Assessing locomotor-stimulating effects of cocaine in rodents.

Locomotor activity procedures are useful for characterizing the behavioral effects of a drug, the influence of pharmacological, neurobiological, and environmental manipulations on drug sensitivity, and changes in activity following repeated administration (e.g., tolerance or sensitization) are thought to be related to the development of an addiction-like behavioral phenotype. The effects of cocaine on locomotor activity have been relatively extensively characterized. Many of the published studies use between-subject experimental designs, even though changes in sensitivity within a particular individual due to experimental manipulations, or behavioral and pharmacological histories is potentially the most important outcome as these changes may relate to differential development of an addiction-like phenotype in some, but not all, animals (including humans). The two behavioral protocols described herein allow extensive within-subject analyses. The first protocol uses daily locomotor activity levels as a stable baseline to assess the effects of experimental manipulations, and the second uses a pre- versus post-session experimental design to demonstrate the importance of drug-environment interactions in determining the behavioral effects of cocaine.

Animal models of addiction: fat and sugar.

The concept of "food addiction" is gaining acceptance among the scientific community, and much is known about the influence of various components of food (e.g. high-fat, sugar, carbohydrate, salt) on behavior and physiology. Most of the studies to date have studied these consequences following relatively long-term diet manipulations and/or relatively free access to the food of interest. It is suggested that these types of studies are primarily tapping into the energy regulation and homeostatic processes that govern food intake and consumption. More recently, the overlap between the neurobiology of "reward-related" or hedonic effects of food ingestion and other reinforcers such as drugs of abuse has been highlighted, contributing to the notion that "food addiction" exists and that various components of food may be the substance of abuse. Based on preclinical animal models of drug addiction, a new direction for this field is using self-administration procedures and identifying an addiction-like behavioral phenotype in animals following various environmental, genetic, pharmacological, and neurobiological manipulations. Here we provide examples from this research area, with a focus on fat and sugar self-administration, and how the sophisticated animal models of drug addiction can be used to study the determinants and consequences of food addiction.

Effects of 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) on the self-administration of cocaine, heroin, and cocaine/heroin combinations in rats.

Pharmacotherapies utilizing long-acting agonists and mixed function agonists-antagonists have been successful in the treatment of opiate addiction but no comparable treatment exists for cocaine abuse. Long-acting tropane analogues have been synthesized that could be candidates for such pharmacotherapies. 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) is one such compound that is a relatively selective dopamine (DA) transporter blocker that has a significantly longer duration of action than cocaine. The purpose of this study was to assess the effects of PTT on the intravenous self-administration of cocaine, heroin, or cocaine/heroin combinations. Groups of rats were trained to self-administer cocaine, heroin, or cocaine/heroin combinations using a within session dosing procedure in which three doses were available each session. PTT pretreatment reduced cocaine and cocaine/heroin combinations intake in a dose-dependent manner while having only minor effects on heroin intake. These results suggest that the neurobiological substrates of cocaine and heroin self-administration are different, and that these cocaine/heroin combinations may function more like cocaine alone, even when the dose of heroin in the mixture will function independently as a reinforcer. These results further support the potential use of long-acting dopamine reuptake inhibitors as pharmacotherapeutic adjuncts to a comprehensive treatment program for cocaine and cocaine/heroin abuse.

Involvement of cholinergic neuronal systems in intravenous cocaine self-administration.

Recent studies suggest the participation of cholinergic neurons in the brain processes underlying reinforcement. The involvement of cholinergic neurons in cocaine self-administration has been recently demonstrated in studies using muscarinic and nicotinic agonists and antagonists, microdialysis, assessment of choline acetyltransferase activity and acetylcholine (ACh) turnover rates. The present experiment was initiated to identify subsets of cholinergic neurons involved in the brain processes that underlie cocaine self-administration by lesioning discrete populations with a selective neurotoxin. Rats were trained to self-administer cocaine and the cholinergic neurotoxin 192-IgG-saporin or vehicle was then bilaterally administered into the posterior nucleus accumbens (NAcc)-ventral pallidum (VP). The 192-IgG-saporin induced lesions resulted in a pattern of drug-intake consistent with either a shift in the dose intake relationship to the left or downward compared to sham-treated controls. A second experiment used a self-administration threshold procedure that demonstrated this lesion shifted the dose intake relationship to the left compared to the sham-vehicle treated rats. The magnitude and extent of the lesion was assessed by measuring the expression of p75 (the target for 192-IgG-saporin) and choline acetyltransferase (ChAT) in the NAcc, VP, caudate nucleus-putamen (CP) and vertical limb of the medial septal nucleus-diagonal band (MS-DB) of these rats using real time reverse transcriptase-polymerase chain reaction. Significant reductions in gene expression for p75 (a selective marker for basal forebrain cholinergic neurons) and ChAT were seen in the MS-DB and VP while only small decreases were seen in the NAcc and CP of the 192-IgG-saporin treated rats. These data indicate that the overall influence of cholinergic neurons in the MS-DB and VP are inhibitory to the processes underlying cocaine self-administration and suggest that agonists directed toward subclasses of cholinergic receptors may have efficacy as pharmacotherapeutic adjuncts for the treatment of cocaine abuse.

Time-dependent recovery from the effects of 6-hydroxydopamine lesions of the rat nucleus accumbens on cocaine self-administration and the levels of dopamine in microdialysates.

RATIONALE: Neurotoxin induced lesions of dopamine-releasing neurons that innervate the nucleus accumbens (NAcc) alter cocaine self-administration. In addition, elevated extracellular levels of NAcc dopamine (DA) are thought to be central to the biological mechanisms that underlie this behavior. OBJECTIVES: This study assessed the long-term effects of 6-hydroxydopamine (6-OHDA) induced lesions of the NAcc on cocaine self-administration and the dialysate levels of dopamine ([DA](d)) in this structure to determine if recovery of drug intake was correlated with the DA response. METHODS: Rats implanted with jugular catheters and bilateral cannulas were trained to self-administer cocaine and subsequently received bilateral intracranial micro-injections of 6-OHDA or vehicle into the NAcc. The levels of DA and cocaine were determined in microdialysates of the NAcc collected during experimental sessions 6-7, 14-16, 29-30, and 44-46 days post-treatment. RESULTS: The 6-OHDA induced lesions significantly reduced cocaine self-administration for 3 weeks while vehicle treatment had a moderate effect for the first several days. Cocaine-induced increases in NAcc [DA](d) did not return to sham/vehicle treated control levels for 6 weeks in the lesioned group and DA content in the NAcc was 46% of control at 44 days post-lesion. CONCLUSIONS: Although dopaminergic lesions of the NAcc produced profound effects on cocaine self-administration, responding recovered to control levels before cocaine-induced increases in NAcc [DA](d) while content of DA in the NAcc did not recover. These data suggest that the plasticity of neuronal systems in the NAcc related to cocaine self-administration and their response following 6-OHDA lesions is more complex than restoration of DAergic tone.