James K. Rowlett

Conditioned place preference using opiate and stimulant drugs: A meta-analysis

A meta-analysis was conducted on the data obtained from published articles that have used the conditioned place preference (CPP) paradigm to assess the rewarding effects of morphine, heroin, amphetamine and cocaine in rats. Using a histogram analysis of the data, significant dose-effect curves were evident with all of the drugs examined, except for cocaine. Analysis of the data also revealed that several methodological variables moderated the effect size for CPP, at least with some of the drugs examined. In particular, the following methodological variables significantly moderated CPP effect size: strain of rat used; housing condition (single or group cages); type of apparatus (2 or 3 compartments); preconditioning test (present or absent); route of drug administration; intervening saline trials (present or absent); conditioning trial duration; and drug compartment (nonpreferred, counterbalanced or white). No significant effect size differences were evident using sex, number of drug trials, or test duration as moderator variables in the analyses. These meta-analytic results may be useful to investigators for maximizing the effect size of drug-induced CPP.

Cocaine Administered into the Medial Prefrontal Cortex Reinstates Cocaine-Seeking Behavior by Increasing AMPA Receptor-Mediated Glutamate Transmission in the Nucleus Accumbens

One of the major determinants of reinstatement to cocaine use among human addicts is acute reexposure to the drug, which often precipitates cocaine craving and relapse. We used an animal model of cocaine relapse to determine the role of the glutamatergic pathway from the medial prefrontal cortex (mPFC) to the nucleus accumbens in the reinstatement of cocaine-seeking behavior after a cocaine priming injection. Rats were trained to self-administer cocaine intravenously on a second order schedule. Responding was extinguished subsequently by substituting saline for cocaine. During subsequent reinstatement sessions, drug-seeking behavior was assessed after noncontingent priming injections. Results indicated that reinstatement induced by a systemic cocaine injection was blocked by intra-mPFC administration of the dopamine antagonist flupenthixol. Consistent with this finding, administration of cocaine directly into the mPFC reinstated cocaine-seeking behavior. Administration of cocaine into the nucleus accumbens also reinstated drug seeking, whereas microinjection of cocaine into the neostriatum or lateral septum did not. Reinstatement of cocaine seeking induced by intra-mPFC cocaine was blocked by administration of the AMPA receptor antagonist CNQX into the nucleus accumbens. Administration of the NMDA receptor antagonist AP-5 into the nucleus accumbens had variable effects on reinstatement induced by intra-mPFC cocaine in that AP-5 had no effect in some animals but augmented reinstatement in others. Subsequent experiments showed that intra-accumbal microinjection of AP-5 alone dose-dependently reinstated cocaine seeking. These data indicate that the glutamatergic pathway from the mPFC to the nucleus accumbens plays an important role in cocaine priming-induced reinstatement of drug seeking. Moreover, the present results demonstrate that AMPA and NMDA receptors in the nucleus accumbens have opposing roles in the reinstatement of cocaine-seeking behavior.

Pharmacological and Environmental Determinants of Relapse to Cocaine-Seeking Behavior

Animal models have been developed that simulate relevant features of relapse to cocaine-seeking behavior in humans. These models have provided valuable information about pharmacological and environmental factors that precipitate reinstatement of extinguished cocaine-seeking in rats and monkeys, as well as new insights about potential pharmacotherapies for relapse prevention. Reinstatement of cocaine-seeking behavior in animals can be induced by cocaine priming or by cocaine-paired environmental stimuli: however, maximum reinstatement of drug-seeking appears to be induced when cocaine priming and cocaine-paired stimuli are combined. Drugs that share cocaines indirect dopamine agonist properties or that act as direct agonists at D2-like dopamine receptors also induce reinstatement of cocaine-seeking behavior, whereas with some exceptions (e.g., caffeine, morphine) drugs from other pharmacological classes do not. D1-like receptor agonists block rather than mimic the priming effects of cocaine, suggesting different roles for D1- and D2-like receptor mechanisms in cocaine relapse. Although considerable overlap exists, drugs that exhibit cocaine-like discriminative stimulus and/ or reinforcing effects in other situations do not invariably induce cocaine-like reinstatement of drug-seeking and vice versa, implying that these effects are not simply different behavioral expressions of a unitary neurobiological process. Finally, recent findings with D1-like receptor agonists, partial agonists, and antagonists suggest that some of these drugs may be viable candidates for development as antirelapse pharmacotherapies.

The effect of environmental enrichment on amphetamine-stimulated locomotor activity, dopamine synthesis and dopamine release

In two separate experiments, rats were raised in either an enriched condition (EC) or impoverished condition (IC) from 21 to 60 days of age. Experiment 1 assessed amphetamine-stimulated locomotor activity and in vivo dopamine (DA) synthesis and metabolism in the nucleus accumbens (NA) and striatum (Str). In Experiment 2, amphetamine-stimulated DA release in the NA and Str was assessed in vitro. The results showed that EC rats have lower basal levels of locomotor activity than IC rats. However, in the presence of amphetamine, EC rats showed a greater increase in locomotion over IC when compared to their own controls. Concomitant with this behavioral difference, EC rats also showed an enhanced neurochemical response to amphetamine in vivo. That is, relative to IC rats, amphetamine produced a greater synthesis of DA in the Str of EC rats, as well as a greater metabolism of DA in the NA of EC rats. In the in vitro DA release experiment, EC rats had a lower concentration of tissue DA than IC. However, in contrast to the in vivo experiment, there were no significant differences between EC and IC rats in amphetamine-stimulated release of DA in vitro in either the Str or NA. The failure of amphetamine to produce differential neurochemical effects in EC and IC rats in vitro may be because this experiment eliminated either pharmacokinetic effects or neurochemical differences in brain regions outside the NA and Str.

Environmental enrichment attenuates locomotor sensitization, but not in vitro dopamine release, induced by amphetamine

Rats were raised from weanling until young adulthood in either an enriched condition (EC) or isolated condition (IC). Following this, the locomotor and rewarding effects of amphetamine were determined using the conditioned place preference (CPP) paradigm. EC rats were more sensitive to the acute locomotor stimulant effect and rewarding effect of amphetamine relative to IC rats. In contrast, EC rats were less sensitive than IC rats to the locomotor sensitization effect obtained across repeated amphetamine injections. To determine the effect of environmental enrichment on alteration of brain dopamine (DA) function induced by amphetamine, the effect of amphetamine on electrically evoked release of DA and dihydroxyphenylacetic acid (DOPAC) was determined in vitro using tissue slices from the nucleus accumbens and striatum of EC and IC rats. No differences between EC and IC rats in release of DA or DOPAC were evident, suggesting that the environmentally induced difference in sensitivity to the behavioral effects of amphetamine involves a neural mechanism extrinsic to the mesolimbic and nigrostriatal terminal field regions.

Abuse and dependence liability of benzodiazepine-type drugs : GABAA receptor modulation and beyond

Over the past several decades, benzodiazepines and the newer non-benzodiazepines have become the anxiolytic/hypnotics of choice over the more readily abused barbiturates. While all drugs from this class act at the GABA(A) receptor, benzodiazepine-type drugs offer the clear advantage of being safer and better tolerated. However, there is still potential for these drugs to be abused, and significant evidence exists to suggest that this is a growing problem. This review examines the behavioral determinants of the abuse and dependence liability of benzodiazepine-type drugs. Moreover, the pharmacological and putative biochemical basis of the abuse-related behavior is discussed.

Behavioral effects of cocaine and dopaminergic strategies for preclinical medication development

Abstract Rationale. The illicit use of cocaine is a persistent health problem worldwide. Currently, there are no broadly effective pharmacotherapies to treat cocaine addiction. A prerequisite for development of useful anti-cocaine medications is an understanding of the pharmacological basis of cocaines effects. The functional analysis of behavior in laboratory animals has allowed for the development of strategies identifying candidate medications to treat cocaine addiction. Objectives. This review summarizes the current status of dopaminergic compounds as cocaine pharmacotherapies in animal models of cocaine addiction. Results. Maintenance medications should share key subjective effects with cocaine, yet have limited abuse liability and side effects. However, maintenance medications often have reinforcing effects that could contribute to abuse potential and side effects that could deter patient compliance. Combined with cocaine, these drugs enhance cocaines effects. Cocaine antagonists should block the effects of cocaine and have no cocaine-like effects or side effects on their own. However, the cocaine-modulating effects of candidate cocaine antagonists are often surmountable, and, on their own, these drugs produce severe motoric side effects. In contrast, dopamine (DA) partial agonists should exhibit reduced abuse potential relative to agonists, as well as less severe motoric effects relative to antagonists. Combined with cocaine, these drugs should antagonize cocaines effects. Conclusions. DA partial agonists, in particular the D3-selective and the D1-like partial agonists, offer a more encouraging profile for novel anti-cocaine medications. Neither class of drug is self-administered, and side effects are often less severe and only observed at doses above those that antagonize the effects of cocaine.

κ Agonist-Induced Reinstatement of Cocaine Seeking in Squirrel Monkeys: A Role for Opioid and Stress-Related Mechanisms

κ Opioid agonists were at one time proposed as candidate pharmacotherapies for cocaine addiction, mainly because of their ability to decrease dopamine neurotransmission and attenuate the behavioral effects of cocaine in laboratory animals. Recent studies, however, suggest that κ agonists also may mimic and/or enhance some of the effects of cocaine through mechanisms related to stress. The current study used a reinstatement procedure to examine the ability of the κ agonists spiradoline and enadoline to reinstate extinguished cocaine seeking in squirrel monkeys previously trained to self-administer cocaine under a second-order schedule of i.v. drug injection. Opioid- and stress-related mechanisms were evaluated in antagonism studies with the opioid antagonists naltrexone and nor-binaltorphimine (nor-BNI), the corticotropin-releasing factor receptor antagonist butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine (CP 154,526), and the α2-adrenoceptor agonist clonidine combined with either spiradoline or enadoline. When tested alone, priming with spiradoline and enadoline induced significant reinstatement of cocaine-seeking behavior to approximately 45% of the maximum reinstatement induced by cocaine. Reinstatement of cocaine seeking induced by intermediate doses of spiradoline was greater in the presence than in the absence of response-contingent presentations of a cocaine-paired stimulus. Spiradoline- and enadoline-induced reinstatement of drug seeking was attenuated by naltrexone but not by nor-BNI. Spiradoline-induced reinstatement of cocaine seeking was also antagonized by CP 154,526 and clonidine. The results point to interactions between a subpopulation of κ opioid receptors and central corticotropin-releasing factor and noradrenergic stress systems in the reinstatement of cocaine seeking induced by κ agonists.

Biogeography of the Intestinal Mucosal and Lumenal Microbiome in the Rhesus Macaque

The gut microbiome is widely studied by fecal sampling, but the extent to which stool reflects the commensal composition at intestinal sites is poorly understood. We investigated this relationship in rhesus macaques by 16S sequencing feces and paired lumenal and mucosal samples from ten sites distal to the jejunum. Stool composition correlated highly with the colonic lumen and mucosa and moderately with the distal small intestine. The mucosal microbiota varied most based on location and was enriched in oxygen-tolerant taxa (e.g., Helicobacter and Treponema), while the lumenal microbiota showed inter-individual variation and obligate anaerobe enrichment (e.g., Firmicutes). This mucosal and lumenal community variability corresponded to functional differences, such as nutrient availability. Additionally, Helicobacter, Faecalibacterium, and Lactobacillus levels in stool were highly predictive of their abundance at most other gut sites. These results quantify the composition and biogeographic relationships between gut microbial communities in macaques and support fecal sampling for translational studies.

Parametric analysis of cocaine self-administration under a progressive-ratio schedule in rhesus monkeys

The present study was designed to investigate parameters and quantitative analysis of cocaine self-administration under a progressive-ratio (PR) schedule of reinforcement, with the goal of enhancing the resolution of PR schedules for measuring reinforcing efficacy. Six rhesus monkeys were prepared with chronic intravenous catheters and trained to self-administer cocaine under a PR schedule. The schedule consisted of five components, each made up of four trials (i.e., 20 trials total). Each trial within a component had the same response requirement. Three initial response requirements were tested: fixed-ratio (FR) 60, FR 120 and FR 240. The response requirements doubled in successive components to a maximum of FR 960, FR 1920 or FR 3840, respectively, in the fifth component. A trial ended with an injection or the expiration of a 12- or 24-min limited hold (LH). The inter-trial interval (ITI) was 15 or 30 min. Four dependent measures were assessed: break point (last FR completed), injections/session, responses/session and response rate (responses/s). For the three initial FRs, the break point, number of injections/session, responses/session and rate increased with dose of cocaine (0.013–0.1 mg/kg per injection) at both ITI/LH values. At the ITI15/LH12, responding decreased at higher doses, i.e., the dose-response functions were biphasic. In contrast, at the ITI30/LH24, responding reached an asymptote at higher doses. In general, cocaine maintained significantly higher break points, injections/session, responses/session and rate at ITI30/LH24 than at ITI15/LH12. However, at both ITI/LHs, as initial FR was increased, injections/session at the higher doses decreased while break point, total responses/session and rate did not change. A ceiling on performance, as assessed by break point, total responses/session and response rate, may have limited the number of cocaine injections an animal could take in a session. The results of this study indicate that optimal conditions for measuring the reinforcing efficacy of cocaine were obtained at the longer ITI/LH and at initial FRs above 60.