Effects of selective D1- or D2-like dopamine receptor antagonists with acute "binge" pattern cocaine on corticotropin-releasing hormone and proopiomelanocortin mRNA levels in the hypothalamus.

We have previously demonstrated that there are stimulatory effects of acute (1 day) "binge" cocaine on corticotropin-releasing hormone (CRH) gene expression in the rat hypothalamus and on the stress responsive hypothalamic-pituitary-adrenal (HPA) activity. The first aim of the present study was to investigate the possible role of dopamine (DA) D1- or D2-like receptors (D1R or D2R) in modulating these acute effects. Administration of acute "binge" cocaine (3x15 mg/kg, i.p.) was preceded by injections of either the selective D1R antagonist (SCH23390, 2 mg/kg) or D2R antagonist (sulpiride, 50 mg/kg). The D1R or D2R blockade by SCH23390 or sulpiride, respectively, did not alter the mRNA levels of CRH in the hypothalamus, CRH-R1 or proopiomelanocortin (POMC) in the anterior pituitary. However, the acute "binge" cocaine-induced increase in hypothalamic CRH mRNA levels was not found in the rats that received either D1R or D2R antagonist pretreatment. In the anterior pituitary, acute "binge" cocaine or its combinations with either DA antagonist did not alter CRH-R1 receptor or POMC mRNA levels. Both the D1R and D2R antagonists attenuated the elevation of plasma corticosterone levels induced by acute "binge" cocaine. These results suggest that both D1R and D2R mediate acute cocaine's stimulatory effect on HPA axis at the hypothalamic CRH level. Neurobiological evidence has demonstrated functional interactions between dopaminergic and opioidergic systems that regulate preproenkephalin and preprodynorphin gene expression in the striatum. The second aim of our study was to investigate the roles that D1R or D2R could play in regulation of POMC mRNA levels in the hypothalamus in response to acute "binge" cocaine. The D2R blockade by sulpiride increased POMC mRNA levels in the hypothalamus, indicating that D2R exerts a tonic inhibitory effect on hypothalamic POMC gene expression. The POMC mRNA increases induced by the D2R blockade were attenuated by acute "binge" cocaine. Neither the D2R blockade nor acute "binge" cocaine altered POMC mRNA levels in the amygdala, anterior pituitary or neurointermediate lobe of the pituitary. In contrast to the D2R, the D1R blockade by SCH23390, acute "binge" cocaine or their combination had no effect on hypothalamic POMC mRNA levels. These results support a specific role for D2R in acute cocaine's effects on hypothalamic POMC gene expression.

Effects of acute "binge" cocaine on preprodynorphin, preproenkephalin, proopiomelanocortin, and corticotropin-releasing hormone receptor mRNA levels in the striatum and hypothalamic-pituitary-adrenal axis of mu-opioid receptor knockout mice.

Cocaine administration increases activity at dopamine receptors, increases preprodynorphin (ppDyn) gene expression in the caudate-putamen (CPu), and activates the stress responsive hypothalamic-pituitary-adrenal (HPA) axis. To examine the hypothesis that mu-opioid receptors (MOR) may play roles in these cocaine effects, we tested the effects of acute "binge" pattern cocaine administration in mice with targeted disruption of the MOR gene. Wild-type (+/+) and homozygous MOR-deficient (-/-) mice received three injections of 15 mg/kg cocaine at 1-h intervals. Mice were sacrificed 30 min after the last injection and mRNAs for ppDyn and preproenkephalin (ppEnk) in the CPu and nucleus accumbens (NAc), and for type I corticotropin-releasing hormone receptor (CRH(1) receptor) and pro-opiomelanocortin (POMC) in the hypothalamus and pituitary, were measured by solution hybridization RNase protection assays. Cocaine elevated ppDyn mRNA in the CPu, but not NAc, of both the MOR -/- and wild-type mice. ppEnk mRNA in the CPu, but not NAc, was lower in MOR -/- mice than in wild-type mice following cocaine administration. Hypothalamic CRH(1) receptor and POMC mRNAs were expressed at similar levels in untreated and in cocaine-treated mice of each genotype. However, there were lower basal levels of CRH(1) receptor mRNA in the anterior pituitary of the MOR -/- mice than in wild-type mice and the MOR -/- mice failed to show the cocaine-induced decreases in CRH(1) receptor mRNA found in the wild-type mice. Cocaine activated the HPA axis similarly in MOR -/- and wild-type mice, as reflected in similar increases in plasma corticosterone levels in both genotypes. These results support a specific role for MORs in acute cocaine effects on striatal ppEnk gene expression and fail to support critical roles for these receptors in acute cocaine's effects on either ppDyn gene expression or HPA activation. MOR -/- mice are useful models for studying cocaine effects on ppEnk gene expression that could aid interpretation of the similar postmortem phenomena found in human cocaine addicts.