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Director's Report to the National Advisory Council on Drug Abuse - February, 2010

Research Findings - Basic Behavioral Research

Cellular Mechanisms of Corticostriatal Plasticity and Associated Striatal-Dependent Learning

Adenylyl cyclase 5 (AC5), the enzyme that catalyzes cAMP production, is essential for induction of long-term potentiation. AC5 couples glutamate-mediated increases in calcium to cAMP accumulation, and has been successfully knocked out in AC5 KO mice. Jeff Beeler and colleagues used this genetically altered mouse to examine the contribution of cAMP to corticostriatal plasticity and dorsal striatum-dependent learning. Water cross maze performance was used to evaluate dorsal striatal-dependent response learning. In the water cross maze task, wildtype (WT) and knockout (KO) mice were trained to find a submerged hidden platform using an egocentric response strategy (e.g. making the same body turn on each trial to find the goal arm). The KO mice took significantly longer to learn this task as compared to WT mice. This does not appear to be a global learning deficit, as there was no significant difference between WT and KO performance on the Morris water maze, in which the mice find a hidden platform using spatial cues. Performance on an accelerating rotorod was used to evaluate corticostriatal plasticity in motor learning. Although initial performance was comparable, the WT mice improved their performance over the first day's trials (4 trials/day) whereas the KO mice did not. This resulted in significant differences between the groups after 3 days of testing. The difference was not due to general locomotion, as 3 days of locomotor activity testing revealed no group differences. Involvement in cAMP signaling in the corticostriatal long-term depression (LTD) was evaluated using electrophysiological and electrochemical recordings. AC5 KO mice exhibited larger miniature excitatory post synaptic current (mEPSC) amplitudes, likely due to an increased density of AMPA and NMDA receptors, as there were no differences in AMPA to NMDA ratios. Long-term potentiation (LTP) was induced by pairing high-frequency electrical stimulation of glutamatergic afferent fibers with post-synaptic depolarization. In tissue slices from AC5 KO mice, although there was some heterogeneity, there was no overall induction of LTP. To investigate whether this deficit was due to presynaptic deficits, a cannabinoid 1 (CB1) agonist was applied. Tissue slices from both KO and WT mice exhibited robust excitatory post synaptic currents (EPSCs). Application of a mGluR agonist to elicit dopamine-independent endocannabinoid-mediated LTP also elicited LTP in both KO and WT tissue slices. Thus, there was no difference in endocannabinoid-mediated LTP. In summary, the behavioral deficits were correlated with deficits in LTP in the dorsal striatum. These deficits in LTP could be rescued by activation of the endocannabinoid system, suggesting that AC5 regulation of cAMP production during LTP induction facilitates endocannabinoid release and activation of presynaptic CB1 receptors, to suppress glutamatergic signaling. These findings provide insight into the molecular mechanisms underlying development of plasticity (LTD and LTP) in the dorsal striatum and to the dopaminergic regulation of this plasticity via an AC5-cAMP-endocannabinoid-CB1 pathway. Kheirbek MA, Britt JP, Beeler JA, Ishikawa Y, McGehee DS, Zhuang X. Adenylyl cyclase type 5 contributes to corticostriatal plasticity and striatum-dependent learning. J Neurosci. 2009; 29:12115-12124.

Alpha6 Receptor Subunit is Involved in Nicotine Reward and Affective Changes during Nicotine Withdrawal

The alpha6 (a6) nicotinic receptor subunit has recently been found to play a role in nicotine-induced locomotor activity and reinforcement. In the current study, Darlene Brunzell sought to expand on these recent findings demonstrating that mice lacking the a6 subunit fail to self-administer nicotine. However, nicotine is self-administered by mice after restoration of this subunit in the VTA via lenti-viral re-expression. Using a selective a6 antagonist alpha-conotoxin as a pharmacological blockade, Dr. Brunzell and colleagues further examined the role of this subunit in the pharmacological and behavioral effects of nicotine. They employed a battery of behavioral tests, including tail flick and hot-plate tests for analgesia, measures of locomotor activity, conditioned place preference, and the elevated plus maze. Pretreatment with alpha-conotoxin prevented the expression of nicotine conditioned place preference. Affective and somatic signs of withdrawal were assessed following chronic infusion of nicotine with a osmotic mini-pump. Nicotine-withdrawn mice show anxiety (spend less time in the open arms of a plus maze) and decreased latencies on the hot-place (withdrawal-induced hyperalgesia). Pretreatment with the a6 antagonist blocked affective (anxiety, measured on the plus maze), but not physical (including hyperalgesia), signs of nicotine withdrawal. Under conditions of continuous nicotine infusion (animals in which osmotic pumps were not removed), administration of the a6 antagonist did not precipitate withdrawal. Administration of mecamylamine, a nicotinic receptor antagonist, did precipitate withdrawal, as evidenced by the development of a significant conditioned taste aversion (CTA). The CTA could be blocked by some doses of the a6 antagonist. Taken together, these data suggest that a6-containing subunits play a critical role in nicotine's rewarding effects following chronic nicotine administration. Therefore, blocking a6 subunits may provide a novel target for treating nicotine addiction, and may be particularly useful for alleviation of the negative withdrawal symptoms. Jackson KJ, McIntosh JM, Brunzell DH, Sanjakdar SS, Damaj MI. The role of alpha6-containing nicotinic acetylcholine receptors in nicotine reward and withdrawal. J Pharmacol Exp Ther. 2009; 331(2):547-54. Epub 2009 Jul 30.

Differential Involvement of Ventral Tegmental Area in Motivated Maternal Behavior Versus Cocaine-Conditioned Reinforcement

In rats, as well as every other mammalian species, females demonstrate a remarkable motivation to seek out and interact with unique natural stimuli, such as offspring. In addition, female rats are also highly responsive to pharmacological stimuli, such as cocaine, and are consistently more motivated to seek out and consume drugs of abuse compared with their male counterparts. Motivated behaviors directed toward natural and drug stimuli are mediated by an extended, overlapping neural circuitry that includes the ventral tegmental area (VTA) and its ascending mesocorticolimbic projections. Limited research has explored how discrete components of this extended circuit participate in females' motivation to seek out natural and/or drug stimuli and the contexts that predict them. Thus, it remains unclear whether intact VTA function is necessary for female motivated behavior to seek contexts repeatedly paired with natural stimuli and/or pharmacological stimuli. In this study, conditioned place preference (CPP) was induced with highly salient natural or drug stimuli attributed with strong incentive-motivational value in each of two paradigms: (1) Postpartum females were conditioned to associate one unique context in the CPP apparatus with young offspring (pups) and a second context with a neutral stimulus, and (2) virgin females were conditioned to associate unique contexts with either cocaine (5 mg/kg ip) or saline injections. Immediately before CPP testing, each female received a microinfusion of bupivacaine bilaterally into the VTA to transiently inactivate the region; control subjects received a saline microinfusion. In postpartum females, VTA inactivation prevented pup CPP. Additionally, it disrupted select maternal behaviors, including reduction of anogenital licking of pups, and extended latencies to retrieve all pups to the nest, hover over them, and assume a low crouch position over them, suggesting that in postpartum females, intact VTA function is required for the expression of both pup CPP and motivated pup-directed behaviors. Neither cocaine CPP nor locomotion was affected by VTA inactivation. The researchers concluded that the VTA is differentially involved in the expression of conditioned preference for contexts paired with pups, a salient natural stimulus, and contexts paired with cocaine. Seip KM, Morrell JI. Transient inactivation of the ventral tegmental area selectively disrupts the expression of conditioned place preference for pup- but not cocaine-paired contexts. Behav Neurosci. 2009;123:1325-1338.

Two-Phases of Drug-Induced Microglia Migration May Be Involved in Undesirable Effects of Morphine Therapy

Research conducted with animal behavioral models demonstrate that microglia play a critical role in chronic pain and opioid-induced hyperalgesia. The present study, conducted by Drs. Ryan Horvath and Joyce DeLeo (Dartmouth Medical School), employed an in vitro culture system with rat neurons. These researchers found that morphine rapidly increased microglial migration via a novel interaction between mu-opioid and P2X4 receptors, and that this increase was dependent upon PI3K/Akt pathway activation. In particular, morphine enhanced the migration of primary microglial cells toward adenosine diphosphate in a dose-dependent fashion. Migration was confirmed to be mu-opioid receptor-dependent through the use of selective agonists and antagonists. Furthermore, Iba1 protein, a microglial marker, and P2X4 receptor expression, were significantly increased after 6, 12, 24, and 48 hours of morphine stimulation. Collectively, these results suggest that there are two phases of morphine effects on microglia migration. The initial phase takes place in minutes and involves PI3K/Akt pathway activation. A longer-term phase occurs over hours and involves increased expression of Iba1 and P2X4 receptor proteins. These data implicate microglial migration as an important process in opioid-induced hyperalgesia, and may suggest novel targets for agents that prevent or attenuate morphine's undesirable side effects, including the development of tolerance and hyperalgesia. Additional behavioral pain studies will be needed to assess the functional impact of altering microglial migration on pain and opioid tolerance. Horvath RJ, DeLeo JA. Morphine enhances microglial migration through modulation of P2X4 receptor signaling. J Neurosci. 2009;29(4):998-1005.

The Cognitive Enhancer D-cycloserine Shows Promise for Improving Cue-Exposure Therapy

Augmentation of cue exposure (extinction) therapy with pharmacotherapies may offer an effective strategy to combat cocaine relapse. Kathleen Kantak and her colleagues are studying combined extinction-drug treatment effects with self-administration paradigms in rats and squirrel monkeys. Animals in their studies are trained to self-administer cocaine paired with a brief visual cue. Then lever pressing is extinguished by withholding cocaine injections while maintaining response-contingent presentations of the cue. They evaluated two doses of the glycine partial agonist D-cycloserine (DCS) on rate of extinction and subsequent reacquisition of cocaine self-administration. In rats, pretreatment with the higher dose of DCS, administered half an hour before training enhanced extinction (measured by a decrease in the number of responses and the latency to reach the extinction criterion). By contrast, neither dose altered extinction responding in monkeys. In both species, pretreatment with the higher dose of DCS before extinction training significantly reduced reacquisition of cocaine self-administration. These results suggest that DCS augments consolidation of extinction learning, to deter reacquisition of cocaine self-administration, in both rats and monkeys. Further, the results suggest that DCS combined with exposure therapy may constitute a rational strategy for the clinical management of cocaine relapse. Nic Dhonnchadha BA, Szalay JJ, Achat-Mendes C, Platt DM, Otto MW, Spealman RD, Kantak KM. D-cycloserine deters reacquisition of cocaine self-administration by augmenting extinction learning. Neuropsychopharmacology. 2010 Jan;35(2):357-67. [Epub].

Relapse to Cocaine Seeking Comprises both Habitual and Goal-Directed Behaviors

Cues present during cocaine self-administration become associated with the drug and if encountered during abstinence, increase the probability of relapse. However, despite much research on human relapse, including the use of animal behavioral models, the way in which relapse-inducing cues are interpreted by the user has remained elusive. Recent theories propose that, after long experience with self administration, drug taking shifts from goal-directed to a habit-like behavior, and therefore cues induce relapse automatically, thus bypassing information processing related to the consequences of relapse. But an alternative hypothesis is that relapse-inducing cues produce an expectation of the drug's consequences, triggering a goal-directed relapse. In animal behavioral experiments, a common procedure used to discriminate between habit and goal-directed responding is reward devaluation: if responding occurs despite devaluation, then the response is considered a habit, or automatic behavior; whereas, if responding is modulated by the current value of the reward, then the response is determined to be goal directed. The current report, by Mark West and colleagues, is the first study to test for goal-directed vs. habitual responding by directly devaluing cocaine reward in a self-administration paradigm. Rats were presented with a tone signaling availability of cocaine, which the rat obtained by pressing a lever. After extensive self-administration training, one group of animals received non-contingent cocaine injections, patterned after their individual sessions of self-administration, followed by a lithium chloride (LiCl) injection on the same day - a method of devaluation similar to that used to induce conditioned taste aversions. Animals in an explicitly unpaired group received cocaine and LiCl on separate days. After several cycles of paired or unpaired injections, all rats were kept abstinent for 30 days and then their propensity to press the lever in the absence of cocaine was assessed. For the first hour of relapse testing, animals were in a self-administration chamber with the lever present, but the tone was not presented. During this time, both groups pressed the lever the same amount, suggesting a habitual component to relapse in the presence of non-discrete cues. However, when the tone cue was turned on for the remainder of the test session, the cocaine-LiCl paired animals showed greatly decreased cue-induced responding relative to unpaired controls, indicating goal-directed behavior. In the last phase of the experiment, the animals were allowed to self-administer again. In this phase, under the influence of cocaine, both groups self-administered the same amount of drug. The study shows that both habitual and goal-directed responding occurs during abstinence and that habitual or goal-directed responding appears to be induced by cues that differ in their correlation with the cocaine infusion. The non-discriminative cues (chamber and lever), which were weakly correlated with drug infusion, failed to evoke a representation of the value of cocaine which leads to habitual behavior. However, the discriminative stimulus (tone), which was nearly perfectly correlated with the infusion, likely evoked a representation of the "value" of the infusion, leading to goal-directed behavior. These data indicate that abstinent cue-induced responding is multifaceted, comprised of both habitual and goal-directed components. Since goal-directed behavior terminated the habitual component during testing, therapeutic approaches aimed at reducing the perceived value of cocaine in addicted individuals may reduce the capacity of cues to induce relapse. Root DH, Fabbricatore AT, Barker DJ, Ma S, Pawlak AP, West MO. Evidence for habitual and goal-directed behavior following devaluation of cocaine: A multi-faceted interpretation of relapse. PLoS One. 2009 Sep 25;4(9):e7170.

Changes in Dendritic Morphology After Psychostimulant Exposure Correspond to Associative Conditioning Rather than Non-Associative Drug Sensitization

Studies have shown that systemic exposure to amphetamine (AMPH) produces a number of changes in dendritic morphology in the nucleus accumbens (NAcc) and cortical areas of the rat. The current study by Paul Vezina and colleagues was designed to determine whether these changes relate to associative drug conditioning or to non-associative drug sensitization, two forms of behavioral plasticity produced by repeated exposure to AMPH. Non-associative sensitization is reflected by increased locomotor response to AMPH, following previous exposures to the drug, and increased dopamine overflow in the NAcc, whereas associative conditioning is demonstrated by increased locomotor activity in the environment where drug was previously received, but in the absence of the drug. The investigators compared behavioral, neuronal, and morphological consequences of exposing rats either to intraperitoneal (IP) AMPH or AMPH applied to the ventral tegmental area (VTA). Direct infusions into VTA sensitizes AMPH-induced locomotion and NAcc DA overflow, but unlike systemic infusions, this mode of exposure does not produce conditioned locomotion. In the morphological analysis, they found that IP AMPH exposure increased spine density and dendritic length and branching in the NAcc and cortical areas, while exposure to VTA AMPH produced the opposite effects. These findings suggest that the morphological changes seen following IP AMPH exposure reflect associative drug conditioning rather than non-associative drug sensitization. Decreases observed in dendritic measures from the VTA in AMPH exposed rats may reflect the inability of these infusions to induce conditioning, which as with other forms of learning, may require increased synaptic transmission supported by increases in dendritic spines, length, and branching. Singer BF, Tanabe LM, Gorny G, et al. Amphetamine-induced changes in dendritic morphology in rat forebrain correspond to associative drug conditioning rather than nonassociative drug sensitization. Biol Psychiatry. 2009 May 15;65(10):835-840.

Underdeveloped Dendrite Stabilization May Underlie Enhanced Sensitivity to Cocaine in Adolescence

Adolescence is a critical period for the maturation of cortico-striatal neurocircuitry and is characterized by increased novelty seeking behavior and vulnerability to addictive drugs that, with repeated use, are associated with cognitive dysfunction in adulthood. The Abl-related gene (Arg) stabilizes cortical dendritic arbors beginning in adolescence. The present study used Arg knockout mice (arg-/-) as a model of adolescent-onset dendritic simplification. Cortical axons, dendrites, and synapses develop normally in arg-/- mice, but their adult dendrites destabilize and regress. Thus, this study used adult arg-/- mice to test the hypothesis that the transition from dendritic refinement and synaptic pruning that occurs in adolescent prefrontal cortex (PFC), to the dendritic stabilization in adulthood, characterizes a period of vulnerability to cocaine. The arg-/- mice were impaired in a behavioral test of inhibitory control, and this deficit was exacerbated by low-dose cocaine administra-tion. This behavior is similar to that seen in animals with orbital frontal cortex (OFC) lesions, and in rats receiving chronic cocaine. Arg-/- mice were also more sensitive to the locomotor activating effects of cocaine, as has been observed in adolescent animals. Further studies indicated that the behavioral deficits in the arg-/- mice are linked to reduced dopamine D2 receptor signaling in the OFC. These findings provide evidence that stabilization of dendritic structure beginning in adolescence is critical for the development of adaptive and flexible behavior after cocaine exposure. Because cocaine expo-sure itself disrupts dendritic stabilization in OFC, the results also suggest a mechanism to explain why drug use in adolescence has particularly profound effects on later vulnerability to addiction.Gourley SL, Koleske AJ, Taylor JR. Loss of dendrite stabilization by the Abl-related gene (Arg) kinase regulates behavioral flexibility and sensitivity to cocaine. PNAS USA. 2009 Sep 29;106(39):16859-16864.

Behavioral and Neural Interaction of Natural and Drug Reward Experiences

Natural reward and drugs of abuse converge on the mesolimbic system where drugs of abuse induce a number of well-characterized neuronal alterations that are thought to underlie compulsive drug seeking and vulnerability to relapse. It is currently unclear, however, whether similar alterations in the mesolimbic system occur with repeated exposure to natural rewards. Determining what changes are or are not uniquely induced by drugs of abuse could lead to a better understanding of the mechanisms that lead to addictive behaviors. One way to address such a question is to study natural rewards, such as those involved in mating and other social behaviors that can be introduced in a controlled manner. In this study, Lique Coolen and her colleagues tested the effects of sexual experience in male rats on behavioral sensitization and conditioned place preference associated with d-amphetamine (AMPH), and on alterations in dendritic morphology in nucleus accumbens (NAcc). Repeated sexual behavior induced a sensitized locomotor response to AMPH compared to AMPH's effects on sexually naive control subjects. Sexually experienced animals also formed a conditioned place preference for lower doses of AMPH than sexually naive males. Sexual experience also increased the number of dendritic and spines in the NAcc core and shell. Interestingly, this sensitization effect was apparent the first day after the last mating session and lasted for at least 28 days, while the conditioned place preference and dendritic alterations required a period of abstinence of 7-10 days. This delayed effect is similar to the period of abstinence required for the emergence of behavioral and neuronal changes induced by drugs of abuse and suggests that loss of reward may contribute to neuroplasticity in this system. The authors hypothesize that abstinence from natural rewards may induce a generalized state of increased reward seeking and vulnerability to addictive substances. The findings suggest that some alterations in the mesolimbic system are common following the experience of natural and drug reward and may play a role in general reward conditioning. Pitchers KK, Balfour ME, Lehman MN, Richtand NM, Yu L, Coolen LM. Neuroplasticity in the mesolimbic system induced by natural reward and subsequent reward abstinence. Biol Psychiatry. 2009 Dec 14. [Epub ahead of print]

Environmental Enrichment Enhances Nucleus Accumbens Signaling of Reward Predictive Cues

Many environmental influences have been identified as risk factors for drug abuse and addiction. Animal models are useful for studying the neurobiological mechanisms that translate environmental influences into risk or resilience for drug abuse behavior. Rats reared in enriched environments (EC) are more responsive to changing contingencies and demonstrate more adaptive learning than those reared in isolated environments (IC). While much is known about neuroanatomical differences between EC and IC reared animals, Dr. George Rebec and colleagues have recorded electrophysiological activity from single cells in the nucleus accumbens (NAS) of EC versus IC reared rats, to characterize the functional changes responsible for these behavioral differences. In an appetitive learning paradigm, rats are trained to respond to a reward predictive cue by nosepoking in the correct hole of the chamber to receive sucrose. Over three training sessions, EC animals acquired the discrimination faster than IC rats, with significant group differences apparent on the third session. However, even before behavioral differences emerged, a significantly greater proportion of NAS core neurons in the EC group responded to motor aspects of the discrimination task; that is, corresponding to correct nosepoke responses and to sucrose consumption. Thus, it appears that enhanced neuronal responses in EC animals may underlie accelerated learning in this appetitive task. Moreover, the patterning of cellular responses in EC rats was also significantly different during the third session: At the time EC animals demonstrated increased accuracy of the discrimination response, recording from NAS core cells revealed a significantly greater proportion of excitations (increases above baseline firing rates) triggered by onset of an important sensory aspect of discrimination learning - the predictive cue for correct nosepoking, in EC than in IC rats. The authors infer that EC enhances core reactivity to both motor and sensory aspects of appetitive learning and a shift in core signaling from motor response to reward predictive cues over training is responsible for accelerated learning. Wood DA, Rebec GV. Environmental enrichment alters neuronal processing in the nucleus accumbens core during appetitive conditioning. Brain Res. 2009; 1259:59-67.

Escalation of Cocaine Intake is Related to Impulsivity in Female Rats

Dr. Marilyn Carroll has been studying individual differences in impulsivity as a predictor of drug self-administration and relapse. In a recent study, she extends these studies to examine a role for impulsivity in escalated drug intake seen when cocaine is made available during extended access conditions. Whereas animals provided with access to drug for 2 h per day (Short Access, SA) demonstrate stable intake over many days, those provided with access for 6 h per day (Long Access, LA) escalate their intake over days. Impulsivity is a multidimensional construct and can be assessed in different behavioral paradigms. In the present study, Dr. Carroll tested female rats selected for high (HI) or low impulsivity (LI) on a delay-discounting task that measures impulsive choice. In this task, animals are presented with two levers that produce either a small-immediate reinforcer, or a large-delayed reinforcer, contingent upon lever presses. HI and LI rats were trained to self-administer cocaine on a FR1 schedule, followed by progressive ratio (PR) testing to determine the animal's motivation for the drug. After PR testing, all rats were given daily 2hr SA self-administration sessions until stable and then switched to LA for 21 days. Then animals were returned to the SA testing, and the PR assessment was repeated. While HI and LI groups did not differ on acquisition (a rapid acquisition that does not allow for usual HI versus LI differences), or SA intake, HI rats infused significantly more cocaine over sessions 17-21 of LA than LI animals, and significantly exceeded their own initial intake on this LA schedule (sessions 7-21significantly greater than sessions 1-3 for HI only). Moreover, HI rats exposed to LA conditions continued to take significantly more drug than LI rats when switched back to SA. Comparisons on PR responding for 0.2, 0.8 and 3.2 mg/kg cocaine revealed no significant differences between HI and LI rats on the rate of infusions for any dose, either before or after LA experience. These results demonstrate that individual differences in impulsive choice may confer vulnerability for the development of uncontrollable drug taking in female abusers, who are prone to develop binge-like patterns of cocaine intake. However, results from PR testing suggest that impulsive choice may not influence reward sensitivity or hedonic tolerance, since there were no group differences on PR responding. Thus, the mechanism for this enhanced vulnerability remains to be determined. Anker JJ, Perry JL, Gliddon LA, Carroll ME. Impulsivity predicts the escalation of cocaine self-administration in rats. Pharmacol Biochem Beh. 2009; 93:343-346.

Different Dimensions of Affective Responding Predict Cocaine Intake in Adolescent Versus Adult Rats

Adolescents who begin abuse at a younger age are more likely to escalate to addiction and dependence than those who begin later. Animal studies reveal differences in vulnerability as a function of age, and a differential sensitivity to both rewarding and aversive properties of many drugs of abuse. Drs. Cynthia Kuhn, Nicole Schramm-Sapyta and their colleagues have been investigating individual differences in adolescent rats that predict addiction-like behaviors. Recently they have examined choice behavior for animals provided with cocaine in drinking solutions (combined as a saccharin+cocaine mixture) versus the natural reward, saccharin (sacc). Choice behavior is a powerful and ecologically relevant metric in the study of addiction because drugs of abuse are often prioritized above other rewards, such as family, health and safety. Prior to measuring drug intake, rats were tested for individual differences in response to novelty and in an elevated plus measure of anxiety. They found that adolescent rats (Ado) drank more of a sacc+cocaine solution than their adult (Adu) counterparts, and more of the sacc+drug mixture when a second bottle of sacc was offered in a two bottle choice test. Furthermore, while there were no age differences in ambulation or open arm entries from individual differences testing, regression analyses were conducted to examine the relationships between these behavioral traits and drug consumption. Locomotion in a novel environment predicted intake of the sacc+drug solution for Ado animals, but not for Adu. The novelty response also predicted greater cocaine intake from a sacc+drug mixture when a second bottle of sacc alone was presented in a choice situation, but again for Ado animals only. By contrast, for Adu rats, regression analyses revealed that animals spending a lower percentage of time on open arms of the maze (thus, more "anxious" rats) consumed higher cocaine doses in the choice (sacc+drug versus sacc alone) situation. While these findings may be specific for the consumption model employed by the present group of investigators and should be further examined in different drug intake paradigms, they suggest that different behavioral traits may serve as vulnerability phenotypes in different stages of development. Walker QD, Schramm-Sapyta NL, Caster JM, Waller, ST, Brooks MP, Kuhn CM. Novelty-induced locomotion is positively associated with cocaine ingestion in adolescent rats; anxiety is correlated in adults. Pharmacol Biochem Beh. 2009; 91:398-408.

An Animal Model of Sleep Deprivation: Effects on Cocaine Intake

During drug abstinence human drug abusers have difficulty sleeping and report insomnia. Sleep deprivation can also lead to relapse. Until now, few studies have studied the effect of sleep deprivation on the rewarding effects of drugs of abuse. Dr. Sue Grigson and her colleagues at Pennsylvania State University have examined the effects of 0, 4 or 8 h sleep deprivation in studies of i.v. cocaine administration in the rat. Animals trained to self-administer this psychostimulant were grouped on the basis of their intake patterns: Low (LI) and high intake (HI) animals. HI rats made more total responses, more responses on an active lever to infuse drug, and increased their response rates as trials progressed. They were also faster to take the first infusion when placed in the self-administration chambers. Both groups responded on an active lever during extinction when drug was removed from the infusion pump. As others have reported, HI drug histories predicted greater reinstatement when animals were tested for drug-induced relapse by delivering a single, passive infusion of cocaine during extinction (a model of human relapse). Comparisons between sleep deprivation (SD) conditions revealed that SD had no effect on HI rats, but abolished reinstatement in LI animals. SD was also examined for effects on progressive ratio (PR) responding, to determine if SD effects an animal's willingness to "work" to receive cocaine (thus, perceived value). While HI animals had higher break points on the PR schedule, thus, making a greater number of responses to receive drug, SD conditions were without effect on this measure. SD did affect inter-infusion intervals on the PR schedule, however, for both groups (i.e., increasing the rate at which rats self-administer drug). When comparing responding on the active (drug-associated) and inactive lever in this paradigm, investigators found that low drug-takers distributed an equal number of responses on active versus inactive levers during PR testing with 0 h of SD. By contrast, 4 and 8 h of SD in the LI group enhanced "goal directed" behavior in this PR procedure. The researchers infer that motivation for drug was high in the HI group and the motivation induced by another deprivation state could not overcome this drive. LI groups, by contrast, were affected by motivation to sleep during drug-primed reinstatement after 4 and 8 h of SD. These results reveal an increased drive to respond for drug in LI animals, who made greater responses on the drug-correct lever after an imposed period of SD, and in both groups with increased infusion rates under PR testing. Additional studies are needed to more precisely characterize SD effects on the motivation to seek and take drugs of abuse, at various stage of an addiction cycle. Puhl MD, Fang J, Grigson PS. Acute sleep deprivation increases the rate and efficiency of cocaine self-administration, but not the perceived value of cocaine reward in rats. Pharmacol Biochem Beh. 2009; 94:262-270.

A Role for Hormones in Subjective Drug Affects and Potential Addictions Pharmacotherapy

In a recent review, Dr. Nancy Mello from McLean Hospital summarizes research on subjective responses to cigarette smoking and concomitant changes in HPA-axis hormone levels using a rapid sampling procedure to collect measures at 2 minute intervals for 20 minutes following smoking and at 25, 30, 40, 50, 50, 80, 100 and 120 minutes. Smoking a single cigarette was associated with increases in both cortisol and DHEA. Results from previous studies reveal higher basal levels of these hormones in smokers than nonsmokers, and a relation between decreased cortisol on the first day of cigarette cessation and relapse during a subsequent week. DHEA is an adrenal androgen precursor of testosterone and is believed to improve feelings of well being and sexuality in the elderly, although the evidence is conflicting. Although other HPA axis hormone levels fluctuated over smoking one, two or three cigarettes in succession, peak levels of DHEA did not differ significantly across successive cigarettes, and ratings of cigarette "craving" increased as DHEA and plasma nicotine levels decreased at the end of each smoking interval. Interestingly, in prior research, Dr. Mello has shown that i.v. cocaine also increases levels of this hormone in blood, suggesting a relationship to abuse-related subjective effects of both drugs. In prior studies from McLean, a significant temporal covariance between cocaine's positive subjective effects and activation of the HPA axis has been observed in cocaine abusers. Thus, Dr. Mello and her colleagues have proposed that the hormonal milieu may be an important modulator of the reinforcing effects of drugs. Given research showing that DHEA treatment improves mood and alleviates depression, Dr. Mello further speculates that DHEA may contribute to the subjective effects of nicotine, including mood elevation and reduced anxiety and depression. She points out that DHEA has been suggested as a potential medication for smoking cessation. Data from her studies with cocaine support this possibility and suggest that DHEA's potential as an addiction medication may not be limited to smoking cessation. This line of research contributes significantly to understanding of the neurobiological effects of drugs of abuse that may induce their addiction, in part, through activation of the HPA axis. Whether these hormones might play a differential role in addiction, and addiction treatment, in male versus female drug abusers remains to be investigated. Mello, NK. Hormones, nicotine, and cocaine: Clinical studies. Hormones and Behavior. [Epub ahead of print], 2009.


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