Chronic amphetamine treatment enhances corticotropin-releasing factor-induced serotonin release in the amygdala.

Amphetamine use is associated with dysphoric states, including heightened anxiety, that emerge within 24h of withdrawal from the drug. Corticotropin-releasing factor increases serotonin release in the central nucleus of the amygdala, and this neurochemical circuitry may play a role in mediating fear and anxiety states. We have previously shown that chronic amphetamine treatment increases corticotropin-releasing factor receptor type-2 levels in the serotonergic dorsal raphe nucleus of the rat. Therefore, we hypothesized that chronic amphetamine treatment would enhance the amygdalar serotonergic response to corticotropin-releasing factor infused into the dorsal raphe nucleus. Male rats were injected once-daily with d-amphetamine (2.5mg/kg i.p., or saline) for two weeks. Serotonin release within the central nucleus of the amygdala in response to intra-raphe infusion of corticotropin-releasing factor (100 ng) was measured 24h after the last treatment in urethane-anesthetized (1.8 mg/kg, i.p.) rats using in vivo microdialysis. Rats pretreated with amphetamine showed significantly enhanced serotonin release in the central nucleus of the amygdala in response to corticotropin-releasing factor infusion when compared to saline pretreated rats. Furthermore, this enhanced response was blocked by the corticotropin-releasing factor type-2 receptor antagonist antisauvagine-30 (2 microg) infused into the dorsal raphe nucleus. These results suggest increased sensitivity to corticotropin-releasing factor as mediated by type-2 receptors following chronic amphetamine treatment, which may underlie dysphoric states observed during amphetamine withdrawal.