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

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 Cart tm1Amgen 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.

Injection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens reduces cocaine self-administration in rats

“…Couceyro et al (2005) found a decrease in cocaine self-administration as well as altered amphetamine-induced locomotor activation and sensitization in CART knockout mice [ 8 ]. In contrast, another study found no differences in cocaine self-administration or cocaine-induced locomotor sensitization between wild type and CART knockout mice [ 33 ].…”

Genetic regulation of hypothalamic cocaine and amphetamine-regulated transcript (CART) in BxD inbred mice

“…ICV and intraaccumbal CART administration modulates mesolimbic dopaminergic (DA) activity (Yang et al, 2004;Shieh, 2003;Kuhar et al, 2005) and DA-mediated behaviors. For example, intraventral tegmental area (VTA) CART injections induce locomotor activation (which is blocked by DA antagonists), attenuates cocaine-induced spontaneous locomotion, and promotes conditioned placed preference (Jaworski et al, 2003;Couceyro et al, 2005;Kimmel et al, 2000). In addition, CART peptides have been shown to be potent anorectic and anxiogenic agents.…”

CART peptides as modulators of dopamine and psychostimulants and interactions with the mesolimbic dopaminergic system

“…In studies in CART knockout mice, repeated doses of amphetamine produce a much smaller and delayed locomotor sensitization than in controls [38]. This is in direct contrast to a separate study, using different CART knockout mice, that found no change in the sensitization to cocaine in CART knockouts [39].…”

“…CART knockout mice also did not show any sensitization to the effects of amphetamine. The same mice, however showed no inhibition of open field activity and sucrose preference, indicating that the elimination of the CART gene did not effect locomotor ability or taste preference [38]. In contrast, separate studies using the different strain of CART knockout mice did not detect a difference in cocaine-induced locomotor activity, cocaine self-administration or sensitization to the behavioral effects of cocaine [39,42].…”

“…Couceyro et al [38], using the mice generated by Wierup et al [41] reports that locomotor activity was decreased after cocaine and that vertical and stereotypic activity were decreased after amphetamine in the CART knockout group. In addition, responding for intravenous cocaine and total cocaine consumption were reduced in CART knockouts.…”