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Opposing Roles of Rapid Dopamine Signaling Across the Rostral-Caudal Axis of the Nucleus Accumbens Shell in Drug-Induced Negative Affect.

ABSTRACT: Negative reinforcement theories of drug addiction posit that addicts use drugs to alleviate negative mood states. In a preclinical model developed in our laboratory, rats exhibit negative affect to a normally rewarding taste cue when it predicts impending but delayed cocaine. The emergence of this state is accompanied by a reduction in dopamine concentration in the rostral nucleus accumbens shell. However, the rostral and caudal regions of the shell have been implicated in promoting opposing appetitive and aversive states, respectively. Here, we tested whether dopamine transmission along the rostral-caudal axis of the shell plays differential roles in the emergence of drug-induced negative affect.In TH::Cre rats, the dopaminergic pathways from the ventral tegmental area to the rostral and caudal regions of the shell were optogenetically stimulated during intraoral delivery of a taste cue signaling delayed cocaine. Affective responses to the taste cue were measured using taste reactivity, and optical self-stimulation of the rostral and caudal shells was also examined.Optical stimulation of the rostral shell during tastant infusion prevented the emergence of negative affect, but activation of the caudal shell exacerbated aversive responses. These effects endured in the absence of optical stimulation, and the degree of negative affect in our model predicted self-stimulation responding.These findings reveal unprecedented, pronounced, and opposing roles of rapid dopamine signaling across the rostral-caudal axis of the nucleus accumbens in the control of drug-induced negative affect, a hallmark of continued drug seeking and use in human addicts.

SUBMITTER: Hurley SW

PROVIDER: S-EPMC5675798 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Opposing Roles of Rapid Dopamine Signaling Across the Rostral-Caudal Axis of the Nucleus Accumbens Shell in Drug-Induced Negative Affect.

Hurley Seth W SW West Elizabeth A EA Carelli Regina M RM

Biological psychiatry 20170511 11

<h4>Background</h4>Negative reinforcement theories of drug addiction posit that addicts use drugs to alleviate negative mood states. In a preclinical model developed in our laboratory, rats exhibit negative affect to a normally rewarding taste cue when it predicts impending but delayed cocaine. The emergence of this state is accompanied by a reduction in dopamine concentration in the rostral nucleus accumbens shell. However, the rostral and caudal regions of the shell have been implicated in pro ...[more]

PMID: 28624112

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Project description:The aim of this work was to determine the effect of nicotine desensitization on dopamine (DA) release in the dorsal striatum and shell of the nucleus accumbens (NAc) from brain slices. In vitro fast-scan cyclic voltammetry analysis was used to evaluate dopamine release in the dorsal striatum and the NAc shell of Sprague-Dawley rats after infusion of nicotine, a nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (Mec), and an α4β2 cholinergic receptor antagonist (DHβe). DA release related to nicotine desensitization in the striatum and NAc shell was compared. In both structures, tonic release was suppressed by inhibition of the nicotine receptor (via Mec) and the α4β2 receptor (via DHβe). Paired-pulse ratio (PPR) was facilitated in both structures after nicotine and Mec infusion, and this facilitation was suppressed by increasing the stimulation interval. After variable frequency stimulation (simulating phasic burst), nicotine infusion induced significant augmentation of DA release in the striatum that was not seen in the absence of nicotine. In contrast, nicotine reduced phasic DA release in NAc, although frequency augmentation was seen both with and without nicotine. Evaluation of DA release evoked by various trains (high-frequency stimulation (HFS) 100 Hz) of high-frequency stimulation revealed significant enhancement after a train of three or more pulses in the striatum and NAc. The concentration differences between tonic and phasic release related to nicotine desensitization were more pronounced in the NAc shell. Nicotine desensitization is associated with suppression of tonic release of DA in both the striatum and NAc shell that may occur via the α4β2 subtype of nAChR, whereas phasic frequency-dependent augmentation and HFS-related gating release is more pronounced in the striatum than in the NAc shell. Differences between phasic and tonic release associated with nicotine desensitization may underlie processing of reward signals in the NAc shell, and this may have major implications for addictive behavior.

Project description:BackgroundTraumatic brain injury is known to impact dopamine-mediated reward pathways, but the underlying mechanisms have not been fully established.MethodsNicotine-induced conditional place preference was used to study rats exposed to a 6-psi fluid percussion injury with and without prior exposure to nicotine. Preference was quantified as a score defined as (C1 - C2) / (C1 + C2), where C1 is time in the nicotine-paired compartment and C2 is time in the saline-paired compartment. Subsequent fast-scan cyclic voltammetry was used to analyze the impact of nicotine infusion on dopamine release in the shell portion of the nucleus accumbens. To further determine the influence of brain injury on nicotine withdrawal, nicotine infusion was administered to the rats after fluid percussion injury. The effects of fluid percussion injury on conditional place preference after prior exposure to nicotine and abstinence or withdrawal from nicotine were also assessed.ResultsAfter traumatic brain injury, dopamine release was reduced in the nucleus accumbens shell, and nicotine-induced conditional place preference preference was significantly impaired. Preference scores of control, sham-injured, and fluid percussion injury groups were 0.1627±0.04204, 0.1515±0.03806, and -0.001300±0.04286, respectively. Nicotine-induced conditional place preference was also seen in animals after nicotine pretreatment, with a conditional place preference score of 0.07805±0.02838. Nicotine preexposure substantially increased tonic dopamine release in sham-injured animals, but it did not change phasic release; nicotine exposure after fluid percussion injury enhanced phasic release, though not to the same levels seen in sham-injured rats. Conditioned preference was related not only to phasic dopamine release (r=0.8110) but also to the difference between tonic and phasic dopamine levels (r=0.9521).ConclusionsTraumatic brain injury suppresses dopamine release from the shell portion of the nucleus accumbens, which in turn significantly alters reward-seeking behavior. These results have important implications for tobacco and drug use after traumatic brain injury.

Dataset Information

Opposing Roles of Rapid Dopamine Signaling Across the Rostral-Caudal Axis of the Nucleus Accumbens Shell in Drug-Induced Negative Affect.

Publications

Opposing Roles of Rapid Dopamine Signaling Across the Rostral-Caudal Axis of the Nucleus Accumbens Shell in Drug-Induced Negative Affect.

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