Functional consequences of the acute administration of the cannabinoid receptor antagonist, SR141716A, in cannabinoid-naive and -tolerant animals:: a quantitative 2-[14C]deoxyglucose study

Cannabinoid systems have been shown to be involved in the regulation of ingestive behaviors. Administration of the cannabinoid antagonist, SR141716A, markedly reduces intake of sucrose solutions, food pellets, and ethanol. The purpose of the present studies was to identify the neural substrates that mediate these actions in rats using the quantitative autoradiographic 2-[C-14]deoxyglucose (2-DG) method. In the first study, rats were trained to lever press in daily 15-min sessions for food pellets under a fixed-ratio schedule of food presentation. On the day of the experiment, rats received SR141716A (0, 1 or 3 mg/kg, i.p.) 15 min prior to behavioral testing, and the 2-DG procedure was initiated immediately after the operant test session. The acute administration of SR141716A dose-dependently decreased rates of responding and was accompanied by decreases in glucose utilization concentrated in the limbic system, particularly those areas mediating motivated behavior. Because the effects of SR141716A on behavior are intensified in animals tolerant to the effects of Delta(9)-THC, the purpose of the second study was to assess the effects of the SR141716A administration on food-maintained responding and rates of glucose utilization in tolerant animals. The suppression of responding was greater in tolerant than in drug-naive animals. Furthermore, decreases in cerebral metabolism were more intense and widespread. Although still concentrated in limbic regions, functional changes now included areas subserving the regulation of ingestive behavior including the hypothalamus. These data suggest that the effects of SR141716A administration shift in the tolerant animal and may involve different aspects of feeding behavior than in cannabinoid-naive animals. (C) 2002 Elsevier Science B.V. All rights reserved.