Repeated administration of methamphetamine causes hypersensitivity of D2 receptor in rat ventral tegmental area.

To elucidate whether the methamphetamine (MAP)-induced hypersensitivity to dopamine occurs in the ventral tegmental area (VTA), patch clamp studies were performed using brain slice preparations. MAP or physiological saline was administered to 8-10-day-old rats daily for 5 days. On day 5, patch clamp studies were performed on VTA dopamine neurons which were identified by morphological and electrophysiological characteristics. Dopamine (1-100 microM) and talipexole (a dopamine D2 receptor agonist, 1-100 microM) produced a dose-dependent hyperpolarization in these neurons; treatment with SKF 38393 or PD128907 (Dl and D3 receptor agonists, respectively) had no effect. The extent of hyperpolarization was significantly greater in the MAP group compared to the saline controls, suggesting that repeated MAP administration causes a hypersensitivity to dopamine that is D2 receptor-dependent. This hypersensitivity reduces the excitability of VTA dopamine neurons, thus decreasing dopamine release in the nucleus accumbens area. This may compensate for the MAP-induced elevation of dopamine levels and modulate the dopamine-induced signal transduction cascades, leading to reverse tolerance in nucleus accumbens neurons.