Augmenting glutamatergic, but not dopaminergic, activity in the nucleus accumbens shell disrupts responding to a discrete alcohol cue in an alcohol context.

Discrete alcohol cues and contexts are relapse triggers for people with alcohol use disorder exerting particularly powerful control over behaviour when they co-occur. Here, we investigated the neural substrates subserving the capacity for alcohol-associated contexts to elevate responding to an alcohol-predictive conditioned stimulus (CS). Specifically, rats were trained in a distinct 'alcohol context' to respond by entering a fluid port during a discrete auditory CS that predicted the delivery of alcohol and were familiarized with a 'neutral context' wherein alcohol was never available. When conditioned CS responding was tested by presenting the CS without alcohol, we found that augmenting glutamatergic activity in the nucleus accumbens (NAc) shell by microinfusing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) reduced responding to an alcohol CS in an alcohol, but not neutral, context. Further, AMPA microinfusion robustly affected behaviour, attenuating the number, duration and latency of CS responses selectively in the alcohol context. Although dopaminergic inputs to the NAc shell were previously shown to be necessary for CS responding in an alcohol context, here, chemogenetic excitation of ventral tegmental area (VTA) dopamine neurons and their inputs to the NAc shell did not affect CS responding. Critically, chemogenetic excitation of VTA dopamine neurons affected feeding behaviour and elevated c-fos immunoreactivity in the VTA and NAc shell, validating the chemogenetic approach. These findings enrich our understanding of the substrates underlying Pavlovian responding for alcohol and reveal that the capacity for contexts to modulate responding to discrete alcohol cues is delicately underpinned by the NAc shell.

Learning processes in relapse to alcohol use: lessons from animal models.

RATIONALE: Alcohol use is reliably preceded by discrete and contextual stimuli which, through diverse learning processes, acquire the capacity to promote alcohol use and relapse to alcohol use. OBJECTIVE: We review contemporary extinction, renewal, reinstatement, occasion setting, and sex differences research within a conditioning framework of relapse to alcohol use to inform the development of behavioural and pharmacological therapies. KEY FINDINGS: Diverse learning processes and corresponding neurobiological substrates contribute to relapse to alcohol use. Results from animal models indicate that cortical, thalamic, accumbal, hypothalamic, mesolimbic, glutamatergic, opioidergic, and dopaminergic circuitries contribute to alcohol relapse through separable learning processes. Behavioural therapies could be improved by increasing the endurance and generalizability of extinction learning and should incorporate whether discrete cues and contexts influence behaviour through direct excitatory conditioning or occasion setting mechanisms. The types of learning processes that most effectively influence responding for alcohol differ in female and male rats. CONCLUSION: Sophisticated conditioning experiments suggest that diverse learning processes are mediated by distinct neural circuits and contribute to relapse to alcohol use. These experiments also suggest that gender-specific behavioural and pharmacological interventions are a way towards efficacious therapies to prevent relapse to alcohol use.

Supplementary dataset of context-dependent conditioned responding to an alcohol-predictive cue in female and male rats.

This supplementary dataset is supportive of the research article entitled 'The role of context on responding to an alcohol-predictive cue in female and male rats' [1]. This article describes the raw data pertaining to the behaviour of male and female rats during intermittent to ethanol and Pavlovian conditioning training and testing procedures. Specifically, the dataset describes the alcohol consumption and ingested-dose of ethanol during home-cage ethanol exposure, as well as the conditioned responding during Pavlovian discrimination training, a test assessing the effect of context on responding to an alcohol-predict cue in the absence of alcohol, and a reinstatement test assessing the effect of context on conditioned responding to an extinguished alcohol-predictive cue.

The role of context on responding to an alcohol-predictive cue in female and male rats.

In male rats, physical contexts that are associated with alcohol can amplify the response to a discrete, alcohol-predictive conditioned stimulus (CS), and amplify prime-induced reinstatement. Here, we examined these effects as a function of biological sex. Male and female Long-Evans rats were acclimated to drinking ethanol (15% v/v) in their home cages. Next, they were trained to associate an auditory conditioned stimulus (CS) (10 s; white noise or clicker; 15 trials per session) with ethanol delivery (0.2 mL per CS; 3.0 mL per session) into a fluid port for oral intake. Training occurred in a distinctive context containing specific visual, olfactory, and tactile stimuli. During alternating sessions, rats were exposed to a second context wherein they did not receive ethanol. At test, CS trials occurred in both contexts without ethanol delivery. Rats then underwent extinction using repeated unreinforced presentations of the CS in both contexts. An alcohol-primed reinstatement test was then conducted, in which 0.2 mL of ethanol was presented at the start of the session and during the first CS trial, after which no ethanol was delivered for the remainder of the session. At both test and reinstatement, male rats made significantly more CS port-entries in the context associated with alcohol delivery than in the context in which alcohol was never experienced. Unlike males, female rats made a similar number of CS port-entries at the test in both the alcohol context and the neutral context. The reinstatement observed in female rats was also not affected by context. These findings suggest that the capacity of an alcohol-associated context to modulate responding to a discrete, alcohol-predictive cue is less pronounced in female than male rats.

Reduced caloric intake allows access-induced consumption differences to emerge with concentrated sucrose solutions.

Rats given intermittent access to 4% (w/v) sucrose solution elevate their consumption of solution relative to rats with continuous access, a difference that does not appear at higher concentrations. Here, we examined the hypothesis that a limit on the intake of sucrose calories prevents rats from demonstrating access-induced differences in consumption of a more concentrated sucrose solution. Energy-replete rats were given every day (ED) or every third day (E3D) access to sucrose solutions adulterated with bitter quinine which reduced solution palatability and consumption levels while intake was measured. In experiment 1, previously collected data were compiled to examine the trajectory of consumption of continuously available 4% sucrose solution which was shown to stabilize by day 3 and then informed group assignment. In experiment 2, daily consumption levels were higher for rats with E3D access to 4% sucrose solution than rats with ED access to the same solution, whereas rats consumed similar amounts of 8% sucrose solution across access schedules. In the first hour of solution availability rats with E3D access showed elevated sucrose solution consumption, relative to rats with ED access, for both 4% and 8% sucrose solution. Upon the addition of quinine (0.005%) sucrose solution consumption decreased and the E3D access group consumed more daily sucrose solution than the ED access group for both 4% and 8% sucrose solution. In experiment 3, four groups of rats were given ED or E3D access to 8% sucrose solution adulterated with 0.0025%, 0.005%, 0.01%, or 0.02% quinine. Quinine adulteration reduced 8% sucrose solution consumption and allowed rats with E3D access to elevate their consumption levels relative to rats with ED access; this effect persisted when all groups were switched to 8% sucrose + 0.02% quinine solution. Thus, daily access-induced consumption differences develop but do not emerge because of a caloric limit on sucrose solution intake. This work underscores the interaction of availability and caloric intake as determinants of sugar consumption and highlights an important distinction between animal models of food addiction and binge eating.

Dissociable mesolimbic dopamine circuits control responding triggered by alcohol-predictive discrete cues and contexts.

Context can influence reactions to environmental cues and this elemental process has implications for substance use disorder. Using an animal model, we show that an alcohol-associated context elevates entry into a fluid port triggered by a conditioned stimulus (CS) that predicted alcohol (CS-triggered alcohol-seeking). This effect persists across multiple sessions and, after it diminishes in extinction, the alcohol context retains the capacity to augment reinstatement. Systemically administered eticlopride and chemogenetic inhibition of ventral tegmental area (VTA) dopamine neurons reduce CS-triggered alcohol-seeking. Chemogenetically silencing VTA dopamine terminals in the nucleus accumbens (NAc) core reduces CS-triggered alcohol-seeking, irrespective of context, whereas silencing VTA dopamine terminals in the NAc shell selectively reduces the elevation of CS-triggered alcohol-seeking in an alcohol context. This dissociation reveals new roles for divergent mesolimbic dopamine circuits in the control of responding to a discrete cue for alcohol and in the amplification of this behaviour in an alcohol context.

Alcohol-seeking and relapse: A focus on incentive salience and contextual conditioning.

Environmental stimuli that reliably accompany alcohol intake can become associated with the pharmacological effects of alcohol through classical (Pavlovian) conditioning. Of growing interest to addiction researchers is whether or not this process results in the attribution of incentive salience to alcohol-predictive cues, which could motivate alcohol-seeking behavior and relapse. To evaluate this question, we present a review of rodent behavioral studies that examined the capacity of alcohol-predictive cues to (i) support sign-tracking behavior, (ii) serve as conditioned reinforcers, and (iii) produce Pavlovian-to-instrumental transfer. A second, emerging area of research is focused on delineating the role of context in alcohol-seeking behavior and relapse. Here, we review studies showing that alcohol-associated contexts (i) support conditioned place preference, (ii) renew extinguished alcohol-seeking behavior, and (iii) modulate alcohol-seeking responses elicited by discrete alcohol-predictive cues. These behavioral effects may be mediated by unique psychological processes, and have important implications for cue-reactivity studies and neurobiological research.