Synaptic and Morphological Neuroadaptations in the Putamen Associated with Long-Term, Relapsing Alcohol Drinking in Primates

Abstract

Alcoholism and alcohol use disorders are characterized by several months to decades of heavy and problematic drinking, interspersed with periods of abstinence and relapse to heavy drinking. This alcohol-drinking phenotype was modeled using macaque monkeys to explore neuronal adaptations in the striatum, a brain region controlling habitual behaviors. Prolonged drinking with repeated abstinence narrowed the variability in daily intake, increased the amount of ethanol consumed in bouts, and led to higher blood ethanol concentrations more than twice the legal intoxication limit. After the final abstinence period of this extensive drinking protocol, we found a selective increase in dendritic spine density and enhanced glutamatergic transmission in the putamen, but not in the caudate nucleus. Intrinsic excitability of medium-sized spiny neurons was also enhanced in the putamen of alcohol-drinking monkeys in comparison with non-drinkers, and GABAeric transmission was selectively suppressed in the putamen of heavy drinkers. These morphological and physiological changes indicate a shift in the balance of inhibitory/excitatory transmission that biases the circuit toward an enduring increase in synaptic activation of putamen output as a consequence of prolonged heavy drinking/relapse. The resultant potential for increased putamen activation may underlie an alcohol-drinking phenotype of regulated drinking and sustained intoxication.

Hampered long-term depression and thin spine loss in the nucleus accumbens of ethanol-dependent rats

“…In the latter study, the increased AMPArmediated mEPSC amplitude was associated with enhanced membrane insertion of GluA-lacking AMPA receptors, which are characterized by high unitary channel conductance (55). Consistent with previous studies in rodents and nonhuman primates (53,54), ethanol withdrawal was accompanied by an increased MSN intrinsic excitability. Such an effect was not associated with altered AP threshold value, but could possibly be related to the increased input resistance that predicts a higher voltage change (i.e., higher depolarization) in response to a cationic current.…”

Monkeys that Voluntarily and Chronically Drink Alcohol Damage their Brains: a Longitudinal MRI Study

“…First, the brains of old-world monkeys, such as the rhesus macaque (Macaca mulatta) species studied here, are gyroencephalic and, like humans, have a large fraction of intracranial space occupied by white matter. Second, nonhuman primates are similar to humans in showing wide individual differences in average voluntary daily ethanol consumption, with a significant proportion categorized as chronic heavy drinkers and voluntarily drinking ethanol to physical dependence (Cuzon-Carlson et al, 2011;Welsh et al, 2011). Third, macaques have relatively long life spans, allowing prolonged ethanol exposure (months to years) and enabling insight into mechanisms of long-term physiological adaptations, possibly modeling adverse biomedical outcomes of excessive alcohol consumption in humans (Cheng et al, 2010;Ivester et al, 2007;Shively et al, 2007).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Dorsal striatum and associated sensorimotor structures have been implicated in the development of addiction, particularly in the mediation of habit formation, and this region has also emerged as a site of alcohol-induced neuroadaptations. In cynomolgus monkeys, prolonged 930 intermittent alcohol drinking decreased the frequency of GABA A receptor-mediated miniature IPSCs recorded from the MSNs in the caudoventral area of the putamen (Cuzon Carlson et al, 2011). This area corresponds to the dorsolateral striatum in rodents, and a similar reduction of IPSC frequency was produced by repeated binge drinking in mice in this striatal area, but also in the dorsomedial striatum (Wilcox et al, 2014).…”

“…In the NAc, both chronic alcohol drinking and alcohol withdrawal decreased spine density, accompanied by reduction in NMDAR-mediated synaptic Drug-Induced Neuroplasticity currents and hampered LTD Spiga et al, 2014). On the other hand, prolonged intermittent alcohol drinking in cynomolgus monkeys increased the density of dendritic spines and glutamatergic transmission in the putamen, but not in the caudate nucleus (Cuzon Carlson et al, 2011). Similarly, chronic intermittent alcohol exposure increased spine density in the mPFC in mice (Kroener et al, 2012).…”