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-HT2A receptor function in prefrontal cortex (PFC) have been reported in association with psychostimulant withdrawal. However, it is not known if alterations in 5-HT2A 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-HT2A 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-HT2A receptor mRNA expression in the prefrontal, motor and cingulate cortices, while 5-HT2A receptor mRNA expression in the NAc, caudal CPu and hippocampus were significantly increased. These data indicate that region-specific changes in 5-HT2A 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.

Research highlights
► Amphetamine withdrawal induces dysphoria and anhedonia.
► Dysfunction of the 5-HT system, including 5-HT2A receptors may contribute to these symptoms.
► We examined 5‐HT2A receptor mRNA expression following amphetamine withdrawal.
► 5‐HT2A receptor expression is suppressed in the cortex but increased in other regions of the limbic system.
► Changes in 5-HT2A receptor expression in the limbic system may contribute to withdrawal-induced depression.