Kappa-opioid receptor modulation of nicotine-induced behaviour.
The ability of kappa-opioid receptor ligands to modulate dependence-related behavioural effects of drugs like morphine and cocaine is well documented. The present study examined the effects of kappa-opioid agonists on nicotine-induced locomotor stimulation in rats chronically pre-exposed to nicotine (0.4 mg/kg/day). U50,488 [0.5-3 mg/kg subcutaneously (s.c.)], U69,593 [0.08-0.32 mg/kg intraperitoneally (i.p.)] and CI-977 (0.005-0.02 mg/kg s.c.) administered 30 min prior to nicotine (0.06, 0.2 and 0.4 mg/kg s.c.) dose-dependently antagonised its acute locomotor-activating effect, which was completely prevented by the highest tested dose of each agonist. Baseline activity was unaffected by the largest doses of U50,488 and U69,593, but it was reduced by 0.01 and 0.02 mg/kg of CI-977. The selective kappa-opioid receptor antagonist nor-BNI [30 microg intracerebroventricularly (i.c.v.)] blocked the effects of U69,593 on nicotine-induced behaviour, thus supporting the involvement of kappa-opioid receptors in this effect. In conclusion, the activation of kappa-opioid receptors clearly prevented nicotine-induced locomotor stimulation. The effects of at least two of the kappa-opioid agonists were not due to a general motor suppression. It is suggested that the mechanism entails a depression of nicotine-induced increases in accumbal dopamine by these compounds. The results should encourage further research on the role of the kappa-opioid system in the behavioural and neurochemical effects of nicotine, including those related to nicotine dependence.
Hahn
B
B
Section of Behavioural Pharmacology, Institute of Psychiatry, De Crespigny Park, SE5 8AF, London, UK. b.hahn@iop.kcl.ac.uk
Stolerman
I P
IP
Shoaib
M
M
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D044482:Benzeneacetamides; D001572:Benzofurans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*
D044482:Benzeneacetamides; D001572:Benzofurans; D018722:Nicotinic Agonists; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009538:Nicotine; C045444:U 69593; C067110:enadoline