High Doses Of Cocaine Research Articles

Research Roundup

Animal study finds high cocaine doses cause ‘autophagy’ in brain cells Health officials call on FDA to put black‐box warnings on benzodiazepines and opioids Benzodiazepine OD deaths more than quadrupled from 1996 to 2013

Familiar companions diminish cocaine conditioning and attenuate cocaine-stimulated dopamine release in the nucleus accumbens

This study aimed to assess the impact of companions on the rewarding effects of cocaine. Three cage mates, serving as companions, were housed with each experimental mouse throughout cocaine-place conditioning in a cocaine-induced conditioned place preference (CPP) paradigm using conditioning doses of 10 and 20mg/kg. The presence of companions decreased the magnitude of the CPP. At 20mg/kg, cocaine stimulated dopamine (DA) release in the nucleus accumbens as evidenced by a significant decrease in total (spontaneous and electrical stimulation-provoked) DA release in accumbal superfusate samples. The presence of companions prevented this cocaine-stimulated DA release; such a reduction in cocaine-induced DA release may account for the reduction in the magnitude of the CPP in the presence of the companions. Furthermore, cocaine pretreatment (2.5mg/kg) was found to prevent the companion-produced decreases in cocaine (10mg/kg/conditioning)-induced CPP as well as the cocaine (10mg/kg)-stimulated DA release. Moreover, the presence of methamphetamine (MA) (1mg/kg)-treated companions decreased cocaine (20mg/kg/conditioning)-induced CPP and prevented the cocaine (20mg/kg)-stimulated DA release. Finally, the presence of companions decreased the magnitude of the CPP could not seem to be accounted for by cocaine-stimulated corticosterone (CORT) release. Taken together, these results indicate that familiar companions, regardless of their pharmacological status, may exert dampening effects on CPP induced by moderate to high conditioning doses of cocaine, at least in part, by preventing cocaine-stimulated DA release in the nucleus accumbens.

Evaluation of the Reinforcing Effect of Quetiapine, Alone and in Combination with Cocaine, in Rhesus Monkeys.

There are several case reports of nonmedicinal quetiapine abuse, yet there are very limited preclinical studies investigating quetiapine self-administration. The goal of this study was to investigate the reinforcing effects of quetiapine alone and in combination with intravenous cocaine in monkeys. In experiment 1, cocaine-experienced female monkeys (N = 4) responded under a fixed-ratio (FR) 30 schedule of food reinforcement (1.0-g banana-flavored pellets), and when responding was stable, quetiapine (0.003-0.1 mg/kg per injection) or saline was substituted for a minimum of five sessions; there was a return to food-maintained responding between doses. Next, monkeys were treated with quetiapine (25 mg, by mouth, twice a day) for approximately 30 days, and then the quetiapine self-administration dose-response curve was redetermined. In experiment 2, male monkeys (N = 6) self-administered cocaine under a concurrent FR schedule with food reinforcement (three food pellets) as the alternative to cocaine (0.003-0.3 mg/kg per injection) presentation. Once choice responding was stable, the effects of adding quetiapine (0.03 or 0.1 mg/kg per injection) to the cocaine solution were examined. In experiment 1, quetiapine did not function as a reinforcer, and chronic quetiapine treatment did not alter these effects. In experiment 2, cocaine choice increased in a dose-dependent fashion. The addition of quetiapine to cocaine resulted in increases in low-dose cocaine choice and number of cocaine injections in four monkeys, while not affecting high-dose cocaine preference. Thus, although quetiapine alone does not have abuse potential, there was evidence of enhancement of the reinforcing potency of cocaine. These results suggest that the use of quetiapine in cocaine-addicted patients should be monitored.

Effects of psychostimulants on social interaction in adult male rats.

Psychostimulants are known to have a huge impact on different forms of social behaviour. The aim of the present study was to compare the effects of three different psychostimulants [amphetamine, cocaine and 3,4 methylenedimethoxyamphetamine (MDMA)] on social interaction (SI) in adult male rats. The SI test was performed in a familiar arena and under low-stress environmental conditions. Experimental animals received amphetamine (0.5, 1.0, 1.5 mg/kg), cocaine (0.5, 1.0, 1.5, 2.5, 5.0, 10.0 mg/kg) or MDMA (2.5, 5.0, 10 mg/kg) and control animals received saline (1 ml/kg) 45 min before the SI test. Time spent in SI (individual patterns of social behaviour) and nonsocial activities (locomotion and rearing) were video recorded and then analysed offline, with the following results: (a) all doses of amphetamine decreased SI. Specifically, all doses of amphetamine decreased mutual sniffing, and the higher doses also decreased allo-grooming and following behaviours. (b) The higher doses of cocaine decreased SI, especially mutual sniffing, allo-grooming and climbing over. Cocaine at the dose of 5.0 mg/kg increased genital investigation compared with lower doses. (c) All doses of MDMA decreased mutual sniffing and climbing over; the two higher doses decreased allo-grooming behaviour, and only the highest dose decreased following. The two higher doses of amphetamine and all the doses of MDMA increased locomotion and rearing; cocaine did not affect locomotion, but increased rearing at higher doses. In conclusion, the results confirm the well-known finding that psychostimulants suppress SI, but also show novel differences in the effects of psychostimulants on specific patterns of SI.

Cell-Type Specific Insertion of GluA2-Lacking AMPARs with Cocaine Exposure Leading to Sensitization, Cue-Induced Seeking, and Incubation of Craving.

Addiction is a behavioral disease, of which core components can be modeled in rodents. Much evidence implicates drug-evoked synaptic plasticity in cocaine-evoked locomotor sensitization, cue-induced cocaine seeking, and incubation of cocaine craving. However, the type of plasticity evoked by different modalities of cocaine administration (eg contingent vs non-contingent) and its role in reshaping circuit function remains largely elusive. Here we exposed mice to various regimens of cocaine and recorded excitatory transmission onto identified medium-sized spiny neurons (MSN, expressing fluorescent proteins under the control of either D1R or D2R dopamine receptor promotor) in the nucleus accumbens at time points when behavioral adaptations are observed. In D1-MSN, we found the presence of GluA2-lacking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) after single or chronic non-contingent exposure to cocaine as well as after cocaine self-administration (SA). We also report an increase in the AMPA/NMDA ratio (A/N) in D1-MSN, which was observed only after repeated passive injections associated with locomotor sensitization as well as in a condition of SA leading to seeking behavior. Remarkably, insertion of GluA2-lacking AMPARs was also detected in D2-MSN after SA of a high dose of cocaine but not regular dose (1.5 vs 0.75 mg/kg), which was the only condition where incubation of cocaine craving was observed in this study. Moreover, synapses containing GluA2-lacking AMPARs belonged to amygdala inputs in D2-MSN and to medial prefrontal cortex inputs in D1-MSN. Taken together this study allows for a refinement of a circuit model of addiction based on specific synaptic changes induced by cocaine.

Development of translational preclinical models in substance abuse: Effects of cocaine administration on cocaine choice in humans and non-human primates

Human drug use involves repeated choices to take drugs or to engage in alternative behaviors. The purpose of this study was to examine how response cost for cocaine and the value of an alternative reinforcer (opportunity to play a game of chance) and how ‘free’ doses (with minimal response cost) affected cocaine choice. Two laboratory studies of cocaine self-administration were conducted in a group of humans who were habitual cocaine smokers and in a group of rhesus monkeys that intravenously self-administered cocaine. Nine human cocaine smokers who were not seeking treatment for their cocaine were repeatedly presented with the choice to smoke 25mg cocaine base or play a game of chance for a monetary bonus paid at study completion. The response cost for choosing cocaine varied (up to 4000 responses/dose) and the number of game plays varied (up to 8). In this sample of humans, increasing either the response cost for cocaine or increasing the value of the alternative reinforcer did not significantly affect cocaine choice, while increasing both simultaneously slightly decreased cocaine choice and increased choice of the alternative. In monkeys, the dose–response function for cocaine self-administration (10 choices of 0.0125–0.1mg/kg/infusion vs. candy coated chocolate) was steep and we failed to achieve a 50/50 cocaine/candy choice even after substantially manipulating cost and number of candies available. Providing a large ‘free’ self-administered cocaine dose to humans did not significantly affect cocaine choice, whereas in monkeys, a large free dose of cocaine decreased cocaine choice when higher doses of cocaine were available for self-administration. The present results demonstrate that in the laboratory, it is difficult to modify on-going cocaine self-administration behavior in both humans and non-human primates.

Reward and Toxicity of Cocaine Metabolites Generated by Cocaine Hydrolase.

Butyrylcholinesterase (BChE) gene therapy is emerging as a promising concept for treatment of cocaine addiction. BChE levels after gene transfer can rise 1000-fold above those in untreated mice, making this enzyme the second most abundant plasma protein. For months or years, gene transfer of a BChE mutated into a cocaine hydrolase (CocH) can maintain enzyme levels that destroy cocaine within seconds after appearance in the blood stream, allowing little to reach the brain. Rapid enzyme action causes a sharp rise in plasma levels of two cocaine metabolites, benzoic acid (BA) and ecgonine methyl ester (EME), a smooth muscle relaxant that is mildly hypotensive and, at best, only weakly rewarding. The present study, utilizing Balb/c mice, tested reward effects and cardiovascular effects of administering EME and BA together at molar levels equivalent to those generated by a given dose of cocaine. Reward was evaluated by conditioned place preference. In this paradigm, cocaine (20mg/kg) induced a robust positive response but the equivalent combined dose of EME+BA failed to induce either place preference or aversion. Likewise, mice that had undergone gene transfer with mouse CocH (mCocH) showed no place preference or aversion after repeated treatments with a near-lethal 80mg/kg cocaine dose. Furthermore, a single administration of that same high cocaine dose failed to affect blood pressure as measured using the noninvasive tail-cuff method. These observations confirm that the drug metabolites generated after CocH gene transfer therapy are safe even after a dose of cocaine that would ordinarily be lethal.

A Single Amphetamine Infusion Reverses Deficits in Dopamine Nerve-Terminal Function Caused by a History of Cocaine Self-Administration.

There are ∼ 1.6 million people who meet the criteria for cocaine addiction in the United States, and there are currently no FDA-approved pharmacotherapies. Amphetamine-based dopamine-releasing drugs have shown efficacy in reducing the motivation to self-administer cocaine and reducing intake in animals and humans. It is hypothesized that amphetamine acts as a replacement therapy for cocaine through elevation of extracellular dopamine levels. Using voltammetry in brain slices, we tested the ability of a single amphetamine infusion in vivo to modulate dopamine release, uptake kinetics, and cocaine potency in cocaine-naive animals and after a history of cocaine self-administration (1.5 mg/kg/infusion, fixed-ratio 1, 40 injections/day × 5 days). Dopamine kinetics were measured 1 and 24 h after amphetamine infusion (0.56 mg/kg, i.v.). Following cocaine self-administration, dopamine release, maximal rate of uptake (Vmax), and membrane-associated dopamine transporter (DAT) levels were reduced, and the DAT was less sensitive to cocaine. A single amphetamine infusion reduced Vmax and membrane DAT levels in cocaine-naive animals, but fully restored all aspects of dopamine terminal function in cocaine self-administering animals. Here, for the first time, we demonstrate pharmacologically induced, immediate rescue of deficits in dopamine nerve-terminal function in animals with a history of high-dose cocaine self-administration. This observation supports the notion that the DAT expression and function can be modulated on a rapid timescale and also suggests that the pharmacotherapeutic actions of amphetamine for cocaine addiction go beyond that of replacement therapy.

Levamisole enhances the rewarding and locomotor-activating effects of cocaine in rats

BackgroundThe Drug Enforcement Agency estimates that 80% of cocaine seized in the United States contains the veterinary pharmaceutical levamisole (LVM). One problem with LVM is that it is producing life-threatening neutropenia in an alarming number of cocaine abusers. The neuropharmacological profile of LVM is also suggestive of an agent with modest reinforcing and stimulant effects that could enhance cocaine's addictive effects. MethodsWe tested the hypothesis that LVM (ip) enhances the rewarding and locomotor stimulant effects of cocaine (ip) using rat conditioned place preference (CPP) and locomotor assays. Effects of LVM by itself were also tested. ResultsLVM (0–10mg/kg) produced CPP at 1mg/kg (P<0.05) and locomotor activation at 5mg/kg (P<0.05). For CPP combination experiments, a statistically inactive dose of LVM (0.1mg/kg) was administered with a low dose of cocaine (2.5mg/kg). Neither agent produced CPP compared to saline (P>0.05); however, the combination of LVM and cocaine produced enhanced CPP compared to saline or either drug by itself (P<0.01). For locomotor experiments, the same inactive dose of LVM (0.1mg/kg, ip) was administered with low (10mg/kg) and high doses (30mg/kg) of cocaine. LVM (0.1mg/kg) enhanced locomotor activation produced by 10mg/kg of cocaine (P<0.05) but not by 30mg/kg (P>0.05). ConclusionsLVM can enhance rewarding and locomotor-activating effects of low doses of cocaine in rats while possessing modest activity of its own.

Cognitive-behavioral therapy and educational counseling for chronic pain and opioid dependence

Cognitive-behavioral therapy and educational counseling for chronic pain and opioid dependence

Significantly lower prevalence of psychopathology in Asian compared to non-Asian methadone maintained patients

Significantly lower prevalence of psychopathology in Asian compared to non-Asian methadone maintained patients

Concomitant adrenal hormonal stress responses are required for cocaine-induced locomotor sensitization

Aims: Cocaine-induced locomotor sensitization is a robust increase in locomotion to a standardized dose of cocaine. The associated neuronal changes that underlie increased behavioral sensitization involve addiction-related plasticity. Strong evidence suggests that the systemic stress response is involved in establishing addiction-related behaviors. We previously reported that the systemic adrenal response is required for escalation of addictionrelated behaviors and that glucocorticoids in particular play a role in facilitating long termneural adaptions that result in these behaviors. Here we examine whether increased levels of the adrenal hormones, corticosterone (cort) and epinephrine (epi), either alone or in concert, are required for establishing locomotor sensitization to cocaine. Methods: Male Sprague-Dawley rats underwent surgical adrenalectomy (ADX) with basal cort replacement and were administered cocaine for 10 days. On days 1 and 10 locomotor sensitization was tested by administration of 15mg/kg, ip cocaine, while sensitization was induced on days 2–9 by administering a high dose of cocaine (30mg/kg, ip×8 days). To test the role of the glucocorticoid receptor (GR) in induction of sensitization, the GR antagonist, RU 486 (12.5mg/kg, sc) was administered prior to cocaine administration. To test whether replacement of the adrenal-secreted stress hormones would rescue sensitization in ADX rats, we replaced normal cort (2mg/kg) and/or epi (0.01mg/kg) during cocaine administration. Results: The induction of sensitization was reduced in rats with ADXor pretreatedwith RU486. In ADX rats, replacement using cort or epi alone did not recover locomotor sensitization but did rescue sensitization when co-administered. Conclusions: These findings demonstrate that coordinated systemic stress signaling from the adrenal gland during cocaine administration is required for cocaine-induced locomotor sensitization and may play a role establishing addiction-related neuroplasticity with chronic cocaine use. Financial support:DA015758 to JRMandDiversity Supplement to DFP.

Region and context-specific intracellular responses associated with cocaine-induced conditioned place preference expression

The development and maintenance of cocaine addiction depend heavily on learned reward-environment associations that can induce drug-seeking behavior and relapse. Understanding the mechanisms underlying these cue-induced conditioned responses is important for relapse prevention. To test whether intracellular responses measured after cocaine conditioned place preference (CPP) expression are context-dependent, we re-exposed cocaine-treated rats (drug-free) to an environment previously paired with cocaine or saline, 24h after the CPP test. After 8days of cocaine CPP training with one of two cocaine doses (5mg/kg or 20mg/kg, i.p.), CPP was expressed only after conditioning with the higher cocaine dose. In CPP expressing rats, locomotor responses after re-exposure to the cocaine-chamber were greater than in rats re-exposed to the saline-paired chamber. Nucleus Accumbens (NAc) phosphorylated ERK (pERK) levels were increased after re-exposure to the cocaine-paired, but not the saline-paired chamber, regardless of whether or not CPP behavior was expressed. Caudate Putamen (CPu) pERK and FosB protein levels increased after re-exposure to the cocaine chamber only after conditioning with the higher cocaine dose. Conversely, the higher cocaine dose, independent of environment, resulted in increased NAc FosB, ΔFosB and phosphorylated CREB (pCREB) protein levels compared to those conditioned with 5mg/kg cocaine (non-CPP-expressing). Our results suggest that NAc ERK phosphorylation may be involved with retrieving the contextual information of a cocaine-association, without necessarily motivating the expression of CPP behavior. Additionally, we show distinct patterns of intracellular responses in the NAc and CPu indicating a region-specific role for pERK/pCREB/FosB intracellular signaling in the retrieval of cocaine-context associations.

Continuous exposure to dizocilpine facilitates the acquisition and escalation of cocaine consumption in male Sprague-Dawley rats

BackgroundBlocking N-methyl-d-aspartate (NMDA) glutamate receptors (NMDARs) prevents cocaine locomotor sensitization, but facilitates escalation of cocaine self-administration and produces ambiguous effects on acquisition of cocaine self-administration. This study used a recently described model of acquisition and escalation to test the hypothesis that continuous NMDAR antagonism functionally increases the effects of a given dose of cocaine. MethodsWe assessed acquisition of cocaine self-administration (0.6mg/kg/infusion) in rats treated continuously with either vehicle or the NMDAR antagonist dizocilpine (0.4mg/kg/day) for 14 consecutive 2h fixed ratio 1 (FR1) sessions. In a separate experiment that assessed the effect of dizocilpine treatment on escalation of cocaine self-administration, rats acquired cocaine self-administration (0.6mg/kg/infusion) prior to vehicle or dizocilpine treatment. Then, immediately post-acquisition, rats were treated continuously with either vehicle or dizocilpine and allowed to self-administer either 0.6 or 1.2mg/kg/infusion cocaine for an additional seven consecutive 2h FR1 sessions. ResultsRelative to vehicle-treated rats, a significantly greater percentage of dizocilpine-treated rats acquired cocaine self-administration. During the escalation experiment, both vehicle- and dizocilpine-treated rats escalated intake of 1.2mg/kg/infusion cocaine. Whereas vehicle-treated rats exhibited stable intake of 0.6mg/kg/infusion cocaine, dizocilpine-treated rats escalated intake of this moderate cocaine dose to levels indistinguishable from intake levels produced by self-administration of the high cocaine dose (i.e., 1.2mg/kg/infusion). ConclusionsThese findings suggest that chronic NMDAR blockade potentiates, rather than attenuates, cocaine's effects and argue for reconsideration of the role of NMDARs in cocaine “addiction-like” behavior.

Medial prefrontal cannabinoid CB1 receptors modulate consolidation and extinction of cocaine-associated memory in mice.

Cannabinoid CB1 receptors are implicated in various forms of learning and memory, including acquisition and reinstatement of cocaine-associated memory. However, roles of CB1 receptors in consolidation and extinction processes of cocaine-associated memory and the brain areas potentially involved remain unknown. This study examined the effect of rimonabant, a CB1 receptor antagonist, administered systemically or directly into the medial prefrontal cortex (mPFC) on memory consolidation and extinction of cocaine-induced conditioned place preference (CPP). Male C57BL/6J mice were trained to acquire cocaine-induced CPP. Rimonabant (0.1-3 mg/kg, i.p. or 1.5 μg bilaterally in the mPFC) or vehicle was administered either immediately after each CPP training (consolidation) or forced extinction (extinction) trial. Cocaine-induced CPP was tested after training, extinction, or cocaine priming. Systemic or intra-mPFC administration of rimonabant impaired consolidation of CPP induced by a high dose (20 or 40 mg/kg) of cocaine but facilitated that induced by a low dose (2.5, 5, or 10 mg/kg). Moreover, systemic or intra-mPFC administration of rimonabant enhanced extinction of CPP memory induced by a high-dose (20 mg/kg) cocaine. Our results suggest that antagonism of CB1 receptors in the mPFC bidirectionally modulates consolidation but facilitates extinction of cocaine-induced CPP memory. Therefore, CB1 receptor blockade with the concomitant extinction behavioral procedure may hint important therapeutic intervention strategies for the heavy cocaine addicts in a clinical setting.

Threonine 149 phosphorylation enhances ΔFosB transcriptional activity to control psychomotor responses to cocaine.

Stable changes in neuronal gene expression have been studied as mediators of addicted states. Of particular interest is the transcription factor ΔFosB, a truncated and stable FosB gene product whose expression in nucleus accumbens (NAc), a key reward region, is induced by chronic exposure to virtually all drugs of abuse and regulates their psychomotor and rewarding effects. Phosphorylation at Ser(27) contributes to ΔFosB's stability and accumulation following repeated exposure to drugs, and our recent work demonstrates that the protein kinase CaMKIIα phosphorylates ΔFosB at Ser(27) and regulates its stability in vivo. Here, we identify two additional sites on ΔFosB that are phosphorylated in vitro by CaMKIIα, Thr(149) and Thr(180), and demonstrate their regulation in vivo by chronic cocaine. We show that phosphomimetic mutation of Thr(149) (T149D) dramatically increases AP-1 transcriptional activity while alanine mutation does not affect transcriptional activity when compared with wild-type (WT) ΔFosB. Using in vivo viral-mediated gene transfer of ΔFosB-T149D or ΔFosB-T149A in mouse NAc, we determined that overexpression of ΔFosB-T149D in NAc leads to greater locomotor activity in response to an initial low dose of cocaine than does WT ΔFosB, while overexpression of ΔFosB-T149A does not produce the psychomotor sensitization to chronic low-dose cocaine seen after overexpression of WT ΔFosB and abrogates the sensitization seen in control animals at higher cocaine doses. We further demonstrate that mutation of Thr(149) does not affect the stability of ΔFosB overexpressed in mouse NAc, suggesting that the behavioral effects of these mutations are driven by their altered transcriptional properties.

Lifelong, central corticotropin-releasing factor (CRF) overexpression is associated with individual differences in cocaine-induced conditioned place preference

Stress, through corticotropin-releasing factor (CRF), influences all aspects of cocaine addiction. Earlier studies suggest that individual differences in responsivity to stress affect susceptibility to develop addiction. We have previously found that CRF over-expression alters individual differences in behavioural responses to novelty stress in mice. Therefore, we hypothesised that post-natal, long-term over-expression of brain CRF may alter the rewarding effects of cocaine in a manner that is sensitive to individual differences. In this study we specifically investigated cocaine-induced conditioned place preference (CPP) in transgenic mice over-expressing CRF (CRF-OE) and in wild-type (WT) littermates after determining their individual locomotor and emotional responsivity to inescapable novelty. CRF-OE mice showed decreased overall locomotor activity and increased anxiety-like behaviour in response to novelty compared to WT mice. Low behavioural reactivity to novelty (LR) was associated with heightened anxiety-like behaviour in CRF-OE, but not in WT, mice. WT and CRF-OE mice developed CPP equally to both low (5mg/kg) and high (20mg/kg) doses of cocaine. However, LR CRF-OE mice expressed significantly stronger cocaine CPP than transgenic mice with high locomotor response to novelty (HR). In WT mice, on the other hand, stronger CPP induced by 20mg/kg of cocaine was found in the HR animals. Furthermore, there was a strong negative correlation between locomotor reactivity to novelty and CPP in CRF-OE, but not in WT, mice. Collectively, these results suggest that long-term, post-natal CRF over-expression increases the rewarding effects of cocaine in individuals with high emotional response to stress.

Acute estradiol treatment affects the expression of cocaine-induced conditioned place preference in ovariectomized female rats

Women and female rodents are more responsive to the subjective effects of psychostimulant drugs of abuse compared to males. A growing body of literature supports a role for estradiol as a mechanism underlying these sex differences. However, little is known about the influence of acute elevations in levels of estradiol on drug conditioned behaviors. The aim of the present study was to evaluate the influence of an acute increase in systemic estradiol levels on the expression of cocaine conditioned place preference (CPP). Using a six day conditioning procedure, ovariectomized (OVX) female rats were conditioned with one of four doses of cocaine (2.5, 5, 10, or 15mg/kg) to associate one of two large chambers of a CPP apparatus with cocaine or saline. Thirty minutes prior to the start of the CPP preference test, rats were pretreated with either 5μg estradiol benzoate (EB) or peanut oil (PO). PO-treated rats expressed a significant preference for only the mid-range conditioning doses of cocaine (5 and 10mg/kg). However, acute EB treatment resulted in a rightward shift in the cocaine dose-response curve; rats demonstrated a significant preference at only the moderate and high conditioning doses of cocaine (10 and 15mg/kg). These findings demonstrate that acute elevations in estradiol may dampen the expression of conditioned responses to cocaine's secondary rewards at lower conditioning doses of the drug and facilitate CPP at higher doses while estradiol deficiency decreases the threshold dose of cocaine necessary to induce CPP.

Acute and chronic effects of the M1/M4-preferring muscarinic agonist xanomeline on cocaine vs. food choice in rats

We previously showed that the M1/M4-preferring muscarinic agonist xanomeline can acutely attenuate or eliminate cocaine self-administration in mice. Medications used to treat addictions will arguably be administered in (sub)chronic or repeated regimens. Tests of acute effects often fail to predict chronic effects, highlighting the need for chronic testing of candidate medications. Rats were trained to lever press under a concurrent FR5 FR5 schedule of intravenous cocaine and food reinforcement. Once baseline behavior stabilized, the effects of 7days once-daily injections of xanomeline were evaluated. Xanomeline pretreatment dose-dependently (1.8-10mg/kg/day) shifted the dose-effect curve for cocaine rightward (up to 5.6-fold increase in A 50), with reallocation of behavior to the food-reinforced lever. There was no indication of tolerance, rather effects grew over days. The suppression of cocaine choice appeared surmountable at high cocaine doses, and xanomeline treatment did not significantly decrease total-session cocaine or food intake. In terms of xanomeline's potential for promoting abstinence from cocaine in humans, the findings were mixed. Xanomeline did produce reallocation of behavior from cocaine to food with a robust increase in food reinforcers earned at some cocaine/xanomeline dose combinations. However, effects appeared surmountable, and food-maintained behavior was also decreased at some xanomeline/cocaine dose combinations, suggesting clinical usefulness may be limited. These data nevertheless support the notion that chronic muscarinic receptor stimulation can reduce cocaine self-administration. Future studies should show whether ligands with higher selectivity for M1 or M1/M4 subtypes would be less limited by undesired effects and can achieve higher efficacy.

Abstracts and Commentaries on Key Articles in the Literature

Abstracts and Commentaries on Key Articles in the Literature