Synthetic exendin-4 disrupts responding to reward predictive incentive cues in male rats.

Synthetic exendin-4 (EX4, exenatide), is a GLP-1 receptor agonist used clinically to treat glycemia in Type-2 diabetes mellitus. EX4 also promotes weight loss and alters food reward-seeking behaviors in part due to activation of GLP-1 receptors in the mesolimbic dopamine system. Evidence suggests that GLP-1 receptor activity can directly attenuate cue-induced reward seeking. Here, we tested the effects of EX4 (0.6, 1.2, and 2.4 µg/kg, i.p.) on incentive cue (IC) responding, using a task where rats emit a nosepoke response during an intermittent reward-predictive IC to obtain a sucrose reward. EX4 dose-dependently attenuated responding to ICs and increased the latencies to respond to the IC and enter the sucrose reward cup. Moreover, EX4 dose-dependently decreased the total number of active port nosepokes for every cue presented. There was no effect of EX4 on the number of reward cup entries per reward earned, a related reward-seeking metric with similar locomotor demand. There was a dose-dependent interaction between the EX4 dose and session time on the responding to ICs and nosepoke response latency. The interaction indicated that effects of EX4 at the beginning and end of the session differed by the dose of EX4, suggesting dose-dependent pharmacokinetic effects. EX4 had no effect on free sucrose consumption behavior (i.e., total volume consumed, bout size, number of bouts) within the range of total sucrose volumes obtainable during the IC task (~3.5 ml). However, when rats were given unrestricted access for 1 h, where rats obtained much larger total volumes of sucrose (~30 ml), we observed some dose-dependent EX4 effects on drinking behavior, including decreases in total volume consumed. Together, these findings suggest that activation of the GLP-1 receptor modulates the incentive properties of cues attributed with motivational significance.

Rapid drinking is associated with increases in driving-related risk-taking.

OBJECTIVE: The rate of alcohol drinking has been shown to predict impairment on cognitive and behavioral tasks. The current study assessed the influence of speed of alcohol consumption within a laboratory-administered binge on self-reported attitudes toward driving and simulated driving ability. METHOD: Forty moderate drinkers (20 female, 20 male) were recruited from the local community via advertisements for individuals who drank alcohol at least once per month. The equivalent of four standard alcohol drinks was consumed at the participant's desired pace within 2-h session. RESULTS: Correlation analyses revealed that, after alcohol drinking, mean simulated driving speed, time in excess of speed limit, collisions, and reported confidence in driving were all associated with rapid alcohol drinking. CONCLUSION: Fast drinking may coincide with increased driving confidence because of the extended latency between the conclusion of drinking and the commencement of driving. However, this latency did not reduce alcohol-related driving impairment, as fast drinking was also associated with risky driving.

Alcohol effects on simulated driving in frequent and infrequent binge drinkers.

OBJECTIVE: Compared with non­bingers, binge drinkers are more likely to drive while intoxicated. The extent to which binge frequency impacts confidence in driving and subsequent driving impairment is unknown. This study compared the effects of an experimenter­delivered alcohol binge on subjective impairment and simulated driving ability in female high­frequency and low­frequency bingers. METHODS: Female drinkers were assigned to high­frequency (n = 30) or low­frequency (n = 30) binge groups based on their Alcohol Use Questionnaire responses. At 30­min intervals within a 2­h period, participants received either a placebo drink (n = 15 per group) or a 0.2 g/kg dose of alcohol (n = 15 per group; cumulative dose 0.8 g/kg). Self­reported impairment, driving confidence, and simulated driving were then measured. RESULTS: Self­reported confidence in driving was significantly lower after alcohol than after placebo in low­frequency but not highfrequency bingers. Self­reported impairment and collisions during simulated driving were significantly greater after alcohol than after placebo in both low­frequency and high­frequency bingers. CONCLUSIONS: The impairing effects of a single alcohol binge on driving ability in women are not influenced by binge frequency. However, high binge frequency may be associated with a less cautious approach to post­binge driving.

Response inhibition impairments predict alcohol-induced sedation.

AIMS: The aim of this study was to probe the relationship between the subjective effects of alcohol and impulsive behavior in social drinkers. METHODS: Fifty social drinkers performed a response-inhibition task before consuming alcohol. A 0.8-g/kg dose of alcohol was administered in a binge-like fashion (0.2 g/kg every 30 min) to the participants over a 2-h time period. Participants then completed questionnaires measuring stimulation, sedation and mood following consumption of alcohol. Linear regression analyses were performed by examining the relationship between performance on the response inhibition impulsivity task and subjective responses to alcohol (i.e. stimulation, sedation and arousal). RESULTS: There was a significant positive relationship found between impulsive responding and self-reported sedation following alcohol consumption. Additionally, there was a significant negative relationship between behavioral impulsivity and self-reported stimulation and arousal following alcohol consumption. CONCLUSION: These results suggest that higher levels of impulsivity are associated with experiencing greater sedating than stimulating effects of alcohol. Individuals with high levels of impulsivity may be less sensitive to the stimulating effects of a specified dose of alcohol, which could lead to these individuals consuming more alcohol to experience the stimulating effects of alcohol.

Ventral tegmental area D2 receptor knockdown enhances choice impulsivity in a delay-discounting task in rats.

Impulsivity associated with abnormal dopamine (DA) function has been observed in several disorders, including addiction. Choice impulsivity is the preference for small, immediate rewards over larger rewards after a delay, caused by excessive discounting of future rewards. Addicts have abnormally high discount rates and prefer the smaller rewards sooner. While impulsivity has been inversely correlated with DA D2 receptor (D2R) availability in the midbrain and striatum, it is difficult to mechanistically link the two, due to the diverse neuroanatomical localization of D2Rs, which are found throughout the brain, in many types of neurons and neuronal subcompartments. To determine if ventral tegmental area (VTA) D2R hypofunction is linked to impulsivity, we knocked down D2 receptors from the VTA, using an adeno-associated viral (AAV) vector that delivers short hairpin RNAs (shRNA) targeted against the D2R. The D2R knockdown is restricted to neurons whose cell bodies reside in the VTA, leaving postsynaptic D2Rs intact in the striatum, prefrontal cortex, and other mesocorticolimbic structures. Rats were trained in a delay-discounting task to assess impulsive choice until a stable discounting curve was obtained, and then received bilateral VTA infusions of the D2R shRNA or a scrambled control virus. Over the next six weeks, the discounting curve of the VTA D2R knockdown rats shifted to the left, indicating a preference for the smaller, immediate reward, whereas the curve for control rats remained stable and unchanged. Together these results demonstrate that a decrease in VTA D2Rs enhances choice impulsivity.

The GLP-1 agonist exendin-4 attenuates self-administration of sweetened fat on fixed and progressive ratio schedules of reinforcement in rats.

GLP-1 agonists such as exendin-4 (EX4) are used in the treatment of type-2 diabetes and have the additional benefit of promoting weight loss. GLP-1 agonists decrease feeding through peripheral effects, but recent evidence suggests they may also influence sweet or high fat preference, as well as motivation to obtain these tastants. Yet it remains unclear how GLP-1-induced alterations in food preference influences decreases in overall feeding. The current study sought to determine if EX4 affects the reinforcing strength and consumption of a highly palatable sweet/fat reinforcer. Rats were trained to self-administer sweetened vegetable shortening (SVS) under fixed (FR) and progressive ratio (PR) schedules of reinforcement. EX4 (0.3-2.4µg/kg, i.p.) administered one hour prior to operant sessions significantly reduced responses for SVS under both FR and PR schedules, although the lowest active dose (0.6µg/kg) significantly suppressed FR responding only. EX4 also dose dependently decreased locomotor activity (0.6-2.4µg/kg doses), but did not enhance acute kaolin intake, suggesting that nausea did not influence the self-administration results. Analysis of ED50 values show that EX4 is more effective at inhibiting FR responding versus PR, indicating that EX4 may have more potent effects on amount consumed versus motivation for SVS. Although EX4 caused generalized locomotor suppression, these results do not fully explain the decreases in operant responding. For example, a dose of EX4 (0.6µg/kg) that significantly suppressed locomotor activity did not affect the mean total number of lever presses during PR sessions (59±15), although it did significantly reduce lever presses during FR sessions (21±3). In addition, the pattern of intake was constant at the beginning of the sessions in both PR and FR schedules, regardless of the dose. Together these data suggest that EX4 inhibits consumption of a palatable high sweet/high fat reinforcer potentially through altering satiety.