Behavioral effects of cocaine on a transgenic mouse model of cortical-limbic compulsion

We previously created a transgenic mouse model of cortical-limbic induced c ompulsions in which dopamine D1 receptor-expressing (D1 +) neurons in restr icted regional subsets of the cortex and amygdala express a neuropotentiati ng cholera toxin (CT) transgene. These 'D1CT' mice engage in complex behavi oral abnormalities uniquely resembling human compulsions, such as non-aggre ssive biting of cagemates during grooming, repeated leaping and episodes of perseverance of any and all normal behaviors. Because both compulsions and cocaine-induced behaviors may represent forms of psychomotor activation th at have a shared or overlapping neurological basis, we have examined the be havioral response of these 'compulsive' mice to cocaine. In both control an d D1CT mice, cocaine increased the amount of time spent engaged in typical cocaine-dependent stereotypies such as locomotion, sniffing, or gnawing, wh ile the remainder of behaviors within their normally complete behavioral re pertoires decreased. Cocaine also decreased, rather than facilitated, the i ncidence of D1CT transgene-induced compulsion-like behaviors such as repeat ed leaping and perseverance of any and all normal behaviors. The indistingu ishable cocaine responses of D1CT and normal mice, as well as the masking ( rather than potentiation) of D1CT mouse compulsion-like behaviors by cocain e, suggests that cortical-limbic induced compulsions are significantly diff erent in their origin or circuitry from cocaine-induced stereotyped behavio rs. Specifically, these data suggest that the motor circuits stimulated in compulsions represent only a subset of the parallel circuits stimulated by cocaine. These data are, thus, consistent with the hypothesis that topograp hically restricted subsets of parallel cortical-striatal-thalamic loops ind uce different types of compulsive behaviors. (C) 1999 Elsevier Science B.V. All rights reserved.