2 research outputs found
Image_1_Nucleus Accumbens Dopamine D1-Receptor-Expressing Neurons Control the Acquisition of Sign-Tracking to Conditioned Cues in Mice.TIFF
<p>Following repeated pairings, the reinforcing and motivational properties (incentive salience) of a reward can be transferred onto an environmental stimulus which can then elicit conditioned responses, including Pavlovian approach behavior to the stimulus (a sign-tracking response). In rodents, acquisition of sign-tracking in autoshaping paradigms is sensitive to lesions and dopamine D1 receptor antagonism of the nucleus accumbens (NAc) of the ventral striatum. However, currently, the possible roles of dorsal striatal subregions, as well as of the two major striatal neuron types, dopamine D1-/D2-expressing medium spiny neurons (MSNs), in controlling the development of conditioned responses is still unclear and warrants further study. Here, for the first time, we used a transgenic mouse line combined with striatal subregion-specific AAV virus injections to separately express tetanus toxin in D1-/D2- MSNs in the NAc, dorsomedial striatum, and dorsolateral striatum, to permanently block neurotransmission in these neurons during acquisition of an autoshaping task. Neurotransmission blocking of NAc D1-MSNs inhibited the acquisition of sign-tracking responses when the initial conditioned response for each conditioned stimulus presentation was examined, confirming our initial hypothesis. These findings suggest that activity in NAc D1-MSNs contributes to the attribution of incentive salience to conditioned stimuli.</p
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α4-containing GABAA receptors on DRD2-neurons of the nucleus accumbens mediate instrumental responding for conditioned reinforcers, and its potentiation by cocaine
Extrasynaptic GABAA receptors (GABAARs) composed of α4, β, and δ subunits mediate GABAergic tonic inhibition and are potential molecular targets in the modulation of behavioural responses to natural and drug rewards. These GABAARs are highly expressed within the nucleus accumbens (NAc) where they influence the excitability of the medium spiny neurons. Here we explore their role in modulating behavioural responses to food-conditioned cues and the behaviour-potentiating effects of cocaine. α4-subunit constitutive knockout mice (α4-/-) showed higher rates of instrumental responding for reward-paired stimuli in a test of conditioned reinforcement (CRf). A similar effect was seen following viral knockdown of GABAAR α4 subunits within the NAc. Local infusion of the α4βδ -GABAAR-preferring agonist, THIP, into the NAc had no effect on responding when given alone, but reduced cocaine potentiation of responding for conditioned reinforcers in wildtype but not α4-/- mice. Finally, specific deletion of α4-subunits from dopamine D2, but not D1, receptor-expressing neurons (DRD2- and DRD1-neurons), mimicked the phenotype of the constitutive knockout, potentiating CRf responding and blocking intra-accumbal THIP attenuation of cocaine-potentiated CRf responding. These data demonstrate that α4-GABAAR mediated inhibition of DRD2-neurons reduces instrumental-responding for a conditioned reinforcer, and its potentiation by cocaine, and emphasise the importance of GABAergic signalling within the NAc in mediating cocaine's effects.Significance StatementThis manuscript combines genetic and pharmacological interventions to uncover a critical role for α4-containing GABAA receptors in the nucleus accumbens in instrumental responding for conditioned reinforcers and its potentiation by cocaine, behavioural phenomenon thought to contribute to reward-seeking behaviour. These findings represent an important advancement in our understanding of the neural mechanisms underlying the reinforcing effects of conditioned stimuli and the role of the GABAergic system in this process