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Director's Report to the National Advisory Council on Drug Abuse - February, 2005

Research Findings - Basic Behavioral Research

Environmental Enrichment Decreases DAT in the PFC, Concomitant with Sensitization of DAT-activated Locomotion

Rats reared in an enriched environment (EC), provided with social stimulation and novel objects, appear less fearful as adults and show different responses to psychomotor stimulants than animals reared in isolation (IC). EC animals have greater behavioral activation to amphetamine, but an attenuated sensitization with repeated drug treatment. They also have decreased drug intake when trained to self-administer i.v. amphetamine. The behavioral effects of EC rearing may be linked to neuroanatomical changes, as EC rats have increased cortical spine counts, dendritic length and branching, as well as greater numbers of synapses and synaptic buttons contacting dendritic spines and shafts. Drs. Michael Bardo, Linda Dwoskin, and colleagues at the University of Kentucky examined dopamine transporter (DAT) function in the prefrontal cortex (PFC) and subcortical mesolimbic regions of EC rats to determine if changes in central dopaminergic mechanisms might be responsible for different effects of d-amphetamine. EC versus IC conditions were in effect from post-natal days 21 through 53. After this time, all animals were tested for behavioral response to an acute dose of the DAT inhibitior GBR 12935, for sensitization to repeated DAT inhibition (seven GBR injections/14 days), and assays were performed for [3H] dopamine (DA) uptake, [3H]GBR 12935 binding, and DA, DOPAC concentrations. EC rats had lower basal levels of locomotion, but showed exaggerated behavioral stimulation to acute GBR, in comparison to the IC group. EC animals also showed significant sensitization of this effect after seven GBR injections, whereas the IC group did not. On neurochemical measures of central DA function, EC and IC groups did not differ on Ki values for GBR inhibition of DA uptake into synaptosomes of medial PFC (mPFC), striatum (STR) or nucleus accumbens (NAS). When kinetic parameters of DA uptake were determined, EC significantly decreased Vmax only in the mPFC, with no concomitant change in Km. To determine if EC induced decreases of Vmax were due to a decrease in number of DAT sites, saturation analysis of GBR binding was performed. However, no differences between Bmax or Kd were found for any brain area. Lastly, HPLC analysis of DA and DOPAC content revealed significant differences between EC and IC rats for DOPAC only in the mPFC, where this metabolite was lower in EC animals. The behavioral observations from this study parallel those reported for EC animals treated with acute amphetamine, but differ from those when EC animals have received repeated amphetamine, which is associated with attenuated sensitization. Different mechanisms of drug-induced DAT inhibition and DAT reversal may be responsible for these opposite effects. The findings reported here also suggest that EC may alter the dopaminergic substrate for behavioral effects of psychostimulants by decreasing DAT function and DA metabolism in the mPFC. A specific role for the mPFC in psychostimulant-induced behavioral effects is congruent with prior experimental evidence implicating PFC glutamatergic regulation of subcortical DA regions in the acute and chronic effects of these drugs. Zhu, J., Green, T., Bardo, M.T. and Dwoskin, L. P. Environmental Enrichment Enhances Sensitization to GBR 12935-induced Activity and Decreases Dopamine Transporter Function in the Medial Prefrontal Cortex. Behavioral Brain Research, 148, pp. 107-117, 2004.

Adolescent Rats Do Not Form Learned Associations Between Nicotine and Associated Environmental Cues

Eighteen percent of U.S. teens are smokers and recent preclinical, as well as epidemiological evidence, suggests that adolescents have a differential response to the drug nicotine than is seen in adulthood. Adolescent rats have been shown to be more sensitive to the locomotor activating effects of nicotine, but some studies reveal that they do not develop behavioral sensitization with repeated nicotine treatment. Neuroadaptations involved in the development of sensitization are believed to play a role in the escalation of drug intake that characterizes addiction. Drs. Charles Landry, Ann Kelley, and colleagues have also examined age-related differences in acute locomotor response to nicotine and the development of behavioral sensitization. Furthermore, they determined if there are differences between adolescent and adult rats in drug-paired cue conditioning. In these studies, conducted with male rats, adults were 70 days of age, and adolescents were 28-42 days old. To assess effects of acute nicotine, all rats were injected with 0.1 mg/kg s.c. and observed in photocell activity chambers after habituation. Adolescents were more active than adults in the test chamber upon their initial, non-drug exposure (habituation), and also when they were injected with saline or nicotine. Also, adolescent animals had a greater mean locomotor count after nicotine, compared to their saline-injected controls, for the first 20 min of the test session. Adult animals, however, showed a typical pattern of initial, behavioral suppression, followed by a rise in activity counts over the session. When given 10 days of 0.4mg/kg s.c. nicotine (Adoles/nic, Adult/nic) or saline (Adoles/sal, Adult/sal) paired with 90-min in a discrete environment, Adult/nic rats showed a significant linear trend for increased locomotor activity, but Adoles/nic rats did not. In tests for cue conditioning, rats from all four groups were given a mock injection and locomotor activity was again monitored in the test chamber for 90 min. Adult animals showed the usual conditioned locomotor activation, as ambulation was greater in the Adult/nic group than in Adult/sal animals. However, there was no difference in ambulatory counts between Adolescents from the nic versus the sal groups. The main finding from this study is that adolescents, (i.e., males), do not seem to develop the usual learned associations that are formed between effects of the drug nicotine, and surrounding environmental cues. In adults, incentive motivational properties of these cues are believed to serve as strong Ôtriggers' for activating and sustaining smoking behavior. The authors speculate that this difference might be linked to prolonged development of the prefrontal cortex, which continues through the adolescent period, and serves as an important substrate for central mechanisms of attention. Furthermore, in agreement with some earlier studies, the observation that adolescent rats fail to develop nicotine sensitization suggests that plasticity-related changes produced by repeated nicotine may be different from those previously measured in adults. Schochet, T.L., Kelley, A.E. and Landry, C.F. Differential Behavioral Effects of Nicotine Exposure in Adolescent and Adult Rats. Psychopharmacology, 175, pp. 265-273, 2004.

Sex Differences in the Escalation of Intravenous Cocaine Following Long- or Short-access to Self-administration

Drs. Megan Roth and Marilyn Carroll from University of Minnesota examined sex differences in the escalation of cocaine self-administration using a procedure similar to that previously reported with male rats (Ahmed and Koob, 1998;1999). This procedure is regarded as an animal model of the transition from drug use to addiction. Initially, rats were given access to cocaine either 6 hours/day (Long Access or LgA) or 1 hour/day (Short Access or Sh) for 21 days. This differential access phase was followed by a post-differential access phase in which all rats had 3 hours/day access to cocaine. As shown previously with male rats, Drs. Roth and Carroll found that for both sexes, in the differential access phase the LgA group self-administered more cocaine infusions than the ShA group. Moreover, they found that LgA females self-administered significantly more cocaine infusions than LgA males. In the post-differential-access phase in which all rats had 3 hours/day access to cocaine, and escalation from use to abuse was measured, LgA females self-administered more cocaine infusions than either LgA males, ShA males or ShA females. This study suggests that given opportunity, females will self-administer more than males and females are more sensitive than males to factors that contribute to the escalation of cocaine intake. Roth, M.E. and Carroll, M.E. Sex Differences in the Escalation of Intravenous Cocaine Intake Following Long- or Short-access to Cocaine Self-administration. Pharmacology, Biochemistry and Behavior, 78, pp. 199-207, 2004.

Morphine's Effects on Brain-Stimulation Reward Thresholds in Young and Aged Rats

There is a dearth of both human and animal research investigating whether there are changes in the rewarding properties of drugs as a function of age. There is evidence, however, that mu-receptor density decreases with age and that dopamine D1 and D2 receptors, which mediate the rewarding effects of mu opioids, also decrease with age. These changes raise the question of whether there are corresponding changes in the rewarding properties of the mu-receptor agonist morphine. This question was examined by Dr. Conan Kornetsky and his colleagues at Boston University using the brain-stimulation reward (BSR) procedure. It is well established that morphine and other abused drugs lower the threshold for BSR; however, the ability of an abused drug to alter the threshold for BSR has not been previously reported as a function of age. In the present experiment, the researchers compared the threshold for BSR (delivered into the lateral hypothalamic region of the medial forebrain bundle) and the ability of morphine to lower the BSR threshold in aged (24 months) and young (5-month) rats. The results indicated that while the older rats had a significantly lower baseline threshold for BSR, morphine produced a similar lowering of the BSR threshold in the two groups. These results suggest that the rewarding effect of morphine does not diminish with age, but rather is preserved. This lack of change in morphine's rewarding effects with age, despite evidence of decreases in opioid receptor density and compromises of the mesolimbic dopaminergic systems with age, warrants further investigation. Jha, S.H., Knapp, E.M. and Kornetsky, C. Effects of Morphine on Brain-Stimulation Reward Thresholds in Young and Aged Rats. Pharmacology, Biochemistry and Behavior, 79, pp. 483-490, 2004.

A New Invertebrate Model System for Investigating the Reinforcing Properties of Psychostimulants

Recent studies in the invertebrate genetic model organism, the fruit fly, suggest that such model systems can be useful for studying molecular, biochemical, and behavioral aspects of drug addiction. However, studies of motivational and learning processes, which are typical of mammalian responses to drugs of abuse, are difficult to carry out in fruit flies. Dr. Robert Huber has therefore begun exploring the use of crayfish as an invertebrate model for measuring the rewarding properties of psychostimulants. The crayfish provides a well-studied neurobiological model system, with a nervous system containing fewer than 1000 individually identifiable, monoamine-containing neurons. Thus, this invertebrate system may serve as a unique model for studying the primary site of action of psychostimulant drugs. In his report, the first set of experiments demonstrated that intramuscular injections of cocaine and amphetamine have robust and distinguishable effects on crayfish behavior. Cocaine produced a rigid flexed body posture, even at low doses, whereas amphetamine caused an exploratory response, sometimes interrupted by grooming bouts. Thus, the effects of amphetamine on crayfish behavior appeared more analogous to those reported for mammals. In the second part of the study, the reinforcing properties of psychostimulants were tested in a series of conditioned place preference (CPP) experiments. The animals were allowed to move freely in an aquarium with two distinct types of floor designs. They were fitted with cannulae so that drugs could be delivered when they were in one or the other of the environments, in a balanced design across animals. Amphetamine, and to a lesser extent cocaine, both produced a CPP. That is, when tested after conditioning, animals spent significantly more time in the drug-paired environment. These results extend studies in other invertebrates to demonstrate that psychostimulants have reinforcing effects on crayfish behavior and suggest that crayfish can provide a complementary approach to using other invertebrate species in addiction research. These findings also support the hypothesis that the fundamental neurobiological alterations involved in drug reinforcement and perhaps addiction may be evolutionarily ancient. Panksepp, J.B. and Huber, R. Ethological Analyses of Crayfish Behavior: A New Invertebrate System for Measuring the Rewarding Properties of Psychostimulants. Behavioural Brain Research, 153, pp. 171-180, 2004.

A Non-human Primate Model of the Behavioral and Physiological Effects of Childhood "Stress Inoculation"

Retrospective studies of resilience in humans have indicated that childhood exposure to moderate stress serves to "inoculate" against subsequent stressful experiences and to enhance coping skills that safeguard against the development of stress-related disorders in adolescence and adulthood. Dr. David Lyons and his colleagues have tested this hypothesis in a prospective study on squirrel monkeys. Twenty monkeys were randomly assigned to either intermittent stress inoculation (IS) or a nonstress control condition (NS) for 10 weeks, starting at postnatal week 17 when they had just been weaned but were still emotionally attached to their mothers. For the IS, individual monkeys were removed from their natal group for one hour once a week and placed in a cage adjacent to an unfamiliar adult. This separation induced isolation calls, locomotor agitation, and an increase in cortisol that returned to baseline soon after reunion with the family. At postnatal week 35, each mother-offspring dyad underwent testing in a moderately stressful novel environment to assess offspring anxiety and stress hormone concentrations. At postnatal week 50, after acclimation to an initially stressful wire-mesh box attached to the home cage, the young monkeys were tested for voluntary exploration and play in the box as an inferential measure of anxiety. In the novel environment test, IS compared with NS offspring demonstrated diminished anxiety as measured by decreased maternal clinging, enhanced exploratory behavior, and increased food consumption. IS offspring also had lower basal plasma ACTH and cortisol and lower post-stress corticoptropin and cortisol levels. In the home-cage wire-box test, IS offspring showed enhanced exploratory and play behaviors compared with NS offspring. This study is the first prospective evidence in non-human primates that moderately stressful early experiences strengthen socioemotional and neuroendocrine resistance to subsequent stressors. Dr. Lyons is pursuing studies with this model to investigate resistance to the effects of drugs of abuse, in contrast to models of chronic stress. Additionally, this preclinical model of stress inoculation will be used to elucidate the etiology and neurobiology of stress resistance. Parker, K.J., Buckmaster, C.L., Schatzberg, A.F. and Lyons, D.M. Prospective Investigation of Stress Inoculation in Young Monkeys. Archives of General Psychiatry, 61, pp. 933-941, 2004.

Studies in Animal Models of Psychiatric Illness Used to Test Hypotheses about Co-morbidity with Drug Abuse

Co-morbidity of substance abuse disorders (SUDs) and other psychiatric illnesses is extremely common. The self-medication hypothesis - that people abuse drugs to control symptoms of their mental illness - is often invoked to explain this co-morbidity, but an alternative explanation is that the neuropathology responsible for psychiatric illnesses also increases the vulnerability for SUDs. Dr. Andrew Chambers has been testing this hypothesis in rat models. Rats with neonatal lesions of the ventral hippocampus (NVHL) exhibit a behavioral syndrome that models multiple features of schizophrenic symptomatology including positive symptoms that can be ameliorated with neuroleptics, negative symptoms, and concomitant cognitive deficits. In earlier studies in collaboration with Dr. David Self, Dr. Chambers showed that NVHL rats, compared to controls, have accelerated acquisition of cocaine self-administration, a greater propensity to binge during maintenance, a resistance to extinguish drug seeking, and greater relapse behaviors. In a recent study in collaboration with Dr. Jane Taylor, Dr. Chambers further tested drug responsivity in NVHL rats by assessing locomotor sensitization to cocaine in adulthood. NVHL animals showed greater activity in response to an initial cocaine injection compared with sham-lesioned and saline-treated groups, and they had elevated locomotor sensitization curves in response to daily cocaine injections over 7 days. In a single session 4 weeks later, NVHL continued to show cocaine-induced locomotor responses to cocaine which were higher than those of sham-lesioned animals. This altered pattern of sensitization in NVHL animals suggests that SUD vulnerability may arise from the same pathophysiological mechanisms that are responsible for schizophrenic symptomatology. In a second study, they performed similar experiments in rats with olfactory bulbectomies (OBX). This lesion model has been suggested to mimic many features of clinical affective disorders, as it produces behavioral abnormalities that include abnormal social interactions, increased aggression, and abnormal responses to fear-inducing or novel stimuli. In addition, OBX animals have alterations in limbic structures thought to be critical in the pathophysiology of affective disorders, and the behavioral symptoms are responsive to chronic, but not acute, antidepressant treatment. OBX animals also have an increased propensity to self-administer amphetamine. To further investigate whether OBX might serve as a useful model for studying the neuropathology of dual diagnosis disorders, Dr. Chambers and his colleagues studied locomotor activity in OBX rats in response to novelty and after acute and repeated injections of cocaine. Lesioned animals showed greater locomotor activity in response to a novel environment and significantly heightened locomotor activation upon initial cocaine exposure. However, over 7 days of repeated cocaine injections, OBX animals did not increase their response to cocaine, suggesting that they are "presensitized" - that is, their response is already at such a high level that it does not increase with repeated psychostimulant treatment (as is typically seen in non-lesioned animals). These studies and previous work by these investigators and others demonstrate that NVHL and OBX models involve perturbations of the neurobiological substrate responsible for the behavioral effects of drugs of abuse. The studies also support the potential utility of these models for studying neurobiological mechanisms involved in co-morbidity. Chambers, R.A. and Taylor, J.R. Animal Modeling Dual Diagnosis Schizophrenia: Sensitization to Cocaine in Rats with Neonatal Ventral Hippocampal Lesions. Biological Psychiatry, 56, pp. 308-316, 2004; Chambers, R.A., Sheehan, T., and Taylor, J.R. Locomotor Sensitization to Cocaine in Rats with Olfactory Bulbectomy. Synapse, 52, pp. 167-175, 2004.

Behavioral Correlates of Synaptic Potentiation in the Ventral Tegmental Area

In previous studies, the laboratories of Dr. Antonello Bonci and Dr. Robert Malenka showed that single injections of drugs of abuse potentiate excitatory input to the VTA by increasing synaptic currents through AMPA glutamate receptors. In two recent studies, they examined the behavioral correlates and other features of this synaptic enhancement. In one study from Dr. Bonci's laboratory, the researchers examined correlations between amount of synaptic enhancement and drug-induced locomotor activity or stereotypy after single and repeated injections of cocaine. Glutamatergic synaptic enhancement was positively correlated with locomotor activity and stereotypy after single injections, but there was no further increase in synaptic potentiation after seven days of injections, nor was the amount of potentiation correlated with the degree of behavioral sensitization produced by multiple injections. These results suggest that cocaine-induced synaptic plasticity at VTA excitatory synapses is transient and depends upon the last cocaine injection (i.e., it is not influenced by previous history of cocaine exposure). The authors propose that cocaine-induced locomotor activity in na•ve animals reflects motivational effects of the drug, and that the correlated synaptic plasticity is involved in the formation of associations between drug-paired cues and these motivational effects. Another study, from Dr. Malenka's laboratory, combined behavioral and molecular approaches. In this study, the investigators demonstrated that cocaine-induced synaptic enhancement involves an up-regulation of AMPA receptors, and that the receptor subunit GluRA is necessary for this upregulation. Thus, synaptic enhancement was not seen in GluRA(-/-) mice. GluRA(-/-) mice did, however, show behavioral sensitization with repeated injections of cocaine, indicating that synaptic potentiation in the VTA is not necessary for the induction of sensitization. Next, the investigators tested GluRA(-/-) mice in two cocaine-conditioned behaviors. The mice did not show a conditioned locomotor response when exposed to a context previously paired with cocaine, nor did they exhibit a preference for environments where cocaine was administered (i.e., a conditioned place preference). The authors suggest that drug-induced enhancement of excitatory synaptic transmission in midbrain DA neurons, although not required for behavioral sensitization, may contribute to the development of incentive motivation with drug-associated cues. The results of these two studies elucidate cellular mechanisms underlying drug-induced excitatory enhancement in the VTA and the role of synaptic potentiation in specific drug-induced behaviors. Borgland, S.L., Malenka, R.C. and Bonci. A. Acute and Chronic Cocaine-induced Potentiation of Synaptic Strength in the Ventral Tegmental Area: Electrophysiological and Behavioral Correlates in Individual Rats. Journal of Neuroscience, 24, pp. 7482-7490, 2004; Dong, Y., Saal, D., Thomas, M., Faust, R., Bonci, A., Robinson, T. and Malenka, R.C. Cocaine-induced Potentiation of Synaptic Strength in Dopamine Neurons: Behavioral Correlates in GluRA(-/-) Mice. Proceedings of the National Academy of Sciences U.S.A, 101, pp. 14282-14287, 2004.

Glutamate-associated Plasticity in the VTA is Necessary for the Acquisition and Expression of Morphine Conditioned Place Preference

The mesocorticolimbic dopamine (DA) system has long been implicated in reinforcement involved in drug abuse, but more recent research has focused on the role of DA in learning and motivation for drug-related conditioned behaviors, including drug-induced place conditioning. In this study, Drs. Glenda Harris and Gary Aston-Jones and colleagues asked whether neural plasticity in the glutamatergic inputs to VTA is involved in associating environmental stimuli with morphine reinforcement. Opiates increase DA release from the VTA by suppressing inhibitory inputs to the DA neurons, while conditioned environmental stimuli are thought to excite DA neurons via glutamatergic afferents. Previous studies have shown that these glutamatergic inputs are enhanced when an animal is exposed to opiates, and in other brain systems, glutamatergic synaptic enhancement is known to depend on activation of cAMP-dependent protein kinase A (PKA). Thus, the investigators tested whether activation of the glutamate receptors and protein kinase A is needed for acquisition and expression of a morphine-conditioned place preference (CPP). Rats were given focal, bilateral microinjections of either the NMDA antagonist AP5, the AMPA antagonist CNQX, or vehicle into the VTA prior to each of three morphine-conditioning sessions. Both the AMPA and NMDA receptor antagonists blocked the development of morphine CPP. A PKA inhibitor also blocked the acquisition of morphine CPP when given into the VTA immediately after morphine conditioning. In separate experiments, microinjections of glutamate antagonists or the PKA blocker given immediately prior to the preference test blocked expression of morphine CPP. Although these studies did not directly measure synaptic plasticity in the VTA, the necessity of NMDA and AMPA receptor activation, and involvement of the second messenger PKA, strongly implicate synaptic enhancement in morphine CPP. These data suggest that the VTA is an important site for synaptic modifications involved in the learning and memory of environmental cues predicting drug reward. Harris, G.C., Wimmer, M., Byrne, R., Aston-Jones, G. Glutamate-associated Plasticity in the Ventral Tegmental Area is Necessary for Conditioning Environmental Stimuli with Morphine. Neuroscience, 129, pp. 841-847, 2004.

Impulsivity and Relapse to Smoking

Individual differences in some personality traits increase susceptibility for relapse to smoking. NIDA supported researcher, Dr. Dennis McChargue, studied the effect of trait impulsivity on abstinence maintenance, or its failure, relapse. Trait impulsivity is defined as a long-standing preference for readily available rewards, coupled with difficulty delaying or resisting response to such rewards. Previous research has shown that trait-impulsive people are initially drawn to use cigarettes for their rewarding properties, but little is known about how impulsivity affects smoking cessation. The roles of craving, positive and negative affect were also studied for their effect on relapse. The present research was part of a larger study designed to test the efficacy of a 1-day workshop intervention to promote tobacco abstinence. Workshops focused on training participants in the use of smoking cessation and mood management skills. Following the workshop, participants were paid to quit smoking for 48 hr. Relapse status was assessed at 24 and 48 hr post-quit and at four weekly follow-up sessions. Breath samples were analyzed for carbon monoxide (CO) and saliva samples were analyzed for cotinine. Participants were judged to have relapsed if they reported any amount of smoking on 7 consecutive days or any smoking in each of 2 successive weeks. Participants also were considered to have relapsed if they reported abstinence but had Ecolyzer values great than 10 parts per million CO or cotinine values greater than 20ng/ml. Results indicated that more impulsive participants relapsed more quickly than less impulsive participants. That is, smokers with higher levels of trait impulsivity had greater difficulty maintaining abstinence than those with lower levels. However, there was no relation between relapse and either craving, or positive or negative affect. That is, the adverse effect of impulsivity on abstinence was not attributable to heightened craving or to negative affect or to decreased positive affect. These findings suggest that processes other than craving and affective changes may account for an impulsive smoker's difficulty maintaining abstinence. One possible explanation is that rewarding environmental stimuli, including cigarettes, may be especially salient for impulsive smokers, making such stimuli difficult to ignore and prompting responses to smoking- related cues. Doran, N., Spring, B., McChargue, D., Pergadia, M. and Richmond, M. Impulsivity and Smoking Relapse. Nicotine and Tobacco Research, 6, pp. 641-647, 2004.

Cannabinoids and Opioids Interact To Reduce Heroin Self Administration In Rats

Interactions between cannabinoid and opioid systems have important implications for addictive behaviors. In recently completed research, George Koob and his colleagues tested the effect of a cannabinoid CB1 receptor antagonist (SR141716A, 0.03 - 3.0 mg/kg) on heroin (0.03 mg/kg/infusion) self-administration in dependent and non-dependent rats. The investigators compared both dependent and non-dependent animals because it has been hypothesized that drug abuse in the non-dependent individual is motivated by primary reinforcing properties of the drug, whereas the opiate intake by the dependent abuser appears motivated by negatively reinforcing effects of relief from aversive withdrawal symptoms. In this study, rats were trained to self-administer heroin and were then tested for the effects of SR141716A. Following tests at 5 doses of the SR compound, animals were implanted with two morphine pellets, allowed to self-administer heroin and then the dose-response function for SR141716A was re-established. The results indicated that in morphine dependent animals, but not in their non-dependent counterparts, SR141716A at the 3.0 mg/kg dose suppressed heroin self-administration. This differential response to cannabinoid CB1 receptor antagonist in non-dependent and dependent conditions may have a neuropharmacological basis in recently described changes of cannabinoid receptor expression after chronic opioid exposure. Moreover, these results encourage further study of the potential role of cannabinoid CB1 receptor antagonists for the treatment of opiate addiction. Navarro, M., Carrera, M.R.A., del Arco, I., Trigo, J.M., Koob, G.F., de Fonseca, F.R. Cannabinoid Receptor Antagonist Reduces Heroin Self-Administration Only in Dependent Rats. European Journal of Pharmacology, 501, pp. 235-237, 2004.

Greater Vulnerability for Relapse in Rats Provided with Long Access Cocaine Self-administration: Relation to Dopamine D2 mRNA

Rats given an opportunity to self-administer cocaine (coc) for 6 hr/day show an escalation of drug intake over days, whereas those self-administering for 1 hr/day have steady rates of daily intake. Drs. Mary Jeanne Kreek, John Mantsch and colleagues recently examined whether drug escalation predicts vulnerability to relapse in a reinstatement model. They also assessed mRNA for dopamine D2 receptors in the caudate-putamen nuclei and nucleus accumbens (NAS). Central D2 receptor substrates have been related to the reinforcing effects of psychostimulants and are altered with long-term coc administration. Animals were divided into three groups: One short-access group (SAc), and two long-access groups (LAc). All groups were trained to bar press for 0.5 to 2mg/kg/infusion i.v. coc in multi-dose sessions until the groups were performing similarly. Over the next 14 days, all animals continued to be tested in this multi-dose procedure for 1 hr/day, but then the SAc rats remained in the chambers for 7 more hours with no drug available. LAc groups were also tested for 1 hr with the multi-dose procedure, but a LAc-Low dose group (LAc-L) continued to self-administer 0.5 coc for the next 7 hr, while a LAc-High dose group (LAc-H) continued to self-administer 2.0 coc; thus, all animals remained for 10 hr/day in the self-administration chamber. Extinction sessions and two tests of reinstatement, with 0.5, and 2.0mg/kg priming doses of coc, followed. Immediately after the second reinstatement test, animals were sacrificed for mRNA. Over these 14 days, SAc rats showed a slight increase in daily mg/kg coc intake by day 12. LAc-L rats also took more coc during the end of this two week session; in fact, significantly more by day 11. But LAc-H rats showed a steady increase in drug intake over days that was significantly greater, by the 5th session, than the daily dose of cocaine self-administered on day one. While SAc rats reinstated after priming with a single i.v. dose of 2.0 mg/kg, LAc-L animals reinstated with priming doses of either 0.5 or 2.0 mg/kg coc. Statistically significant reinstatement (versus vehicle response means) could not be demonstrated for the SAc-H group due to high inter-subject variability; however, this group had mean bar press rates on the active lever, (previously associated with coc delivery), that were two to three times greater than those of the SAc or LAc-L groups. Furthermore, overall reinstatement responses (two priming doses collapsed) were significantly greater in the LAc-H group when compared to SAc rats. Although not statistically different in an overall analysis, D2 receptor mRNA in the NAS was two times greater for LAc-H rats than for SAc animals (0.92 vs. 0.47 pg/ug total RNA), with values for LAc-L falling in between. Multiple regression analyses revealed that cocaine reinstatement (at the 0.5 dose) was related to D2 mRNA, when this measure was collapsed over the two brain regions. In this study, access and coc dose affected daily intake in a self-administration paradigm, and greater mg/day intake predicted greater reinstatement with cocaine priming. Although differences in D2 receptor mRNA do not necessarily result in increased functional protein, previous studies have shown that D2 agonists can precipitate reinstatement. Thus, the present relationship between the mRNA for D2 receptors and reinstatement supports an important role for the D2 site in compulsive drug taking behavior. Mantsch, J.R., Yuferov, V., Mathieu-Kia, A.-M., Ho, A. and Kreek, M.J. Effects of Extended Access to High Versus Low Cocaine Doses on Self-administration, Cocaine-induced Reinstatement and Brain mRNA Levels in Rats. Psychopharmacology, 175, pp. 26-36, 2004.

Substitutes for Tobacco Smoking: A Behavioral Economic Analysis

Researchers from the University of Vermont recently examined smokers' preference for cigarettes, nicotine gum, and nicotine-free cigarettes using a behavioral economic design. In a series of experiments cigarette-deprived smokers responded on a lever to receive puffs from a cigarette. As the number of lever presses per puff increased, or "price" per puff increased, smoking decreased indicating what economists refer to as elastic demand for cigarette puffs. In separate studies when either nicotine gum or a nicotine-free cigarette was also available, cigarette puff decreased more, suggesting that these two commodities serve as "substitutes" for cigarettes. It is not surprising that nicotine gum can substitute for cigarette smoking as this experiment and other previous clinical research have shown. What is surprising is nicotine-free cigarettes can also reduce smoking of nicotine cigarettes. While it is widely believed that people smoke to obtain the reinforcing effects of nicotine, it is now becoming evident that the "non-pharmacological" aspects of smoking are also reinforcing. This finding is in line with recent pre-clinical animal nicotine self-administration data showing that rats previously trained to press a lever to obtain nicotine in the presence of a light stimulus-cue will also respond to turn on the light without a nicotine infusion. These data further indicate that by virtue of the light being "paired" with nicotine, the light is now desirable. Similarly for the tobacco smoker, other aspects of smoking when paired with nicotine intake may become desirable as well. Taken as a whole, these results show that both pharmacological and non-pharmacological factors can maintain cigarette smoking, and that both factors need to be considered when treating tobacco addiction. Johnson, M.W., Bickel, W.K. and Kirshenbaum, A.P. Substitutes for Tobacco Smoking: A Behavioral Economic Analysis of Nicotine Gum, Denicotinized Cigarettes, and Nicotine-containing Cigarettes. Drug and Alcohol Dependence, 74, pp. 253-264, 2004.


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