Synaptic Plasticity and its Modulation by Alcohol

Abstract

Alcohol is one of the oldest pharmacological agents used for its sedative/hypnotic effects, and alcohol abuse and alcohol use disorder (AUD) continues to be major public health issue. AUD is strongly indicated to be a brain disorder, and the molecular and cellular mechanism/s by which alcohol produces its effects in the brain are only now beginning to be understood. In the brain, synaptic plasticity or strengthening or weakening of synapses, can be enhanced or reduced by a variety of stimulation paradigms. Synaptic plasticity is thought to be responsible for important processes involved in the cellular mechanisms of learning and memory. Long-term potentiation (LTP) is a form of synaptic plasticity, and occurs via N-methyl-D-aspartate type glutamate receptor (NMDAR or GluN) dependent and independent mechanisms. In particular, NMDARs are a major target of alcohol, and are implicated in different types of learning and memory. Therefore, understanding the effect of alcohol on synaptic plasticity and transmission mediated by glutamatergic signaling is becoming important, and this will help us understand the significant contribution of the glutamatergic system in AUD. In the first part of this review, we will briefly discuss the mechanisms underlying long term synaptic plasticity in the dorsal striatum, neocortex and the hippocampus. In the second part we will discuss how alcohol (ethanol, EtOH) can modulate long term synaptic plasticity in these three brain regions, mainly from neurophysiological and electrophysiological studies. Taken together, understanding the mechanism(s) underlying alcohol induced changes in brain function may lead to the development of more effective therapeutic agents to reduce AUDs.

SCH23390 Reduces Methamphetamine Self-Administration and Prevents Methamphetamine-Induced Striatal LTD

“…In the dorsal striatum, D 1 Rs and D 2 Rs play a role in mediating synaptic transmission and synaptic plasticity of GABAergic MSNs [33,[35][36][37][38], such that activation of these receptors produces long-term potentiation (LTP) and long-term depression (LTD). In the context of methamphetamine exposure, protracted withdrawal from experimenter-delivered methamphetamine or self-administered methamphetamine prevents high-frequency stimulation (HFS)-induced LTD in the dorsal striatum and produces LTP in the dorsal striatum [39,40].…”

Neuroligin Plays a Role in Ethanol-Induced Disruption of Memory and Corresponding Modulation of Glutamate Receptor Expression

“…There is some evidence from mammalian neuron culture studies that suggest Nlgn1 mutations can reduce long-term potentiation (LTP; cellular correlate of memory; Shipman and Nicoll, 2012;Jedlicka et al, 2015); however, evidence is lacking with regards to neuroligins recruiting new AMPA receptors to synapses (a hallmark feature of LTP; Shipman and Nicoll, 2012;Bemben et al, 2015). Ethanol has been shown to either inhibit or reverse LTP (Izumi et al, 2005;Yin et al, 2007;Mishra et al, 2012;Avchalumov and Mandyam, 2020). Thus, Nlgn1 function may oppose the effects of ethanol with regards to LTP.…”

“…Further, people who have experienced alcoholinduced blackouts continue to show impaired recall the next day when sober (Jackson et al, 2021). At the neuron level, cellular correlates of memory (primarily long-term potentiation and depression) are both attenuated by ethanol exposure (White et al, 2000;Chandler, 2003;Izumi et al, 2005;Avchalumov and Mandyam, 2020;Mira et al, 2020). Further, chronic alcohol exposure reportedly causes significant changes in expression of the overall brain transcriptome in prefrontal cortex neurons of mice (Liu et al, 2022).…”

Caveolin-1 Expression in the Dorsal Striatum Drives Methamphetamine Addiction-Like Behavior

“…Neurobiological mechanisms in the transition from drug use to drug dependence are heavily investigated, and a relationship between dopamine and corticostriatal synaptic activity is strongly implicated [ 5 , 6 ]. In the dorsal striatum, dopamine D1 receptors (D1Rs) and D2 receptors (D2Rs) play a role in mediating synaptic transmission and synaptic plasticity of GABAergic medium-sized spiny neurons (MSNs; [ 7 , 8 , 9 , 10 , 11 , 12 ]), such that activation of these receptors produces either long-term potentiation (LTP) or long-term depression (LTD). In the context of methamphetamine exposure, protracted withdrawal from experimenter delivered methamphetamine or self-administered methamphetamine prevents high frequency stimulation (HFS)-induced LTD and produces LTP in the dorsal striatum [ 13 , 14 ].…”