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.
Amano
Taku
T
Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi Minami-Ku, 734-8551 Hiroshima, Japan. amanot@hiroshima-u.ac.jp
Matsubayashi
Hiroaki
H
Seki
Takahiro
T
Sasa
Masashi
M
Sakai
Norio
N
D000818:Animals; D000831:Animals, Newborn; D001381:Azepines / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008694:Methamphetamine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology
D001381:Azepines; D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D008694:Methamphetamine; C024763:talipexole; D004298:Dopamine