Nicotine withdrawal and kappa-opioid receptors

作者：McCarthy Michael J; Zhang Hailing; Neff Norton H; Hadjiconstantinou Maria^*

来源：Psychopharmacology, 2010, 210(2): 221-229.

DOI：10.1007/s00213-009-1674-5

• Nicotine withdrawal
• kappa-opioid receptors
• Binding
• mRNA
• [(35)S]GTP gamma S binding
• Adenylyl cyclase
• Desensitization
• Caudate/putamen
• Nucleus accumbens

The synthesis and release of dynorphin are increased in the caudate/putamen (CPU) and nucleus accumbens (NAc) of nicotine-withdrawn mice, suggesting a role in the nicotine abstinence syndrome.
This study aims to investigate the consequences of enhanced dynorphinergic activity on kappa-opioid receptor (KOPr) expression, coupling, and function in CPU and NAc following chronic nicotine administration and withdrawal.
Mice were injected with nicotine-free base 2 mg/kg, or saline, sc, four times daily for 14 days and experiments performed at 24, 48, and 72 h after drug discontinuation. KOPr binding and mRNA were evaluated by [(3)H]-U69,593 autoradiography and in situ hybridization. KOPr coupling and function were investigated by agonist (U69-593)-stimulated [(35)S]GTP gamma S binding autoradiography and inhibition of adenylyl cyclase activity.
KOPr binding density and mRNA in CPU and NAc were unaltered during nicotine withdrawal; however, KPOr mRNA was increased in midbrain. U69,593-stimulated [(35)S]GTP gamma S binding was attenuated in both striatal regions, especially in NAc. In NAc shell and core, stimulated [(35)S]GTP gamma S binding was significantly decreased by 24 h and further declined over the 72 h observation period. In CPU, significant changes were observed only at 72 h. Basal adenylyl cyclase activity decreased early during nicotine withdrawal and recovered by 48 h. Stimulation with U69,593 failed to inhibit adenylyl cyclase activity at all times studied.
These observations suggest that KOPr coupling and function are impaired in NAc and CPU during nicotine withdrawal, and imply receptor desensitization. KOPr desensitization might be a mechanism to ameliorate aversive behavioral symptoms, as nicotine withdrawal evolves.

• 出版日期2010-6