Cocaine- and Amphetamine-Regulated Transcript (CART) Peptides Modulate the Locomotor and Motivational Properties of Psychostimulants

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Abstract
Drug addiction results from a subversion of neural circuits that control motivation. Although the hedonic and addictive properties of psychostimulants and drugs of abuse are predominantly attributed to dopamine and glutamate, it is appreciated that other signaling molecules in the brain are important. This study suggests that cocaine- and amphetamine-regulated transcript (CART) peptides modulate the locomotor and motivational properties of psychostimulants. The behavioral effects of cocaine and amphetamine were examined in Carttm1Amgen knockout (Cart KO) and wild-type (WT) mice. Acute amphetamine administration increased in locomotor activity in WT mice, but this response was attenuated in Cart KO mice. Repeated amphetamine produced locomotor sensitization in WT mice but hardly any in Cart KO mice. Amphetamine elicited conditioned place preference in both genotypes, but amphetamine's potency was reduced in the Cart KO mice. Intravenous cocaine self-administration was observed in both genotypes, but Cart KO mice consumed less cocaine and responded less for cocaine than WT mice. The behavioral effects of psychostimulants were reduced in the mutant Cart KO mice. By contrast, open field activity and sucrose preference of drug-naive mice WT and Cart KO mice were not significantly different. The attenuated effects of amphetamine and cocaine in Cart KO mice suggest a positive neuromodulatory role for CART peptides in the locomotor and motivational properties of psychostimulants and implicate CART peptides in psychostimulant addiction.