am4113 and ecopipam

Behavioral activation is a fundamental feature of motivation, and organisms frequently make effort-related decisions based upon evaluations of reinforcement value and response costs. Furthermore, people with major depression and other disorders often show anergia, psychomotor retardation, fatigue, and alterations in effort-related decision making. Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine induces depressive symptoms in humans, and also preferentially depletes dopamine (DA). Rats were assessed using a concurrent progressive ratio (PROG)/chow feeding task, in which they can either lever press on a PROG schedule for preferred high-carbohydrate food, or approach and consume a less-preferred lab chow that is freely available in the chamber. Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs. The present work demonstrated that tetrabenazine produced an effort-related shift in responding on the PROG/chow procedure, reducing lever presses, highest ratio achieved and time spent responding, but not reducing chow intake. Similar effects were produced by administration of the subtype selective DA antagonists ecopipam (D1) and eticlopride (D2), but not by the cannabinoid CB1 receptor neutral antagonist and putative appetite suppressant AM 4413, which suppressed both lever pressing and chow intake. The adenosine A2A antagonist MSX-3, the antidepressant and catecholamine uptake inhibitor bupropion, and the MAO-B inhibitor deprenyl, all reversed the impairments induced by tetrabenazine. This work demonstrates the potential utility of the PROG/chow procedure as a rodent model of the effort-related deficits observed in depressed patients.

Topics: Animals; Antidepressive Agents; Benzazepines; Benzophenones; Bupropion; Cannabinoid Receptor Antagonists; Choice Behavior; Depression; Dopamine Antagonists; Drug Evaluation, Preclinical; Feeding Behavior; Male; Nitrophenols; Pyrazoles; Rats, Sprague-Dawley; Salicylamides; Selegiline; Tetrabenazine; Tolcapone; Vesicular Monoamine Transport Proteins; Xanthines

Cannabinoid CB1 antagonists/inverse agonists suppress food-motivated behaviors and are being evaluated as potential appetite suppressants. It has been suggested that the effects of CB1 antagonism on food motivation could be related to actions on mesolimbic dopamine (DA). If this were true, then the effects of interference with cannabinoid CB1 transmission should closely resemble the effects of interference with DA transmission.. To directly compare the effects of DA antagonists with those of CB1 antagonists/inverse agonists, the present studies employed a concurrent lever-pressing/chow-intake procedure. With this task, interference with DA transmission shifts choice behavior such that lever pressing for a preferred food is decreased but chow intake is increased.. Rats treated with IP injections of the DA D1 antagonist SCH39166 (ecopipam; 0.05-0.2 mg/kg) or the D2 antagonist eticlopride (0.025-0.1 mg/kg) showed substantial decreases in lever pressing and concomitant increases in chow consumption. In contrast, IP administration of the CB1 neutral antagonist AM4113 (4.0-16.0 mg/kg) or the CB1 antagonist/inverse agonist AM251 (2.0-8.0 mg/kg) decreased operant responding for pellets, but there was no corresponding increase in chow intake.. These effects of CB1 antagonists/inverse agonists were similar to those produced by the appetite suppressant fenfluramine and by prefeeding. In contrast, low doses of DA antagonists leave primary food motivation intact, but shift behaviors toward food reinforcers that can be obtained with lower response costs. These results suggest that the effects of interference with CB1 transmission are readily distinguishable from those of reduced DA transmission.

Topics: Animals; Benzazepines; Choice Behavior; Conditioning, Operant; Dopamine Antagonists; Feeding Behavior; Food Preferences; Injections, Intraperitoneal; Male; Motivation; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Reinforcement Schedule; Salicylamides