Methamphetamine induced dysfunction of spiny projection neurons in the dorsal striatum

Abstract

Methamphetamine (meth) is an addictive psychostimulant, and its use, related hospitalization, and overdose death are increasing, making it classified as the second most illicit drug after cannabis worldwide. Patients suffer from relapse despite abstinence from meth, and the absence of FDA-approved therapy for meth addiction exacerbates the crisis. Continued use of meth results in diverse psychiatric and physiological abnormalities, yet the underlying neuronal changes resulting in meth use disorders are unclear and understudied. Meth primarily binds to vesicular monoamine transporters and reuptake transporters in the monoaminergic neurons, and induces dysfunction of these proteins, causing elevated neurotransmitters in the cytosol and synaptic cleft. Within meth addiction, binding in dopaminergic neurons and increasing dopamine concentration in the synaptic cleft is reinforcing and contributes to the euphorigenic effects of meth. There are two dopaminergic nuclei in the brain, ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Both nuclei form distinctive circuitry; VTA projecting dopamine to the nucleus accumbens, forming the mesolimbic pathway and SNc projecting dopamine to the dorsal striatum, forming nigrostriatal pathway. Extensive studies discovered the role of mesolimbic pathway in drug abuse; it contributes to various forms of drug-taking and drug-seeking behaviors, controlling value of reward, motivation to earn reward, and reinforcement of the reward. However, the nigrostriatal pathway also plays vital role in drug addiction. Repeated cocaine exposure shows increased DAT expressions in dorsal striatum, and lesioning or inactivation of dorsal striatum has attenuated drug-seeking behaviors in rodent models of self-administration. Dorsal striatum can be subdivided into two regions: dorsomedial (DMS) or dorsolateral striatum (DLS) with the DMS implicated in goal-directed and DLS in habitual behaviors. Studies show both regions are involved in drug-seeking behaviors using rodent models of self-administration including alcohol, cocaine, and meth. However, the underlying changes in neuronal function in response to drug exposure in these two regions remain understudied. Both regions primarily consist of spiny projection neurons, that can be subdivided into two groups: D1 dopamine receptor expressing direct-pathway spiny projection neurons (dSPNs) and D2 dopamine receptor expressing indirect spiny projection neurons (iSPNs). Antagonism or transgenic knockdown of either receptors in dorsal striatum decreased drug-seeking behaviors or drug consumptions in rodent models of self-administration, indicating the involvement of these two neurons with drug addiction. However, the drug-induced neurodysfunction, especially in meth, remains understudied, and deciphering their roles in meth addiction would potentially provide a key for developing pharmacotherapy against meth addiction. In this project, I utilized non-contingent meth administration and intravenous self-administration models in mice to show meth-induced changes in iSPN and dSPN function in DLS and DMS. Using transgenic mouse model to differentiate iSPNs and dSPNs, animals underwent either aforementioned paradigm and iSPNs and dSPNs in DLS and DMS were assessed using whole cell patch clamp techniques. I found that during acute abstinence from non-contingent meth administration, DMS iSPN neuronal excitability was increased, whereas during protracted abstinence DMS iSPN excitability was decreased. DMS dSPNs and DLS iSPNs and dSPNs remained unchanged in both acute and protracted abstinence from non-contingent meth administration. I also found that meth self-administration caused DLS dSPN hyperexcitability during acute abstinence, with no change in DLS iSPN excitability. Together, these results indicate the complexity of meth-induced neurodysfunctions in DLS and DMS, that are specific to cell-type, abstinence duration, and route of administration. Lastly using isradipine, L-type Ca2+ channel inhibitor, which also showed neuroprotective effect against meth-induced neurodegeneration, attenuated cue-associated meth-seeking behavior, suggesting a potential candidate for effective pharmacotherapy targeting both addictive and neurotoxic elements of meth.