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.

Repeated cycles of binge alcohol drinking and abstinence are key components in the development of dependence. However, the precise behavioral mechanisms underlying binge-like drinking and its consequences on striatal synaptic physiology remain unclear. In the present study, ethanol and water drinking patterns were recorded with high temporal resolution over 6 weeks of binge-like ethanol drinking using the ‘drinking in the dark' (DID) protocol. The bottle exchange occurring at the beginning of each session prompted a transient increase in the drinking rate that might facilitate the acquisition of ethanol binge-like drinking. Ethanol drinking mice also displayed a ‘front-loading' behavior, in which the highest rate of drinking was recorded during the first 15 min. This rate increased over weeks and paralleled the mild escalation of blood ethanol concentrations. GABAergic and glutamatergic transmission in the dorsal striatum were examined following DID. Spontaneous glutamatergic transmission and the density of dendritic spines were unchanged after ethanol drinking. However, the frequency of GABAA receptor-mediated inhibitory postsynaptic currents was depressed in medium spiny neurons of ethanol drinking mice. A history of ethanol drinking also increased ethanol preference and altered the acute ethanol effects on GABAergic transmission differentially in dorsolateral and dorsomedial striatum. Together, the study shows that the bottle exchange during DID promotes fast, voluntary ethanol drinking and that this intermittent pattern of ethanol drinking causes a depression of GABAergic transmission in the dorsal striatum.

Background Experimental evidence correlates anesthetic exposure during early development with neuronal and glial injury and death, as well as behavioral and cognitive impairments, in young animals. Several, although not all, retrospective human studies of neurocognitive and behavioral disorders after childhood exposure to anesthesia suggest a similar association. Few studies have specifically investigated the effects of infant anesthesia exposure on subsequent neurobehavioral development. Using a highly translational nonhuman primate model, the authors investigated the potential dose-dependent effects of anesthesia across the first year of development. Methods The authors examined the effects of single or multiple early postnatal isoflurane exposures on subsequent behavioral development in 24 socially reared rhesus macaques. Infants were exposed to 5 h of isoflurane anesthesia once, three times (ISO-3), or not at all (control). The authors assessed reflex development and anxiety using standardized tests. At approximately 1 yr, infants (n = 23) were weaned and housed indoors with 5 to 6 other subjects. The authors recorded their response to this move and reassessed anxiety. Results Compared to controls, animals exposed to repeated isoflurane (ISO-3) presented with motor reflex deficits at 1 month (median [range]: ISO-3 = 2 [1 to 5] vs. control = 5 [3 to 7]; P < 0.005) and responded to their new social environment with increased anxiety (median [range]: ISO-3 = 0.4 bouts/min [0.2 to 0.6]; control = 0.25 bouts/min [0.1 to 0.3]; P = 0.05) and affiliative/appeasement behavior (median [range]: ISO-3 = 0.1 [0 to 0.2]; control = 0 bouts/min [0 to 0.1]; P < 0.01) at 12 months. There were no statistically significant behavioral alterations after single isoflurane exposure. Conclusions Neonatal exposure to isoflurane, particularly when repeated, has long-term behavioral consequences affecting both motor and socioemotional aspects of behavior.

Background-Experimental evidence correlates anesthetic exposure during early development with neuronal and glial injury and death as well as behavioral and cognitive impairments in young animals. Several, although not all, retrospective human studies of neurocognitive and behavioral disorders following childhood exposure to anesthesia suggest a similar association. Few studies have specifically investigated the effects of infant anesthesia exposure on subsequent