Inhibition of PSD95‐nNOS protein–protein interactions decreases morphine reward and relapse vulnerability in rats

Glutamate signalling through the N‐methyl‐d‐aspartate receptor (NMDAR) activates the enzyme neuronal nitric oxide synthase (nNOS) to produce the signalling molecule nitric oxide (NO). We hypothesized that disruption of the protein–protein interaction between nNOS and the scaffolding protein postsynaptic density 95 kDa (PSD95) would block NMDAR‐dependent NO signalling and represent a viable therapeutic route to decrease opioid reward and relapse‐like behaviour without the unwanted side effects of NMDAR antagonists. We used a conditioned place preference (CPP) paradigm to evaluate the impact of two small‐molecule PSD95‐nNOS inhibitors, IC87201 and ZL006, on the rewarding effects of morphine. Both IC87201 and ZL006 blocked morphine‐induced CPP at doses that lacked intrinsic rewarding or aversive properties. Furthermore, in vivo fast‐scan cyclic voltammetry (FSCV) was used to ascertain the impact of ZL006 on morphine‐induced increases in dopamine (DA) efflux in the nucleus accumbens shell (NAc shell) evoked by electrical stimulation of the medial forebrain bundle (MFB). ZL006 attenuated morphine‐induced increases in DA efflux at a dose that did not have intrinsic effects on DA transmission. We also employed multiple intravenous drug self‐administration approaches to examine the impact of ZL006 on the reinforcing effects of morphine. Interestingly, ZL006 did not alter acquisition or maintenance of morphine self‐administration, but reduced lever pressing in a morphine relapse test after forced abstinence. Our results provide behavioural and neurochemical support for the hypothesis that inhibition of PSD95‐nNOS protein–protein interactions decreases morphine reward and relapse‐like behaviour, highlighting a previously unreported application for these novel therapeutics in the treatment of opioid addiction.