Synaptic and morphological neuroadaptations in the putamen associated with long-term, relapsing alcohol drinking in primates.

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.

Bidirectional plasticity in the primate inferior olive induced by chronic ethanol intoxication and sustained abstinence.

The brain adapts to chronic ethanol intoxication by altering synaptic and ion-channel function to increase excitability, a homeostatic counterbalance to inhibition by alcohol. Delirium tremens occurs when those adaptations are unmasked during withdrawal, but little is known about whether the primate brain returns to normal with repeated bouts of ethanol abuse and abstinence. Here, we show a form of bidirectional plasticity of pacemaking currents induced by chronic heavy drinking within the inferior olive of cynomolgus monkeys. Intracellular recordings of inferior olive neurons demonstrated that ethanol inhibited the tail current triggered by release from hyperpolarization (I(tail)). Both the slow deactivation of hyperpolarization-activated cyclic nucleotide-gated channels conducting the hyperpolarization-activated inward current and the activation of Ca(v)3.1 channels conducting the T-type calcium current (I(T)) contributed to I(tail), but ethanol inhibited only the I(T) component of I(tail). Recordings of inferior olive neurons obtained from chronically intoxicated monkeys revealed a significant up-regulation in I(tail) that was induced by 1 y of daily ethanol self-administration. The up-regulation was caused by a specific increase in I(T) which (i) greatly increased neurons' susceptibility for rebound excitation following hyperpolarization and (ii) may have accounted for intention tremors observed during ethanol withdrawal. In another set of monkeys, sustained abstinence produced the opposite effects: (i) a reduction in rebound excitability and (ii) a down-regulation of I(tail) caused by the down-regulation of both the hyperpolarization-activated inward current and I(T). Bidirectional plasticity of two hyperpolarization-sensitive currents following chronic ethanol abuse and abstinence may underlie persistent brain dysfunction in primates and be a target for therapy.

Who is at risk? Population characterization of alcohol self-administration in nonhuman primates helps identify pathways to dependence.

Alcohol abuse and dependence are human conditions for which no full equivalent exists in animals. Nevertheless, animal models frequently are used to study various aspects of alcohol dependence that cannot be easily or ethically assessed in humans, including neurobiological mechanisms underlying alcohol dependence. Many of these animal models involve rodents; however, the characteristics (i.e., phenotypes) of chronic heavy drinking may be limited in these species. Nonhuman primates add an important translational aspect to the study of alcohol abuse and alcoholism. Their genetic, anatomical, physiological, and behavioral similarity to humans offers unique opportunities for identifying risk factors that may predispose a person to or accelerate the course of alcohol addiction. Studying alcohol consumption in nonhuman primates, including the distribution of drinking levels in a population, also can be uniquely informative to alcohol research. For example, research on the self-administration procedures in primates can help scientists identify risk factors for excessive alcohol consumption in humans. The phenotype of excessive drinking then can serve as the starting point to test and verify the underlying genetic and environmental influences. The resulting findings, in turn, can help guide prevention and treatment strategies.