Novel mechanisms for correcting opioid-induced synaptic abnormalities

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Abstract The US is facing a crisis of opioid overdoses and addiction. Current therapies consist largely of alternative opioids (i.e. maintenance with methadone or buprenorphine) and do not correct neurobiological factors that underlie drug craving and relapse. These factors include the long-lasting changes at glutamatergic synapses in the nucleus accumbens (NAc), which both resemble and differ from changes induced by other highly addictive drugs such as cocaine. Our recent studies suggest these synaptic effects of opioids are opposed by acid- sensing ion channels (ASICs). ASICs conduct inward Na+ and Ca2+ current at post-synaptic dendritic spines where they are activated during synaptic transmission by protons released into the synaptic cleft from neurotransmitter-containing vesicles. Because these protons are removed from the synaptic cleft via the actions of carbonic anhydrase 4 (CA4), genetically disrupting CA4 or pharmacologically inhibiting CA4 with acetazolamide (AZD) dramatically increases synaptic ASIC currents. These observations have led to our hypothesis that AZD will reverse synaptic changes following opioid withdrawal by inhibiting CA4 and increasing ASIC activity, and thereby reduce craving and relapse. In this proposal we plan to test this hypothesis by rigorously assessing effects of opioids on synaptic physiology and behavior. Together the experiments in this proposal will pave the way to a better understanding of the neurobiology underlying opioid addiction and to new molecular targets for treating opioid use disorder (OUD). Knowledge gained from these studies could suggest new ways to treat opioid addiction through non-opioidergic mechanisms, for example by manipulating ASICs, brain pH, or carbonic anhydrase, for which a number of inhibitors are already approved for human use, and might be efficiently repurposed.