Validation of the extinction probe trial as a measure of motivation in male and female Long Evans rats.

BACKGROUND: Ethanol self-administration is governed by appetitive and consummatory behaviors. The sipper model procedurally separates these behaviors by training rats to meet a response requirement within 20 min to obtain continuous access to a sipper tube for an additional 20 min. Variations of this paradigm have been developed to quantify appetitive strength by evaluating lever presses during an extinction probe trial (EPT) or by deriving a break point (BP) from a progressive ratio (PR) schedule of reinforcement. However, no study has assessed the relationship between these tasks, within subjects, in both sexes. METHODS: Male and female rats (n = 16) were trained to meet a response requirement of 20 to access a slightly sweetened ethanol solution (10% ethanol + 1% sucrose). Two EPTs, during which no operant behavior was reinforced, were interleaved between 18 reinforced sessions. Next, rats completed an across-session PR schedule, where the response requirement increased each session. BP was defined as the highest completed response requirement. We then replicated the methodology in the same subjects responding for a 3% sucrose solution. Finally, the experiment was replicated in a separate cohort of rats (n = 24) trained to a response requirement of 4 to earn access to the ethanol solution and paradigm order (EPT vs. PR) was counterbalanced. RESULTS: We report strong, positive correlations between average EPT lever presses and BP across all experiments. No sex differences were observed in appetitive behaviors. However, the two cohorts revealed mixed results when assessing sex differences in consummatory measures. CONCLUSIONS: This study further validates the EPT as a measure of motivation and suggests that similar levels of motivation exist to procure alcohol in males and females. The findings complement the literature showing that appetitive and consummatory processes are distinct and thus should be independently assessed in self-administration paradigms.

Chemogenetic inhibition of a monosynaptic projection from the basolateral amygdala to the ventral hippocampus selectively reduces appetitive, but not consummatory, alcohol drinking-related behaviours.

Alcohol use disorder (AUD) and anxiety/stressor disorders frequently co-occur and this dual diagnosis represents a major health and economic problem worldwide. The basolateral amygdala (BLA) is a key brain region that is known to contribute to the aetiology of both disorders. Although many studies have implicated BLA hyperexcitability in the pathogenesis of AUD and comorbid conditions, relatively little is known about the specific efferent projections from this brain region that contribute to these disorders. Recent optogenetic studies have shown that the BLA sends a strong monosynaptic excitatory projection to the ventral hippocampus (vHC) and that this circuit modulates anxiety- and fear-related behaviours. However, it is not known if this pathway influences alcohol drinking-related behaviours. Here, we employed a rodent operant self-administration regimen that procedurally separates appetitive (e.g. seeking) and consummatory (e.g., drinking) behaviours, chemogenetics and brain region-specific microinjections, to determine if BLA-vHC circuitry influences alcohol and sucrose drinking-related measures. We first confirmed prior optogenetic findings that silencing this circuit reduced anxiety-like behaviours on the elevated plus maze. We then demonstrated that inhibiting the BLA-vHC pathway significantly reduced appetitive drinking-related behaviours for both alcohol and sucrose while having no effect on consummatory measures. Taken together, these findings provide the first indication that the BLA-vHC circuit may regulate appetitive reward seeking directed at alcohol and natural rewards and add to a growing body of evidence suggesting that dysregulation of this pathway may contribute to the pathophysiology of AUD and anxiety/stressor-related disorders.

Sexually dimorphic effects of a modified adolescent social isolation paradigm on behavioral risk factors of alcohol use disorder in Long Evans Rats.

Early life stress (ELS) is a major risk factor for alcohol use disorder (AUD) and comorbid neuropsychiatric conditions. We previously demonstrated that an adolescent social isolation (aSI) model of ELS significantly increased behavioral risk factors for these disorders (e.g. anxiety-like behaviors, alcohol drinking) in male, but not female rats. Since many neurodevelopmental milestones are accelerated in females, we investigated whether an earlier/shorter isolation window (PND 21-38) would yield comparable phenotypes in both sexes. In two experiments, Long Evans rats were socially isolated (SI) or group-housed (GH) on postnatal day (PND) 21 and locomotion was assessed in the open field test (OFT; PND 30). Experiment 1 also assessed behavior on the elevated plus-maze (EPM) (PND 32). In Experiment 2, all rats were single housed on PND 38 to assess home cage alcohol drinking. Experiment 1 revealed that SI females had increased locomotor activity in the OFT but did not differ from GH subjects on the EPM. The OFT results were replicated in both sexes in Experiment 2 and both male and female SI rats had significantly greater ethanol consumption during an eight day continuous access paradigm. In contrast, during subsequent intermittent two-bottle choice drinking, only SI females displayed greater ethanol intake and preference and increased consumption of a quinine-adulterated alcohol solution. These findings demonstrate that early life social isolation can promote AUD vulnerability-related phenotypes in female rats but that there are profound sex differences in the vulnerability window to this early life stressor. Uncovering the neural mechanisms responsible for these sexually dimorphic differences in sensitivity to ELS may shed light on the biological substrates associated with vulnerability to AUD and comorbid disorders of negative emotion in men and women.

The behavioral economics of alcohol demand in Greek-affiliated college students.

BACKGROUND: College students affiliated with fraternity and sorority, or "Greek" life represent a known high-risk group for alcohol consumption and related consequences, but little is known about demand for alcohol in this population. The current study examined behavioral economic demand for alcohol in a sample of Greek life-affiliated undergraduate students using the alcohol purchase task (APT) and a novel variation of the APT that included a fixed-price, nonalcoholic alternative (APT Choice). METHODS: Participants (n = 229) completed the APT, APT Choice, Alcohol Use Disorders Identification Test (AUDIT), and Daily Drinking Questionnaire (DDQ). Group demand indices were calculated for the entire sample and then separately for participants who met or did not meet the legal drinking age (21+ or underage, respectively). Independent-sample t tests assessed whether there were any significant differences between the two age cohorts in the percent change in each behavioral economic index from the APT to APT Choice. Tests of correlation evaluated the construct validity of the demand indices from both hypothetical purchase tasks. RESULTS: Descriptive statistics on alcohol use in this Greek-affiliated sample revealed "hazardous" drinking scores, with AUDIT-C scores exceeding the threshold of alcohol misuse. These measures were significantly correlated with demand indices from both APT conditions, and demand was inversely related to price; however, demand for alcohol was reduced when a nonalcoholic alternative was available. Both age cohorts reported a reduction in BP1 (highest price of nonzero consumption) and an increase in α (rate of change in elasticity), but these changes were significantly greater among underage participants. CONCLUSIONS: Although Greek life-affiliated students demonstrate high demand for alcohol, the concurrent availability of a nonalcoholic alternative reduces alcohol demand, particularly for underage students. These findings suggest that nonalcoholic options may enhance the effectiveness of increasing alcohol prices to reduce alcohol consumption among students at higher risk for alcohol use.