Involvement of Mouse Cerebellar Neuronal Nitric Oxide Synthase (nNOS) System in the Functional Interaction and Cross-Tolerance between Nicotine and Ethanol

Abstract

Despite cannabinoid and nicotine co‐abuse, no study has examined co‐infused intracerebellar (ICB) THC and nicotine effect on cerebellar ataxia (CA). Aims (i) evaluate ICB THC + nicotine effect on CA; (ii) obtain evidence for nNOS's role in THC‐induced CA, THC – nicotine FA and cross‐tolerance. Methods Rotorod evaluated CA in male CD‐1 mice. All drugs [THC 20μg; nicotine 5ng; nNOS inhibitor (nNOSI; 1,2,5 ng), N’‐nitroguanidine tristrifluracetate] were given by ICB infusion. Results Increased THC‐induced CA by nNOSI indicated nNOS mediation. nNOSI opposed nicotine‐induced attenuation of CA by THC. The antagonism was abolished by 5 ng nNOSI. The response curves of nNOSI + nicotine + THC and aCSF + THC treatments overlapped, further evidence of nNOS mediation. We have previously observed robust cross‐tolerance between nicotine and THC. Results of ongoing chronic study involving nNOSI and nicotine infusion<em style=”mso‐bidi‐font‐style: normal;”> (once daily x 5 days followed 16 h later by acute THC) may further support nNOS role. Discussion Nicotine activates NOS [present in cerebellar neurons except Purkinje cells (PCs)] via release of glutamate. Alleviation of CA is likely due to: increased release of glutamate ►enhanced glutamate transmission ►diffusion of NO into PCs► activation of GC and cGMP production ►low PC firing► removal of CA. Overall, the results support a role of cerebellar nNOS in the nicotine ‐‐THC FA and cross‐tolerance.