Intravenous Ethanol Administration and Operant Self-Administration Alter Extracellular Norepinephrine Concentration in the Mesocorticolimbic Systems of Male Long Evans Rats.

BACKGROUND: Norepinephrine has been suggested to regulate ethanol (EtOH)-related behaviors, but little is known about the effects of EtOH on norepinephrine release in mesocortical and mesolimbic brain areas that are targets of EtOH actions. METHODS: We used in vivo microdialysis to examine the effects of EtOH on extracellular norepinephrine concentrations in mesocorticolimbic brain regions of male Long Evans rats. We determined the effects of intravenous infusion of saline or EtOH in the medial prefrontal cortex (mPFC) and the basal forebrain. We also measured dialysate norepinephrine concentrations during operant self-administration of EtOH in the mPFC. RESULTS: Intravenous infusion (1 or 0.25 ml/min) of 1.0 g/kg EtOH stimulated an increase in dialysate norepinephrine in mPFC and in basal forebrain. In the basal forebrain, an infusion of 0.5 g/kg EtOH did not stimulate dialysate norepinephrine concentrations. In both regions, saline infusions did not increase dialysate norepinephrine concentrations. In the behavioral experiment, 1 week of experience with operant self-administration of sweetened EtOH resulted in an apparent reduction in basal dialysate norepinephrine concentrations in the mPFC relative to the sucrose control. Dialysate norepinephrine increased during the transfer from home cage to the operant chamber in all groups. CONCLUSIONS: We conclude that acute EtOH stimulates both the locus coeruleus (which projects to the mPFC) and the nucleus tractus solitarius (which projects to the basal forebrain) noradrenergic neurons. Additionally, limited EtOH self-administration experience alters dialysate norepinephrine in the mPFC in a manner consistent with a decrease in tonic norepinephrine release. Further studies are necessary to elucidate the mechanisms by which EtOH exerts these variable effects.

Behavioral, neurobiological, and neurochemical mechanisms of ethanol self-administration: A translational review.

Alcohol use disorder has multiple characteristics including excessive ethanol consumption, impaired control over drinking behaviors, craving and withdrawal symptoms, compulsive seeking behaviors, and is considered a chronic condition. Relapse is common. Determining the neurobiological targets of ethanol and the adaptations induced by chronic ethanol exposure is critical to understanding the clinical manifestation of alcohol use disorders, the mechanisms underlying the various features of the disorder, and for informing medication development. In the present review, we discuss ethanol's interactions with a variety of neurotransmitter systems, summarizing findings from preclinical and translational studies to highlight recent progress in the field. We then describe animal models of ethanol self-administration, emphasizing the value, limitations, and validity of commonly used models. Lastly, we summarize the behavioral changes induced by chronic ethanol self-administration, with an emphasis on cue-elicited behavior, the role of ethanol-related memories, and the emergence of habitual ethanol seeking behavior.

Regional Analysis of the Pharmacological Effects of Acute Ethanol on Extracellular Striatal Dopamine Activity.

BACKGROUND: The objective of this study was to characterize the acute pharmacological effects of ethanol (EtOH) on extracellular dopamine in the dorsomedial and dorsolateral striata. This is the first study to quantify and directly compare the effects of acute EtOH on dopamine in these subregions. Therefore, we also tested the nucleus accumbens as a positive control. We hypothesized that while EtOH may increase extracellular dopamine in the dorsomedial striatum and dorsolateral striatum, the magnitude of this increase and the temporal profiles of extracellular dopamine concentrations would differ among the dorsomedial striatum, dorsolateral striatum, and nucleus accumbens. METHODS: We performed in vivo microdialysis in adult, male Long Evans rats as they received a single (experiment 1) or repeated (experiment 2) doses of EtOH. RESULTS: The results of our positive control study validate earlier work by our laboratory demonstrating that acute intravenous EtOH immediately and robustly increases extracellular dopamine in the nucleus accumbens (Howard et al., ). In contrast, a single 1-g/kg dose of intravenous EtOH did not significantly affect extracellular dopamine in the dorsomedial striatum or the dorsolateral striatum. However, following a cumulative EtOH dosing protocol, we observed a ramping up of tonic dopamine activity in both the dorsomedial striatum and dorsolateral striatum over the course of the experiment, but this effect was more robust in the dorsomedial striatum. CONCLUSIONS: These results suggest that distinct mechanisms underlie the stimulating effects of acute EtOH on extracellular dopamine in striatal subregions. Additionally, our findings suggest a role for the dorsomedial striatum and minimal-to-no role for the dorsolateral striatum in mediating the intoxicating effects of acute moderate to high doses of EtOH.

Medial Prefrontal Cortical Dopamine Responses During Operant Self-Administration of Sweetened Ethanol.

BACKGROUND: Medial prefrontal cortex (mPFC) dysfunction is present in heavy alcohol consumers. Dopamine signaling in mPFC is associated with executive functioning and affects drinking behavior; however, direct measurement of extracellular mPFC dopamine during appetitive and consummatory ethanol (EtOH) self-administration behavior has not been reported. METHODS: We used in vivo microdialysis in freely behaving, adult, male, Long Evans rats to determine extracellular dopamine concentration in the mPFC during operant self-administration of an EtOH-plus-sucrose or sucrose solution. The model separated appetitive/seeking from consummatory phases of the operant session. Dopamine was also monitored in an untrained handling control group, and dialysate EtOH was measured in the EtOH-drinking group. RESULTS: Home cage baseline dopamine was lower in rats that experienced a week of drinking sweetened EtOH compared with sucrose-drinking and handling controls. Transfer into the operant chamber and the initiation of consumption stimulated a relatively higher change in dopamine over baseline in the sweetened EtOH group compared with sucrose and handling controls. However, all groups show a dopamine response during transfer into the operant chamber, and the sucrose group had a relatively higher change in dopamine over baseline during initiation of consumption compared with handling controls. The time courses of dopamine and EtOH in the mPFC differ in the EtOH-consuming rats. CONCLUSIONS: Differences in extracellular mPFC dopamine between EtOH drinkers compared with control groups suggest that mPFC dopamine is involved in the mechanism of operant self-administration of sweetened EtOH and sucrose. Furthermore, the increase in dopamine during consumption is consistent with a role of mPFC dopamine in reward prediction.

Temporal profiles dissociate regional extracellular ethanol versus dopamine concentrations.

In vivo monitoring of dopamine via microdialysis has demonstrated that acute, systemic ethanol increases extracellular dopamine in regions innervated by dopaminergic neurons originating in the ventral tegmental area and substantia nigra. Simultaneous measurement of dialysate dopamine and ethanol allows comparison of the time courses of their extracellular concentrations. Early studies demonstrated dissociations between the time courses of brain ethanol concentrations and dopaminergic responses in the nucleus accumbens (NAc) elicited by acute ethanol administration. Both brain ethanol and extracellular dopamine levels peak during the first 5 min following systemic ethanol administration, but the dopamine response returns to baseline while brain ethanol concentrations remain elevated. Post hoc analyses examined ratios of the dopamine response (represented as a percent above baseline) to tissue concentrations of ethanol at different time points within the first 25-30 min in the prefrontal cortex, NAc core and shell, and dorsomedial striatum following a single intravenous infusion of ethanol (1 g/kg). The temporal patterns of these "response ratios" differed across brain regions, possibly due to regional differences in the mechanisms underlying the decline of the dopamine signal associated with acute intravenous ethanol administration and/or to the differential effects of acute ethanol on the properties of subpopulations of midbrain dopamine neurons. This Review draws on neurochemical, physiological, and molecular studies to summarize the effects of acute ethanol administration on dopamine activity in the prefrontal cortex and striatal regions, to explore the potential reasons for the regional differences observed in the decline of ethanol-induced dopamine signals, and to suggest directions for future research.