Central amygdala CART modulates ethanol withdrawal-induced anxiety

Cocaine- and amphetamine-regulated transcript (CART), as its name implies, was initially identified as an upregulated transcript in response to psychostimulant administration. Consequently, it has been posited to play a role in psychostimulant abuse and dependence. Spurred on by the finding that a polymorphism in the CART gene was associated with alcoholism, we initiated studies designed to elucidate the role of CART peptide in alcohol dependence. We first investigated the functional significance of CART peptide in alcohol dependence in vivo using a CART KO mouse. We found that CART KO mice had a significant decrease in ethanol consumption that could not be attributed to differences in total intake, taste perception, metabolism, or sensitivity to ethanol. In vitro we found that CART peptide facilitated NMDA receptor-mediated currents in central amygdala neurons. Given the emerging role of CART peptide in anxiety and stress, we decided to examine basal and stress-induced anxiety behaviors in CART KO mice. Under basal and acute stress conditions, CART KO mice did not differ in anxiety-like behaviors from WT mice; however, in response to a stressor, CART KO mice exhibited a potentiated corticosterone response. Using chronic intermittent ethanol exposure (CIE), we tested CART KO and WT mice for common signs of ethanol dependence including an escalation of volitional consumption and the presence of withdrawal-induced anxiety. We further investigated glutamatergic neuroadaptations within the central amygdala of CART KO and WT mice following CIE exposure and early withdrawal. CIE increased ethanol consumption and anxiety-like behaviors in mice of both genotypes but to a lower extent in CART KO mice. Electrophysiologically, CIE enhanced spontaneous excitatory postsynaptic currents in both genotypes and decreased the probability of presynaptic release in WT mice only. We believe that these electrophysiological neuroadaptations contribute to the development of ethanol dependence and may mediate withdrawal-induced anxiety behaviors. Overall, these studies indicate a role for CART peptide in alcohol dependence and specifically in modulating ethanol withdrawal-induced anxiety.