Nicotine withdrawal and kappa-opioid receptors.
BACKGROUND
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synthesis and release of dynorphin are increased in the caudate/putamen (CPU) and nucleus accumbens (NAc) of nicotine-withdrawn mice, suggesting a role in the nicotine abstinence syndrome.


OBJECTIVE
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.


METHODS
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]GTPgammaS binding autoradiography and inhibition of adenylyl cyclase activity.


RESULTS
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]GTPgammaS binding was attenuated in both striatal regions, especially in NAc. In NAc shell and core, stimulated [(35)S]GTPgammaS 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.


CONCLUSIONS
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.
McCarthy
Michael J
MJ
Department of Psychiatry, The Ohio State University College of Medicine, 5038 Graves Hall, 333 West 10th Ave, Columbus, OH 43210, USA.
Zhang
Hailing
H
Neff
Norton H
NH
Hadjiconstantinou
Maria
M
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects* / Q000378:metabolism; D044482:Benzeneacetamides / Q000494:pharmacology; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D004399:Dynorphins / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D009538:Nicotine / Q000009:adverse effects*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*
D000067956:Adenylyl Cyclase Inhibitors; D044482:Benzeneacetamides; D011759:Pyrrolidines; D012333:RNA, Messenger; D017473:Receptors, Opioid, kappa; D009538:Nicotine; D004399:Dynorphins; D019204:GTP-Binding Proteins; C045444:U 69593