Indiana University-Purdue University Indianapolis (IUPUI) / Tolerance is a diagnostic criterion for alcohol use disorder (AUD) and dependence and is often measured metabolically or behaviorally by comparing blood ethanol concentrations (BEC) or locomotor performance to an ethanol (EtOH) challenge before and after a drinking history, respectively. To explore another aspect of chronic behavioral tolerance in a family history positive (FH+) model of AUD, crossed High Alcohol Preferring (cHAP) mice were allowed to respond instrumentally for an EtOH reinforcer after either a five-week history of continuous home cage two-bottle choice (2BC) drinking or a concurrent five-week water-drinking period. Additionally, some of these animals were placed back into the operant box after home cage drinking histories to respond in extinction, allowing for the quantification of alcohol-motivated seeking alone in the absence of EtOH taking and its intoxicating effects. The results demonstrate that an alcohol history does not lead to a subsequent increase in active lever responding or inactive lever responding when compared to water-drinking controls. However, female cHAP mice with an EtOH-drinking history respond more on the inactive lever in extinction compared to water controls, suggesting that home cage EtOH history potentiates variation in responding in extinction. Overall, female mice responded more on the active lever and drank more alcohol in the reinforced condition, but again, there was not an effect of drinking history on this sex-specific effect. Together these results suggest that while female cHAPs, regardless of drinking history, are more motivated to work to drink EtOH, reinforced and non-reinforced instrumental responding are not reliable readouts for tolerance in cHAP mice compared to other endpoints such as drinking in the dark (DID) assays.

<p>Tolerance is a diagnostic criterion for alcohol use disorder (AUD) and dependence and is often measured metabolically or behaviorally by comparing blood ethanol concentrations (BEC) or locomotor performance to an ethanol (EtOH) challenge before and after a drinking history, respectively. To explore another aspect of chronic behavioral tolerance in a family history positive (FH+) model of AUD, crossed High Alcohol Preferring (cHAP) mice were allowed to respond instrumentally for an EtOH reinforcer after either a five-week history of continuous home cage two-bottle choice (2BC) drinking or a concurrent five-week water-drinking period. Additionally, some of these animals were placed back into the operant box after home cage drinking histories to respond in extinction, allowing for the quantification of alcohol-motivated seeking alone in the absence of EtOH taking and its intoxicating effects. The results demonstrate that an alcohol history does not lead to a subsequent increase in active lever responding or inactive lever responding when compared to water-drinking controls. However, female cHAP mice with an EtOH-drinking history respond more on the inactive lever in extinction compared to water controls, suggesting that home cage EtOH history potentiates variation in responding in extinction. Overall, female mice responded more on the active lever and drank more alcohol in the reinforced condition, but again, there was not an effect of drinking history on this sex-specific effect. Together these results suggest that while female cHAPs, regardless of drinking history, are more motivated to work to drink EtOH, reinforced and non-reinforced instrumental responding are not reliable readouts for tolerance in cHAP mice compared to other endpoints such as drinking in the dark (DID) assays.</p>

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Indiana University-Purdue University Indianapolis (IUPUI) / It has been proposed that the GABAB receptor subtype plays a role in alcoholism and alcohol use disorders (AUDs) (Cousins et al., 2002; Agabio et al., 2012). Specifically, the GABAB agonist baclofen has been looked at extensively in clinical and pre-clinical studies. In various animal models of chronic and intermittent consumption, baclofen has been shown to both increase (Petry, 1997; Smith et al., 1999; Czachowski et al., 2006; Moore et al., 2007) and decrease (Colombo et al., 2000; 2002; 2005; Stromberg, 2004; Moore et al., 2009) drinking. A critical issue in determining pharmacological effects of a drug is using the appropriate animal model. The drinking-in-the-dark (DID) model, developed by Rhodes et al. (2005, 2007), produces high levels of drinking in a binge-like paradigm and has been used to assess many pharmacological targets (e.g. Kamdar et al., 2007; Gupta et al., 2008; Moore et al., 2007; 2009). While DID produces high-levels of binge drinking, it is unclear what areas of the brain are involved in this behavior. A direct way to target areas that are believed to be involved in the circuitry of particular behaviors is through microinjection of drugs (Kiianmaa et al., 2003). Of particular recent interest involving motivated behaviors and addiction is the nucleus accumbens (Acb) (Everitt & Robbins, 2005); specifically the accumbens shell (AcbSh) (e.g. Rewal et al., 2009, 2012; Nie et al., 2011; Leriche et al., 2008). The current study aimed to investigate the role of GABAB receptors in the AcbSh by examining the ability of two different enantiomers of baclofen to alter ethanol and saccharin intake in male C57BL/6J (B6) mice. B6 mice underwent bilateral cannulation surgery targeting the AcbSh. After 48 hours of recovery time, animals began a five day Drinking-in-the-Dark (DID) procedure where they received 20% ethanol or 0.2% saccharin for two hours, three hours into the dark cycle, each day. Throughout the five drinking sessions, animals were kept in home-cage locomotor activity chambers to monitor activity throughout the drinking cycle. Day 4 drinking was immediately preceded by a mock microinjection, whereas Day 5 drinking was immediately preceded by a drug microinjection. Microinjection of one of five doses of baclofen was given in ng/side dissolved in 200 µl of aCSF (aCSF alone, 0.02 R(+)-, 0.04 R(+)-, 0.08 S(-)-, or 0,16 S(-)-). Intake was recorded every twenty minutes on Days 4 and 5. Retro-orbital sinus blood samples were taken from ethanol animals immediately following the Day 5 drinking period to determine blood ethanol concentrations (BECs). A one-way ANOVA on total Day 4 ethanol consumption revealed no baseline differences between dose groups. A one-way ANOVA on total Day 5 ethanol consumption revealed that the 0.04 R(+)- baclofen dose reduced total drinking, but the 0.16 S(-)- baclofen dose increased total drinking (p’s<0.05). This pattern was reflected in the BECs; 0.04 R(+)- baclofen reduced BECs, whereas 0.16 S(-)- baclofen increased BECs (p’s<0.05). These results were also time-dependent, with R(+)-baclofen reducing drinking in the first 20 minutes of the session and S(-)- increasing drinking in the last 40 minutes of the session. There were no effects on saccharin intake. An issue with the locomotor activity boxes led to unreliable locomotor activity counts. However, because there were no drug effects on saccharin consumption, it was concluded that locomotor effects did not contribute to the decreases or increases in ethanol consumption. These results further implicate the role of GABAB receptors in modulating ethanol intake. The bidirectional effects shown highlight the importance of considering enantioselective drug effects when interpreting data. Finally, these results also support previous conclusions that the AcbSh plays an important role in modulating use of drugs of abuse, but not other reinforcers.