Nowak J Z, Arbilla S, Galzin A M, Langer S Z
J Pharmacol Exp Ther. 1983 Aug;226(2):558-64.
The release of recently taken up [3H]dopamine ([3H]DA) elicited by electrical stimulation (3 Hz, 2 min, 16 mA) from slices of the rabbit caudate nucleus is inhibited by apomorphine (0.01-0.1 microM) in a concentration-dependent manner. This action is mediated through the activation of presynaptic inhibitory DA autoreceptors. The inhibition of [3H]DA release by apomorphine (0.1 microM) was antagonized 2 hr, but not 24 hr after the single administration of haloperidol (1 mg/kg s.c.). After 2 days of withdrawal after 28 days of chronic treatment with haloperidol (1 mg/kg s.c.) once daily, apomorphine (0.01-0.1 microM) was more effective in inhibiting [3H]DA release elicited by electrical stimulation when compared with rabbits injected chronically with either the vehicle for haloperidol or with saline. In superfused slices of the rabbit caudate nucleus, exposure to S-sulpiride (0.1 and 1 microM) increased in a concentration-dependent manner the release of [3H] DA elicited by electrical stimulation. After 28 days of chronic treatment with haloperidol, the facilitation of [3H]DA release by S-sulpiride was significantly reduced when compared with the controls. The inhibition of central noradrenergic transmission by DA receptor agonists was studied in hypothalamic slices prelabeled with [3H]norepinephrine ([3H-NE]). Apomorphine (0.01-1 microM) inhibited the electrically evoked (5 Hz, 2 min, 26 mA) release of [3H]NE from hypothalamic slices of untreated rabbits. The sensitivity to the inhibitory effect of apomorphine on [3H]NE overflow remained unaffected after 2 days of withdrawal following 28 days of chronic treatment with haloperidol. In summary, our results indicate that chronic haloperidol administration induces changes in sensitivity of the DA autoreceptors regulating dopaminergic neurotransmission but does not affect the sensitivity of DA receptors modulating NE release in the central nervous system. These results suggest that the DA autoreceptors that regulate dopaminergic neurotransmission may play a physiological role in the modulation of transmitter release and consequently are susceptible to the development of changes in sensitivity after chronic receptor blockade. The possible implication of changes in sensitivity of the DA autoreceptor during the treatment of schizophrenia with neuroleptics is discussed.
电刺激（3赫兹，2分钟，16毫安）诱发兔尾状核切片释放近期摄取的[3H]多巴胺（[3H]DA），可被阿扑吗啡（0.01 - 0.1微摩尔）以浓度依赖的方式抑制。此作用通过激活突触前抑制性DA自身受体介导。单次注射氟哌啶醇（1毫克/千克，皮下注射）2小时后，阿扑吗啡（0.1微摩尔）对[3H]DA释放的抑制作用被拮抗，但24小时后未被拮抗。在每天一次用氟哌啶醇（1毫克/千克，皮下注射）慢性治疗28天后停药2天，与长期注射氟哌啶醇溶媒或生理盐水的兔子相比，阿扑吗啡（0.01 - 0.1微摩尔）在抑制电刺激诱发的[3H]DA释放方面更有效。在兔尾状核的灌流切片中，暴露于S - 舒必利（0.1和1微摩尔）会以浓度依赖的方式增加电刺激诱发的[3H]DA释放。用氟哌啶醇慢性治疗28天后，与对照组相比，S - 舒必利对[3H]DA释放的促进作用显著降低。在预先用[3H]去甲肾上腺素（[3H - NE]）标记的下丘脑切片中研究了DA受体激动剂对中枢去甲肾上腺素能传递的抑制作用。阿扑吗啡（0.01 - 1微摩尔）抑制未处理兔子下丘脑切片中电诱发（5赫兹，2分钟，26毫安）的[3H]NE释放。在每天一次用氟哌啶醇慢性治疗28天后停药2天，阿扑吗啡对[3H]NE溢出的抑制作用敏感性未受影响。总之，我们的结果表明，慢性给予氟哌啶醇会诱导调节多巴胺能神经传递的DA自身受体敏感性发生变化，但不影响调节中枢神经系统中NE释放的DA受体敏感性。这些结果表明，调节多巴胺能神经传递的DA自身受体可能在递质释放的调节中发挥生理作用，因此在慢性受体阻断后易发生敏感性变化。讨论了用抗精神病药物治疗精神分裂症期间DA自身受体敏感性变化的可能意义。
