Differential regulation of 5-HT2A receptor mRNA expression following withdrawal from a chronic escalating dose regimen of D-amphetamine.

Several lines of evidence indicate that psychostimulant withdrawal can induce negative emotional symptoms, such as anhedonia and dysphoria, which may be due in part, to dysfunction of the serotonin (5-HT) system, including alterations in 5-HT receptors. For example, changes in 5-HT(2A) receptor function in prefrontal cortex (PFC) have been reported in association with psychostimulant withdrawal. However, it is not known if alterations in 5-HT(2A) receptor mRNA expression occur in the PFC or other limbic-associated areas following withdrawal from chronic psychostimulant treatment. The goal of the current study was to determine the effects of chronic, escalating doses of D-amphetamine (D-AMPH) and withdrawal on the expression of 5-HT(2A) receptors in the cortex, caudate putamen, NAc and hippocampus of rat brain. Animals were treated three times a day for 4 days with escalating doses of D-AMPH (1-10 mg/kg). Twenty-four hours after the final dose of D-AMPH, animals were sacrificed and the tissue processed for in situ hybridization histochemistry. Chronic, escalating doses of D-AMPH, followed by a 24 h withdrawal period, significantly decreased 5-HT(2A) receptor mRNA expression in the prefrontal, motor and cingulate cortices, while 5-HT(2A) receptor mRNA expression in the NAc, caudal CPu and hippocampus were significantly increased. These data indicate that region-specific changes in 5-HT(2A) receptor mRNA expression occur in limbic system and associated areas following chronic D-AMPH treatment, supporting the notion that alterations in the 5-HT system may contribute to the negative emotional aspects of psychostimulant withdrawal.