Inhibitory and excitatory conditioned cues associated with alcohol differentially modulate the nucleus accumbens shell: involvement of 5-HT7 receptors

Abstract

Introduction: The ability of conditioned cues to evoke drug craving is considered a critical factor precipitating relapse of drug use. The nucleus accumbens shell (AcbSh) is a structure that mediates drug-seeking via the influence of associations formed between conditioned cues and drug reward. Methods: In the present experiments, alcohol-preferring (P) rats were exposed to three conditioned odor cues; CS+ associated with alcohol self-administration, CS- associated with the absence of alcohol (extinction training), and a neutral stimulus (CS0) presented in neutral environment with no association to alcohol. The experiments examined the effects of the conditioned cues on extracellular levels of dopamine (DA), serotonin (5-HT), and glutamate (GLU), as well as the pattern of activation of D1 receptor-containing neurons in the AcbSh. The involvement of 5-HT7 receptors within the AcbSh in regulating context- and cue-induced alcohol-seeking was also determined. Results: Presentation of the CS+ resulted in increased extracellular DA levels and reduced 5-HT levels in the AcbSh, as well as increased activation of D1 receptor-containing neurons. In contrast, presentation of the CS- decreased extracellular DA and GLU levels in the AcbSh. The conditioned cues did not affect DA levels in the Acb core. The intra-AcbSh administration of a 5-HT7 antagonist enhanced context- and cue-induced alcohol seeking, whereas a 5-HT7 agonist reduced these behaviors. Discussion: Overall, the data suggest that there are distinct neurocircuits within the AcbSh that mediating the effects of excitatory and inhibitory conditioned cues on motivated behavior. While this work highlights a complex interaction of several neurotransmitter systems, it may also suggest a potential role for behavioral therapies involving extinction training and 5-HT7 receptor activation as potential targets for the treatment of cue-induced drug-seeking behavior.