine exposure results in long-term changes in neuronal activity, that it does not interact with acute adolescent exposure, but that the neuronal activity of adolescent rats can be significantly altered by a single, acute dose of nicotine. Park, M.K., Loughlin, S.E. and Leslie, F.M. Gestational Nicotine-Induced Changes in Adolescent Neuronal Activity. Brain Research, 1094, pp. 119-126, 2006.

Salvinorin-A, a Κ-Opioid Hallucinogen, Produces Time- and Dose-Dependent Neuroendocrine Effects

Salvinorin A is a potent kappa-opioid agonist in vitro and salvinorin A-containing products have been emerging as drugs of abuse for their hallucinogenic effects. NIDA researcher Dr. Eduardo Butelman recently tested the drug for kappa effects in vivo using serum prolactin levels as biomarkers of efficacy, and also cloned the Macaca mulatto (M. mulatto) OPRK1 gene, which codes for the kappa opioid receptor. He treated M. mulattos with salvinorin A, U69,593 (a kappa-agonist) or vehicle, followed by blood sampling at 5-120 minutes post-injection. Both kappa agonists produced robust, dose-and time-dependent increases in prolactin levels in males. U69,593 produced a longer-lasting effect; however the maximum effect and potency were the same as produced by salvinorin A. In females in the follicular phase, salvinorin A produced robust prolactin release. This was longer lasting, and had a faster onset than in males. In antagonist challenge studies the opioid antagonist nalmefene and/or the serotonin antagonist ketanserin was administered prior to a dose of salvinorin A. In both males and females, antagonist pretreatment with nalmefene produced robust antagonism of salvinorin A-stimulated prolactin release at the high, but not low, dose. Ketanserin produced no antagonism and did not affect prolactin levels, indicating that serotonin receptors were not involved. In these studies, salvinorin A was shown to be a potent kappa agonist, and was effective in both males and females. Butelman, E.R., Mandau, M., Prisinzano, T.E., Yuferov, V. and Kreek, M.J. Effects of Salvinorin A, a Κ-Opioid Hallucinogen, on a Neuroendocrine Biomarker Assay in Non-human Primates with High k-Receptor Homology to Humans. Journal of Pharmacology and Experimental Therapeutics, e-pub, 2006.

Subthreshold Smokers Experience Nicotine Withdrawal

Dr. Joseph DiFranza and colleagues investigated an understudied population of smokers: those who smoke 5 or fewer cigarettes per day, so-called "subthreshold" smokers. The first of two studies used a convenience sample of young adult smokers who met these criteria. Smokers were asked open-ended questions about their withdrawal experiences. Symptoms that were not specifically mentioned in the open-ended responses were further explored so that all 9 listed symptoms (craving, restless, irritable, anxious/nervous, difficulty concentrating, headache, sad/blue, angry, hungry) were considered. Time before symptom onset was also explored, as were strategies for coping with symptoms. Subjects reported on the 9 listed symptoms, as well as some additional ones (e.g., sensitivity to stress). All 36 subjects reported at least one withdrawal symptom, with 29 subjects reporting a specific set duration of abstinence that predictably resulted in the experience of withdrawal. Most reported symptoms within 1-2.4 days, with an average of a single cigarette providing relief. There was an inverse relationship between weekly cigarette consumption and the latency to withdrawal symptom onset. That is, the higher the weekly cigarette consumption, the faster the latency to symptom onset. There were no differences in the number of withdrawal symptoms between those subjects who previously smoked more than 5 cigarettes per day, and those who didn't. In a second study, secondary data analysis of findings from the 2004 NYTS, which surveyed over 27,000 individuals, aged 9-21 years old, was performed. Most of these subjects were subthreshold smokers (78.5%), and only these data were included in the secondary data analysis. These smokers were more likely to be intermittent, rather than daily, smokers. About half of the subjects reported craving, and most reported at least one withdrawal symptom, most notably restlessness and irritability. There was a negative correlation between monthly cigarette consumption and latency to 'need a cigarette'. Taken together, these studies suggest that although subthreshold smokers are often excluded from smoking studies, both children and adults with low rates of smoking experience withdrawal symptoms in a reliable, time-related manner. Fernando, W.W.S.A , Wellman, R.J., and DiFranza, J.R. The Relationship between Level of Cigarette Consumption and Latency to the Onset of Retrospectively Reported Withdrawal Symptoms. Psychopharmacology, 188, pp. 335-342, 2006.

Increases of Endogenous Cannabinoids Accelerate Extinction

Extinction of learned responses and behaviors is considered a form of inhibitory learning, rather than an unlearning of the original response. Recently, there has been considerable interest in developing pharmacotherapeutic approaches to enhance or accelerate extinction processes as a potential treatment for disorders such as phobias, post-traumatic stress, and drug abuse. Drs. Aron Lichtman, Stephen Varvel, and their colleagues have been investigating whether manipulations of the endogenous cannabinoid system can alter extinction of conditioned fear or spatial memory in the Morris water maze task. Previous studies have shown that disruption of signaling via the CB1 cannabinoid receptor impairs extinction of learned responses in these paradigms. Now, in this report, the investigators tested the hypothesis that elevating brain levels of the endogenous cannabinoid anandamide would potentiate extinction in the water maze task. They used two approaches to elevate anandamide levels: genetic deletion and pharmacological inhibition of its primary catabolic enzyme fatty-acid amide hydrolase (FAAH). FAAH (-/-) mice and mice treated with the FAAH inhibitor OL-135, did not display any memory impairment or motor disruption, but they did exhibit a significant increase in the rate of extinction. The CB1 receptor antagonist SR141716 (Rimonabant) delayed extinction when given alone (as they had previously shown), and blocked the effects of OL-135 on extinction. These results indicate that endogenous anandamide plays a facilitatory role in extinction through a CB1 receptor mechanism of action. In contrast, the primary psychoactive constituent of marijuana, _9-tetrahydrocannabinol, did not affect extinction rates, which suggests that FAAH is a more effective target than a direct acting CB1 receptor agonist, for facilitating extinction. These findings suggest that FAAH inhibition represents a promising pharmacological approach to treat psychopathologies characterized by an inability to extinguish maladaptive behaviors, such as post-traumatic stress syndrome, obsessive-compulsive disorder, and cue-induced relapse to drug seeking. Varvel, S.A., Wise, L.E., Niyuhire, F., Cravatt, B.F., and Lichtman, A.H. Inhibition of Fatty-Acid Amide Hydrolase Accelerates Acquisition and Extinction Rates in a Spatial Memory Task. Neuropsychopharmacology, [Oct 18, Epub ahead of print], 2006.

Dopamine Tone Affects the Motivation to Perform Goal-Directed Responses

Dopamine has been implicated in both learning and motivation. There are two general, not mutually exclusive, interpretations of dopamine function. One is that dopamine, particularly phasic dopamine release, facilitates reinforcement learning and stimulus-reward associations by providing a reward prediction error. The other is that dopamine enhances the energizing or motivating effect of reward or reward-predicting cues. This hypothesis predicts that dopamine modulates the expression of learned behavior by scaling the response to previously established associations. In the current study, Dr. Zhuang and his colleagues designed a genetic approach for manipulating dopamine signaling to address the question of whether dopamine can directly scale performance of a learned task in the absence of new learning. They developed an inducible dopamine transporter (DAT) knockdown mouse line in which they could reduce DAT expression, and thereby enhance tonic dopamine levels, without affecting phasic dopamine activity, as assessed by electrophysiology. The inducible knockdown allowed them to isolate the putative performance scaling effects of dopamine from learning effects by training the mice prior to inducing the genetic alteration. The knockdown was induced by giving the mutant mice doxycycline (Dox), which turned off the expression of the DAT gene. Three groups of mice were used for all behavioral testing: wild type mice, which were given Dox as a control, mutant mice given Dox to knockdown DAT, and mutant mice not given Dox as a genetic control group. For the first behavioral test, all mice were first trained on a progressive ratio schedule (PR7, where the number of lever presses increased by 7 after each food reward). Then half the mutant mice and all the wild type mice were fed Dox. Whereas prior to the Dox treatment, all groups exhibited similar numbers of lever presses, after treatment the mutant Dox group responded with almost twice as many presses. Importantly, this difference was seen only when the animals were food deprived; when they were sated, again all groups performed similarly. Then a concurrent choice task was used as a second behavioral measure. In this task, animals learn to press a lever (FR30 schedule) for a preferred food (chocolate-flavored pellets). On alternate days, they either obtained all their food by operant responding (no-choice condition), or by choosing between freely available regular chow and the chocolate pellets for which they had to work (choice condition). On no-choice days, and on choice days before Dox, all groups lever pressed about the same amount. But after Dox, the mutant animals with elevated dopamine again worked almost twice as hard as the others to receive the preferred food. These data provide evidence that dopamine directly scales behavioral performance on goal-directed tasks, in the absence of new learning. Cagniard, B., Beeler, J.A., Britt, J.P., McGehee, D.S., Marinelli, M., and Zhuang, X. Dopamine Scales Performance in the Absence of New Learning, Neuron, 51, pp. 541-547, 2006.

Repeated Cocaine Self-Administration Alters Processing of Cocaine-Related Information in Rat Prefrontal Cortex

Cocaine addicts persist in compulsive drug seeking in the face of known harm. The hypofrontality hypothesis suggests that long-term cocaine exposure reduces the ability of the prefrontal cortex (PFC) to control behavior. A more complex suggestion about PFC function in drug addiction is that lower basal activity may serve to amplify responses to drugs and drug conditioned stimuli, allowing them to exert greater control over behavior. Drs. Sun and Rebec carried out experiments in a rat animal model to examine changes in PFC activity after drug exposure. They monitored the electrophysiological activity of PFC neurons during three weeks of cocaine self-administration. Rats were trained to press a lever to self-administer cocaine in daily 2 hour sessions. In each session, basal activity was measured before the first infusion, and then activity in response to cocaine was measured throughout the session at a time point after each infusion when cocaine effects were maximal (10s), and after the associated environmental stimuli no longer influenced neuronal responses (a period of less than 1s, determined from previous experiments by these investigators). They analyzed the data by comparing neural activity from the first self-administration session with activity from sessions 10-12 and sessions 19-21. In the first self-administration session, the overall firing rate and burst rate of PFC neurons were significantly decreased after cocaine infusions relative to the period immediately before the session (i.e., the basal response). These effects disappeared after 10 days of drug self-administration and were replaced by a significant increase in burst duration and firing rate within a burst. However, the level of basal activity was significantly decreased after multiple weeks of cocaine exposure. These data support the view that repeated sessions of cocaine self-administration decrease basal PFC activity, but at the same time, burst-related firing in response to cocaine infusions is increased. Thus, the data are consistent with the hypothesis that processing of cocaine-related information is enhanced after chronic exposure and may contribute to increased control by cocaine over cocaine-seeking behavior. Collectively, these findings and others indicate that increased dopamine D1 receptor-mediated signaling in the PFC after chronic exposure to cocaine may be an important mechanism underlying compulsive cocaine seeking. Sun, W. and Rebec, G.V. Repeated Cocaine Self-Administration Alters Processing of Cocaine-Related Information in Rat Prefrontal Cortex. Journal of Neuroscience, 26, pp. 8004-8008, 2006.

Environmentally Enriched Conditions Reduce Impulsivity in an Animal Model

Rats reared in an enriched environment (EE) show enhanced cortical plasticity and improved learning. EE also protects against the development of drug abuse behavior in animal models of vulnerability such as i.v. self-administration. As socially isolated (SI) rats react more intensely to light and sound stimuli, they may more easily acquire self-administration because they are more emotionally responsive. A recent study by Dr. George Rebec suggests that either greater arousal, or impaired cognitive function, on the part of SI reared animals interferes with learning a complex appetitive task. In this study all rats were initially cross-fostered to a single mother to control for effects of rearing. At post-natal day 45, they were food deprived to 85% body weight and subjected to three sequential phases of an experiment as follows: Phase I. Associate licking sucrose from a spout with the feeder cue (tone + light). Phase II. Train contingent nose poke responses to elicit this feeder cue; when the light was illuminated animals could nose poke into either of two holes where sucrose was delivered and the tone was provided. Phase III. Only one nose poke hole was lit and nose pokes into that hole activated the feeder cue, followed by sucrose delivery. EE and SI animals showed no differences in learning during Phases I and II, but during phase III SI animals made significantly more "bad nose pokes" (in the incorrect hole) so their mean number of sessions to learn the task was significantly greater. As this group was not hyperactive in the task it appears that the difference is due to an inability to withhold anticipatory responses. In support of this interpretation, SI rats also performed more nose pokes during inter-trial intervals when sucrose was not available. SI and EE groups did not differ in consummatory behavior, as lick measures were no different during any part of the session. The investigators infer that for animals reared in SI conditions, salience of rewarding stimuli is increased and these animals are less able to inhibit approach responding. This interpretation is compatible with the previous finding of greater drug self-administration by SI animals. Wood, D.A., Siegel, A.K. and Rebec, G.V. Environmental Enrichment Reduces Impulsivity During Appetitive Conditioning, Physiology & Behavior, 88, pp. 132-137, 2006.

Adolescent Rats are Less Sensitive to Aversive Properties of Drug and Natural Rewards

Adolescence is a time when individuals are likely to initiate drug use. It is also known that whether the initial experiences are positive or negative can contribute to the likelihood of subsequent drug abuse. Recently, investigators using animal models to study reward sensitivity during adolescence have shown that, compared to older rats, younger rats are more sensitive to the rewarding effects of drugs and less sensitive to the aversive effects of withdrawal. Additional findings suggest that adolescent rats are less sensitive to the aversive properties of drugs such as nicotine and amphetamine. NIDA researcher Dr. Cynthia Kuhn and colleagues used conditioned taste aversion (CTA) procedures to examine developmental differences in aversive properties of cocaine and lithium chloride (LiCl). Male adolescent and adult rats were conditioned with 0.2% saccharin followed by saline, cocaine (10, 20 or 40 mg/kg), or LiCl (19 or 76mg/kg). All groups were also tested in an elevated plus maze for individual differences in anxiety, for response to novelty, and peripheral blood was collected for corticosterone. Cocaine aversions were significantly less in adolescent rats only for the 10 and 20 mg/kg doses. Adolescent rats were also less sensitive to LiCl aversions. Neither anxiety, response to novelty, or basal corticosterone predicted the magnitude of CTA to cocaine when conditioned with a single dose of 10 mg/kg. Multiple regression analysis of variables known to predict vulnerability to the reinforcing effects of drugs revealed a significant effect only for age. Thus, individual differences associated with vulnerability to the rewarding effects of drugs of abuse do not appear to influence cocaine's aversive properties. Separate animals were used to measure corticosterone stimulation with 15 mg/kg cocaine. As corticosterone was found to be significantly greater in adolescent rats than in adult rats, investigators suggest that differences in stress reactivity may be responsible for the diminished CTA seen in the adolescents. It is possible that protection from aversive experiences contributes to increased risk taking and greater impulsivity during adolescent development. Schramm-Sapyta, N.L., Morris, R.W. and Kuhn, C.M. Adolescent Rats Are Protected from the Conditioned Aversive Properties of Cocaine and Lithium Chloride, Pharmacology, Biochemistry and Behavior, 84, pp. 344-352, 2006.

Impulsivity in Methamphetamine Abusers is Correlated with Cognitive Impairment

Methamphetamine dependent individuals show impairments of verbal memory and cognitive inhibition. On the basis of these and other findings it has been argued that drug dependence is characterized by decreased response inhibition and heightened impulsivity. As impulsivity has been observed to predict relapse, it is important to understand the mechanisms of poor cognitive inhibition in drug abusers. Dr. Suzanne Mitchell and her collaborators have been using delay discounting to measure impulsivity in methamphetamine -dependent subjects recruited from treatment programs in Portland, Oregon. Prior studies with this procedure reveal that drug-dependent individuals compared to non-users show greater impulsivity by selecting small immediate rewards over larger delayed rewards. Forty-one subjects meeting DSM-IV criteria for methamphetamine dependence were rated for psychiatric symptoms and took battery of standard neuropsychological tests to assess cognition. Performance on the delayed discounting task was measured by "indifference point", the point at which preference switches from immediate to delayed rewards. Indifference points for a given reward value (e.g., $100) can be fit with an indifference curve that represents more impulsive choices by steeper gradients. Results indicated greater severity of psychiatric symptoms in chronic methamphetamine users, and that methamphetamine subjects were more rigid than controls. Severity of use, duration of use, average daily use and duration of abstinence were not correlated with these measures. Methamphetamine and control subjects differed on tests suggesting memory impairment in the methamphetamine group. Substantial group differences were seen in the extent to which subjects discounted delayed rewards. For all delays tested indifference points for the methamphetamine group were significantly less than for controls and methamphetamine gradients were significantly greater; thus, methamphetamine subjects discounted future rewards more. This measure was not related to use history, severity or time since last use. The researchers suggest that greater impulsivity seen in methamphetamine dependence may result from impairments of working memory. While increased working memory load does lead to greater impulsivity, it is also possible that methamphetamine subjects may differ from non-users in the incentive salience of rewards. Hoffman, W.F., Moore, M., Tamplin, R., McFarland, B., Hitzemann, R.J. and Mitchell, S.H. Neuropsychological Function and Delay Discounting in Methamphetamine-Dependent Individuals, Psychopharmacology, 188, pp. 162-170, 2006.

Sex Differences in Decision Making on the Iowa Gambling Task

On the Iowa Gambling Task subjects choose cards from four decks that provide monetary gains or monetary losses. Selections from two of the decks result in an overall net gain, but choices from the other two produce an overall net loss. Optimal performance requires the subject to identify and select from a low pay/low loss deck, and men typically select significantly more cards from these advantageous decks whereas women consistently choose more cards from disadvantageous decks with high penalties. Successful performance depends on integrity of the prefrontal cortex (PFC) and measurement of PFC activation during the task reveals that men activate bilateral areas of the dorsolateral PFC, right lateral orbital PFC, and right parietal lobe. By contrast, women activate a smaller region of the left medial orbital PFC. Recently, Dr. William Overman conducted a study to determine if a task known to activate dorsolateral PFC areas might improve IGT performance in women. One task that activates this region is deliberation of moral personal dilemmas. In the present study, 200 participants were divided into three groups and asked to contemplate a scenario every 10 trials - either a moral personal dilemma, a moral impersonal dilemma, or a nonmoral dilemma. Results show that sex differences on the Iowa Gambling Task were eliminated in groups contemplating PM whereas men in the other two conditions selected a significantly greater proportion of cards from advantageous decks than did the women. Finally, in order to test whether improvement might be due to generalized emotional arousal, another 229 students were tested after moral personal dilemma deliberation on a Wisconsin Card Sort Task that relies upon dorsolateral and dorsomedial PFC substrates. Wisconsin Card Sort Task scores were unaffected by moral personal dilemma deliberation suggesting that improvement by females on the Iowa Gambling Task is due to a shift in activation of PFC regions and enhanced cognitive control over an emotional response to rewards in the disadvantageous decks. Overman, W., Graham, L., Redmond, A. Eubank, R., Boettcher, L., Samplawski, O. and Walsh, K. Contemplation of Moral Dilemmas Eliminates Sex Differences on the Iowa Gambling Task. Behavioral Neuroscience, 120, pp. 817-825, 2006.

Cannabinoid Receptors Modulate Morphine Reinforcement through Ventral Pallidal GABA

Previous research has demonstrated that endogenous cannabinoid-1 (CB-1) receptors are involved in the reinforcing effects of opiates but not of the psychostimulant, cocaine. However, the mechanism responsible for this modulation is not known. Dr. Loren Parsons has been investigating the role of GABAergic transmission in the ventral pallidum (VP) and dopaminergic activity in the nucleus accumbens (NAS) in the ability of a CB-1 antagonist, SR 141716 (SR, or Rimonabant) to block heroin reinforcement. He tested SR effects on: 1) morphine decreases in VP GABA, 2) morphine increases in NAS dopamine, 3) cocaine decreases in VP GABA, 4) cocaine increases in NAS DA, 5) heroin (self-administration after SR infusion into the VP or NAS, and 6) cocaine self-administration after peripheral SR treatment. An additional study assessed effects of the CB-1 agonist, WIN 55,212, on VP GABA release and determined if the opiate mu antagonist, naloxone, could block WIN 55,212 effects. The investigator found that while SR blocked morphine-induced decreases in VP GABA, it was without effect on morphine-induced dopamine increase in the NAS. Conversely, SR had no effect on cocaine-induced decreases of VP GABA, and increases in NAS DA. SR infused centrally into the NAS but not the VP, attenuated heroin self-administration. Peripherally administered SR was without effect on cocaine self-administration. However, when SR was peripherally administered, it significantly decreased VP GABA and this effect could be blocked by prior naloxone administration. These findings suggest that CB-1 receptors modulate opiate, but not cocaine, reward by changing VP GABAergic activity. Since CB-1 antagonist infusions into the NAS decreased heroin self-administration, it appears that CB-1 attenuation of opiate reward is accomplished by altering GABA in the VP. The neural mechanisms by which NAS CB-1 receptors alter opiate-induced decreases of VP GABA are yet to be determined, but the authors speculate that cyclic-AMP, and/or changes in NAS glutamate, may be involved. Caille, S. and Parsons, L.H. Cannabinoid Modulation of Opiate Reinforcement through the Ventral Striatopallidal Pathway, Neuropsychopharmacology, 31, pp. 804-813, 2006.

Conditioned Psychostimulant Effects Are Moderated by Age and Sex

Individual differences in locomotor response to novelty predict the behavioral activating effects and self-administration of psychomotor stimulants. Rats that are more reactive in a novel environment (high responders, HR) show greater drug-induced stimulation and more readily acquire self-administration of amphetamine, cocaine, and nicotine, than their low-responding (LR) counterparts. Dr. Michael Bardo and colleagues recently completed a study to determine if individual differences in novelty response predict: 1) Locomotor sensitization to the psychostimulant, methylphenidate or 2) methylphenidate-conditioned locomotion in the drug-paired environment. Moreover, they sought to determine if novelty response would predict behavioral change differentially for male versus female rats and for adolescent (25 days old) versus adult (60 days old). A median split between HR and LR rats was based on locomotor counts and time spent in a novel compartment. Rats were then treated with saline, 3.0 or 10.0 mg/kg methylphenidate, for 10 days. After 14 days of withdrawal animals were assessed for conditioned locomotor activity with saline and for sensitization with a single 10.0mg/kg methylphenidate injection in the test cage. The investigators found: 1) adolescent rats selected novelty in a free choice situation significantly more than adults; however, choice did not predict methylphenidate sensitization or conditioning; 2) HR showed greater methylphenidate behavioral activation and adult females had greater dose-dependent activity than adult males; 3) Adolescent rats developed sensitization at 3.0 mg/kg METH, whereas adults only sensitized to 10 mg/kg; 4) only HR adult females had increased sensitization to 5) All animals showed a methylphenidate conditioned to the test environment except the adult males; 6) HR rats showed an greater methylphenidate conditioned locomotor activity but a HR>LR difference was only significant for adolescent males and adult females; 6) only HR adult feamlaes showed greater sensitization on the methylphenidate challenge. These findings suggest that: 1) Gender differences in sensitization emerge during development; 2) adolescent rats in general are more sensitive to psychomotor stimulant sensitization; 3) Initial response to novelty predicts methylphenidate -induced conditioned locomotion to the test chamber and sensitized behavioral response to methylphenidate; and 4) This individual difference is moderated by both age and gender. Wooters, T.E., Dwoskin, L.P. and Bardo, M.T. Age and Sex Differences in the Locomotor Effect of Repeated Methylphenidate in Rats Classified as High or Low Novelty Responders. Psychopharmacology, 188, pp. 18-27, 2006.

Escalation of Cocaine Self-Administration Is not Associated with Neuroadaptations in Dopamine Transporter

Neuroadaptations produced by continued cocaine exposure are believed to be important in the mechanisms underlying addiction. Investigators at the University of California in Santa Barbara recently sought to determine if extended access to cocaine resulted in alterations of the dopamine transporter (DAT). Rats were trained to self-administer 0.25 mg cocaine per infusion in daily 1 h sessions until their responding was stable. They were then assigned to 1 h or 6 h cocaine self-administration group for 8 consecutive days of cocaine self-administration, followed by 14 days of abstinence. Following the abstinence period, receptor autoradiography was used to quantify membrane DAT. Animals in the 6 h group showed significant increases in cocaine infusions over eight days, while 1 h access rats maintained steady intake. However, rats in the1 h condition showed higher densities of DAT in the nucleus accumbens core and the dorsal striatum, relative to rats not exposed to cocaine and rats exposed to cocaine for 6 h per day. There were no differences in DAT densities in the nucleus accumbens shell, the medial prefrontal cortex, or the ventral tegmental area among the groups. These findings suggest that escalation to uncontrollable cocaine intake is associated with different kinds of neuroadaptations than have been observed in pre-synaptic regions of the central dopamine system. Ben-Shahar, O., Moscarello, J.M. and Ettenberg, A. One Hour, but not Six Hours, of Daily Access to Self-Administered Cocaine Results in Elevated Levels of the Dopamine Transporter, Brain Research, 1095, pp. 148-153, 2006.

Menstrual Cycle Phase Effects on Nicotine Withdrawal and Cigarette Craving: A Review

Research over the past several years has uncovered numerous male-female differences in cigarette smoking. In studies of quitting, for example, women are less successful than men, and there is clinical and laboratory evidence that nicotine versus non-nicotine factors play a differential role in smoking for men versus women. The menstrual cycle has been shown to be a factor in smoking for women with several studies finding more smoking in the luteal phase (post-ovulation/premenstrual) of the cycle than in the follicular phase (menses/pre-ovulation). Researchers at the Medical University of South Carolina conducted a literature review to examine whether this higher level of smoking in the luteal phase reflects greater nicotine withdrawal and craving. Using MEDLINE and PsychInfo databases, a total of 13 studies were identified, of which 3 examined the naturalistic time course of withdrawal and craving under ad libitum smoking, 6 examined these measures under laboratory conditions of abstinence, and 4 conducted comparisons of the two conditions. The review yielded mixed results although there was evidence for greater withdrawal and craving in the luteal phase. The authors conclude that "the most striking implication from this review is the need for further research," noting that inconsistencies in outcomes among studies could be due to heterogeneity of methods including differences in statistical power to detect cycle effects, inconsistency in identification and corroboration of menstrual cycle phase, definition of cycle phase (two phases versus four-phases), and inclusion versus exclusion of women with a history of premenstrual dysphoric disorder. The authors recommend that future research in this area uses hormonal verification of menstrual phase status and follows a four-phase conceptualization: early follicular, late follicular, early luteal, and late luteal. This area of research has important clinical implications for choice of quit date for nicotine cessation and thus warrants future study. Carpenter, M.J., Upadhyaya, H.P., LaRowe, S.D., Saladin, M.E., and Brady, K.T. Menstrual Cycle Phase Effects on Nicotine Withdrawal and Cigarette Craving. A Review. Nicotine & Tobacco Research, 8, pp. 627-638, 2006.