5-HT 2A receptor- and M 1 muscarinic acetylcholine receptor-mediated activation of Gα q/11 in postmortem dorsolateral prefrontal cortex of opiate addicts

Chronic exposure to opiates causes the development of tolerance and physical dependence as well as persistent brain neuroplasticity. Despite a wealth of postmortem human studies for opiate addicts, little direct information regarding the functional status of serotonergic and cholinergic receptor-mediated signaling pathways in the human brain of opiate addicts is yet available. Functional activation of Gα proteins coupled to 5-HT and M type muscarinic acetylcholine receptor (mAChR) was assessed by using the method named [ S]GTPγS binding/immunoprecipitation in frontal cortical membrane preparations from postmortem human brains obtained from opiate addicts and matched controls. Concentration-response curves for 5-HT and carbachol in individual subjects were analyzed according to a nonlinear regression model, which generated the values of maximum percent increase (%E ), negative logarithm of the half-maximal effect (pEC ) and slope factor. As for 5-HT receptor-mediated Gα activation, the %E values were reduced significantly and the pEC values were decreased significantly in opiate addicts as compared to the control group. Regarding carbachol-induced Gα activation, no significant difference in %E or pEC values was detected between the both groups, whereas the slope factor was increased significantly in opiate addicts as compared to the control group. Our data demonstrate that the signaling pathways mediated by Gα proteins coupled with 5-HT receptors and M mAChRs in prefrontal cortex are functionally altered in opiate addicts in comparison with control subjects. These alterations may underpin some aspects of addictive behavior to opiate as well as neuropsychological consequences or comorbid mental disorders associated with opioid use.