The Psychological and Neural Mechanisms Underlying a New Model of Reinstatement of Responding to an Alcohol-Predictive Cue

Environmental stimuli that predict alcohol availability pose a significant threat to maintaining abstinence from alcohol use. Through Pavlovian conditioning, these stimuli can become cues that predict alcohol availability which can precipitate relapse in clinical populations and preclinical models. Preclinical research has largely focused on examining the immediate impact of alcohol-cues on the relapse-like return of responding for alcohol (i.e., reinstatement); however, the delayed impact of such cues on behaviour has rarely been investigated. In the current thesis, a new reinstatement model was developed to evaluate the delayed impact of re-exposure to alcohol on the return of responding for alcohol. The psychological and neural mechanisms that underlie delayed reinstatement in the new model were then investigated. A Pavlovian conditioning task was used in which rats learned to respond to a conditioned stimulus (CS) that was paired with alcohol, followed by extinction of this response. Re-exposure to alcohol reinstated responding to the CS 24 h later, relative to responding during extinction. Additional procedures demonstrated that re-exposure to alcohol, and not another liquid made distinct from alcohol, reinstated responding to the alcohol-CS, indicating that preferential reinstatement was produced by re-exposure to alcohol compared to a control liquid. Behavioural studies revealed that the delayed reinstatement of responding to the alcohol-CS was driven by an association that formed between alcohol and the context in which alcohol re-exposure was conducted. Reinstatement was prevented when the context that alcohol re-exposure occurred in was extinguished. Moreover, reinstatement was reduced when alcohol re-exposure was conducted in a context that differed from the test context. Pharmacology studies revealed that µ-opioid receptors (MORs) are necessary for the delayed reinstatement of responding to the alcohol-CS. Systemically blocking MORs attenuated reinstatement, without affecting locomotor activity. Further, it was shown for the first time that blocking MORs in the ventral hippocampus prevented reinstatement. The novel delayed reinstatement model presented in this thesis helps establish a comprehensive understanding of how alcohol-cues can influence relapse. Moreover, a detailed understanding of the psychological and neural mechanisms underlying the delayed reinstatement model can inform the development of new behavioural and pharmacological treatment interventions against relapse

Context and topography determine the role of basolateral amygdala metabotropic glutamate receptor 5 in appetitive Pavlovian responding

Preclinical data have shown that the excitatory metabotropic Gαq-coupled glutamate receptor, mGluR5, has a role in substance abuse and relapse. However, little is known about the contribution of mGluR5 to the expression of conditioned responding elicited by appetitive Pavlovian cues. We investigated this question in rats that were trained to associate a discrete, auditory conditioned stimulus (CS) with a fructose-glucose solution (5.5% fructose/4.5% glucose; ‘sugar’). In subsequent tests for the expression of conditioned responding without sugar delivery, CS-elicited fluid port entries were elevated in a context associated with sugar, relative to an equally familiar, neutral context. Inhibiting mGluR5 via systemic injections of a negative allosteric modulator (MTEP; 5 mg/kg) reduced CS port entries in both the sugar context and neutral context. Targeting MTEP microinjections (3 µg/side; 0.3 µl/min) to the nucleus accumbens (Acb) core had no effect on CS port entries at test, whereas the same manipulation in the basolateral amygdala (BLA) produced effects that were topographically dependent. Specifically, microinjecting MTEP in the posterior BLA had no effect on behavior, whereas inhibiting mGluR5 in the anterior BLA enhanced the contextual discrimination of CS port entries. These data are the first to show a role of mGluR5 in the context-dependent expression of appetitive Pavlovian conditioned responding, with a topographically defined arrangement of mGluR5 in the BLA being particularly important for context-based responding to a discrete, appetitive cue