Alcohol activates orosensory circuits that project to motivationally relevant limbic forebrain areas that control appetite, feeding and drinking. To date, limited data exists regarding the contribution of chemosensory-derived ethanol reinforcement to ethanol preference and consumption. Measures of taste reactivity to intra-orally infused ethanol have not found differences in initial orofacial responses to alcohol between alcohol-preferring (P) and – nonpreferring (NP) genetically selected rat lines. Yet, in voluntary intake tests P rats prefer highly-concentrated ethanol upon initial exposure, suggesting an early sensory-mediated attraction. Here, we directly compared self-initiated chemosensory responding for alcohol and prototypic sweet, bitter, and oral trigeminal stimuli among selectively bred P, NP, and non-selected Wistar (WI) outbred lines to determine whether differential sensory responsiveness to ethanol and its putative sensory components are phenotypically associated with genetically-influenced alcohol preference. Rats were tested for immediate short-term lick responses to alcohol (3–40%), sucrose (0.01–1 M), quinine (0.01–3 mM) and capsaicin (0.003–1 mM) in a brief-access assay designed to index orosensory-guided behavior. P rats exhibited elevated short-term lick responses to both alcohol and sucrose relative to NP and WI lines across a broad range of concentrations of each stimulus and in the absence of blood alcohol levels that would produce significant postabsorptive effects. There was no consistent relationship between genetically-mediated alcohol preference and orosensory avoidance of quinine or capsaicin. These data indicate that enhanced initial chemosensory attraction to ethanol and sweet stimuli are phenotypes associated with genetic alcohol preference and are considered within the framework of downstream activation of oral appetitive reward circuits.

The purpose of this study was to determine whether chronic administration of D 9-tetrahydrocannabinol (THC) during adolescence would (1) modify any sex-specific effects of THC on learning and (2) affect the development of tolerance to THC as an adult. Male and female rats received daily injections of saline or 5.6 mg/kg of THC from postnatal day 35-75, yielding four groups (female/saline, female/THC, male/saline, and male/THC). Rats were then trained on a procedure that assayed both learning and performance behavior and administered 0.32-18 mg/kg of THC acutely as adults (experiment 1). THC produced rate-decreasing and error-increasing effects in both sexes; however, female rats were more sensitive than male rats were to the rate-decreasing effects. Rats were then chronically administered 10 mg/kg of THC (experiment 2). Rats that received THC during adolescence developed tolerance to the rate-decreasing effects more slowly and less completely than did rats that received saline; in addition, females developed tolerance to the error-increasing effects of THC slower than males did. Western blot analysis of brain tissue indicated long-term changes in hippocampal and striatal cannabinoid type-1 receptor (CB1R) levels despite levels that were indistinguishable immediately after chronic treatment during adolescence. Striatal CB1R levels were increased in adult rats that received THC during adolescence; hippocampal CB1R levels varied by sex. In summary, female rats were more sensitive than male rats were to the acute and chronic effects of THC, and chronic administration of THC during adolescence produced long-term changes in CB1R levels that correlated with decreased tolerance development to the rate-decreasing effects of THC.

Learning is believed to be reflected in the activity of the hippocampus. However, neural correlates of learning have been difficult to characterize because hippocampal activity is integrated with ongoing behavior. To address this issue, male rats (n=5) implanted with electrodes (n=14) in the CA1 subfield responded during two tasks within a single test session. In one task, subjects acquired a new 3-response sequence (acquisition), whereas in the other task, subjects completed a well-rehearsed 3-response sequence (performance). Both tasks though could be completed using an identical response topography and used the same sensory stimuli and schedule of reinforcement. More important, comparing neural patterns during sequence acquisition to those during sequence performance allows for a subtractive approach whereby activity associated with learning could potentially be dissociated from the activity associated with ongoing behavior. At sites where CA1 activity was closely associated with behavior, the patterns of activity were differentially modulated by key position and the serial position of a response within the schedule of reinforcement. Temporal shifts between peak activity and responding on particular keys also occurred during sequence acquisition, but not during sequence performance. Ethanol disrupted CA1 activity while producing rate-decreasing effects in both tasks and error-increasing effects that were more selective for sequence acquisition than sequence performance. Ethanol also produced alterations in the magnitude of modulations and temporal pattern of CA1 activity, although these effects were not selective for sequence acquisition. Similar to ethanol, hippocampal micro-stimulation decreased response rate in both tasks and selectively increased the percentage of errors during sequence acquisition, and provided a more direct demonstration of hippocampal involvement during sequence acquisition. Together, these results strongly support the notion that ethanol disrupts sequence acquisition by disrupting hippocampal activity and that the hippocampus is necessary for the conditioned associations required for sequence acquisition.

Alcohol abuse is a serious public health concern, with over three million Americans suffering from an alcohol use disorder annually. Currently available therapeutics for treating alcohol use disorder have limited clinical effectiveness; as such, there is a pressing need for new treatments. Pregabalin (Lyrica®), a voltage‐gated calcium channel inhibitor, has garnered interest as a potential therapeutic to help reduce alcohol intake and maintain abstinence in patients with alcohol use disorder. However, the data supporting such an indication are lacking and there do not appear to be any published studies investigating whether pregabalin can alter the acute effects of alcohol on learning and memory. The purpose of this study was twofold: 1) determine doses of pregabalin that decrease ethanol‐ and food‐maintained responding, and 2) test the hypothesis that doses of pregabalin that decrease ethanol intake will also alter the disruptive effects of ethanol on complex acquisition and performance behavior. Two separate groups of adult Long‐Evans rats were used for these studies. The first group of rats (n=9) responded under a multiple fixed‐ratio 10, variable‐interval 80‐sec schedule of ethanol (32% v/v) and food (45‐mg pellets) reinforcement, respectively. The second group (n=12) responded under a multiple schedule of repeated acquisition and performance of response sequences in which responding in both components was maintained by food reinforcement under a second‐order fixed‐ratio 3 schedule. In the first group, 18 – 180 mg/kg (i.p.) of pregabalin dose‐dependently decreased both ethanol‐ and food‐maintained responding, as well as post‐session blood ethanol concentrations; however, food‐maintained responding was more potently decreased than ethanol‐maintained responding. This lack of selectivity of pregabalin for reducing ethanol intake was further complicated by the effects of pregabalin and ethanol on the acquisition and performance task. In the second group, ethanol alone (0.56 – 2.37 g/kg, i.p.) dose‐dependently decreased response rates and increased percent errors in both the acquisition and performance components, although acquisition was more sensitive to disruption than performance. Furthermore, when doses of pregabalin (18 – 100 mg/kg, i.p.) that had no effect alone under this baseline were administered prior to ethanol, the dose‐effect curves for both response rate and accuracy were shifted leftward (i.e., smaller doses of ethanol were needed to decrease response rates and increase percent errors). These findings indicate that pregabalin can decrease ethanol intake, but that these doses will likely decrease responding for other reinforcers and potentiate the disruptive effects of ethanol on complex acquisition and performance behaviors. As such, pregabalin might not be useful in treating patients with alcohol use disorder even if they are already abstinent from alcohol because there is an increased risk of negative health consequences.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.