Ethanol seeking triggered by environmental context is attenuated by blocking dopamine D1 receptors in the nucleus accumbens core and shell in rats.
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ABSTRACT: Conditioned behavioral responses to discrete drug-associated cues can be modulated by the environmental context in which those cues are experienced, a process that may facilitate relapse in humans. Rodent models of drug self-administration have been adapted to reveal the capacity of contexts to trigger drug seeking, thereby enabling neurobiological investigations of this effect.We tested the hypothesis that dopamine transmission in the nucleus accumbens, a neural structure that mediates reinforcement, is necessary for context-induced reinstatement of responding for ethanol-associated cues.Rats pressed one lever (active) for oral ethanol (0.1 ml; 10% v/v) in operant conditioning chambers distinguished by specific visual, olfactory, and tactile contextual stimuli. Ethanol delivery was paired with a discrete (4 s) light-noise stimulus. Responses on a second lever (inactive) were not reinforced. Behavior was then extinguished by withholding ethanol but not the discrete stimulus in a different context. Reinstatement, expressed as elevated responding for the discrete stimulus without ethanol delivery, was tested by placing rats into the prior self-administration context after administration of saline or the dopamine D1 receptor antagonist, SCH 23390 (0.006, 0.06, and 0.6 microg/side), into the nucleus accumbens core or shell.Compared with extinction responding, active lever pressing in saline-pretreated rats was enhanced by placement into the prior ethanol self-administration context. SCH 23390 dose-dependently reduced reinstatement after infusion into the core or shell.These findings suggest a critical role for dopamine acting via D1 receptors in the nucleus accumbens in the reinstatement of responding for ethanol cues triggered by placement into an ethanol-associated context.
Project description:BackgroundEnvironmental contexts associated with drug use can trigger craving in humans and the renewal of drug-seeking behaviors in animals. Here, we tested the hypothesis that context-induced renewal of Pavlovian-conditioned alcohol-seeking is mediated by dopamine.MethodsMale, Long-Evans rats were trained to discriminate between two, 10-second, auditory conditioned stimuli. One stimulus (CS+) was consistently paired with 15% ethanol (EtOH) (v/v, 0.2 ml per CS+) and the second stimulus (CS-) was not. Each CS occurred 16 times per session, and entries into a fluid port where EtOH was delivered were measured. Pavlovian discrimination training (PDT) occurred in a distinctive context, referred to as Context A. Subsequently, behavior was extinguished by presenting both cues without EtOH in a different context (Context B). At test, rats were injected with a dopamine D1-like receptor antagonist (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390; 0, 3.33, 10 μg/kg; 1 ml/kg; s.c.) and presented with the CS+ and CS- without EtOH in the prior PDT context (Context A).ResultsAcross training, rats developed higher response levels to the alcohol-predictive CS+, compared with the CS-. Port entries during the CS+ decreased across extinction. At test, placement into the alcohol-associated context triggered a selective increase in CS+ responses after saline, which was significantly reduced by SCH 23390 pretreatment. In separate studies, SCH 23390 did not affect lever-pressing for sucrose under reinforced or extinction conditions, but decreased port entries relative to saline in both cases.ConclusionsThese data indicate that dopamine is required for context-induced renewal of Pavlovian-conditioned alcohol-seeking and may also be necessary for preparatory conditioned approach behaviors.
Project description:It is well established that dopamine transmission is integral in mediating the influence of reward expectations on reward-seeking actions. However, the precise causal role of dopamine transmission in moment-to-moment reward-motivated behavioral control remains contentious, particularly in contexts where it is necessary to refrain from responding to achieve a beneficial outcome. To examine this, we manipulated dopamine transmission pharmacologically as rats performed a Go/No-Go task that required them to either make or withhold action to gain either a small or large reward. D1R Stimulation potentiated cue-driven action initiation, including fast impulsive actions on No-Go trials. By contrast, D1R blockade primarily disrupted the successful completion of Go trial sequences. Surprisingly, while after global D1R blockade this was characterized by a general retardation of reward-seeking actions, nucleus accumbens core (NAcC) D1R blockade had no effect on the speed of action initiation or impulsive actions. Instead, fine-grained analyses showed that this manipulation decreased the precision of animals' goal-directed actions, even though they usually still followed the appropriate response sequence. Strikingly, such "unfocused" responding could also be observed off-drug, particularly when only a small reward was on offer. These findings suggest that the balance of activity at NAcC D1Rs plays a key role in enabling the rapid activation of a focused, reward-seeking state to enable animals to efficiently and accurately achieve their goal.
Project description:D-norpseudoephedrine (NPE), also known as cathine, is found naturally in the shrub Catha edulis "Khat." NPE has been widely used as an appetite suppressant for the treatment of obesity. Although it is known that NPE acts on α1-adrenergic receptors, there is little information about the role of dopamine receptors on NPE's induced anorectic and weight loss effects. Equally untouched is the question of how NPE modulates neuronal activity in the nucleus accumbens shell (NAcSh), a brain reward center, and a pharmacological target for many appetite suppressants. To do this, in rats, we characterized the pharmacological effects induced by NPE on weight loss, food intake, and locomotion. We also determined the involvement of dopamine D1- and D2-like receptors using systemic and intra-NAcSh antagonists, and finally, we recorded single-unit activity in the NAcSh in freely moving rats. We found that NPE decreased 24-h food intake, induced weight loss, and as side effects increased locomotor activity and wakefulness. Also, intraperitoneal and intra-NAcSh administration of D1 and D2 dopamine antagonists partially reversed NPE's induced weight loss and food intake suppression. Furthermore, the D1 antagonist, SCH-23390, eliminated NPE-induced locomotion, whereas the D2 antagonist, raclopride, only delayed its onset. We also found that NPE evoked a net activation imbalance in NAcSh that propelled the population activity trajectories into a dynamic pharmacological brain state, which correlated with the onset of NPE-induced wakefulness. Together, our data demonstrate that NPE modulates NAcSh spiking activity and that both dopamine D1 and D2 receptors are necessary for NPE's induced food intake suppression and weight loss.
Project description:The dopamine (DA) hypothesis posits the increase of mesolimbic dopamine levels as a defining commonality of addictive drugs, initially causing reinforcement, eventually leading to compulsive consumption. While much experimental evidence from psychostimulants supports this hypothesis, it has been challenged for opioid reinforcement. Here, we monitor genetically encoded DA and calcium indicators as well as cFos in mice to reveal that heroin activates DA neurons located in the medial part of the VTA, preferentially projecting to the medial shell of the nucleus accumbens (NAc). Chemogenetic and optogenetic manipulations of VTA DA or GABA neurons establish a causal link to heroin reinforcement. Inhibition of DA neurons blocked heroin self-administration, while heroin inhibited optogenetic self-stimulation of DA neurons. Likewise, heroin occluded the self-inhibition of VTA GABA neurons. Together, these experiments support a model of disinhibition of a subset of VTA DA neurons in opioid reinforcement.
Project description:Caloric restriction during drug abstinence increases the risk for relapse in addicts. In rats, chronic food restriction during a period of withdrawal following heroin self-administration augments heroin seeking. The mechanisms underlying this effect are largely unknown. Here, we investigated the role of nucleus accumbens (NAc) shell and core dopamine (DA) in food restriction-induced augmentation of heroin seeking. Rats were trained to self-administer heroin (0.1 mg/kg/infusion) for 10 days. Next, rats were moved to the animal colony for a withdrawal period, during which rats were food restricted to 90% of their original body weight (FDR group) or given unrestricted access to food (sated group). On day 14 of food restriction, rats were returned to the operant conditioning chambers for a heroin-seeking test under extinction conditions. Extracellular DA levels were assessed using in vivo microdialysis. In separate experiments, the DA D1-like receptor antagonist SCH39166 (12.5, 25.0, or 50.0 ng/side) was administered into the NAc before the heroin-seeking test. In the NAc shell, pre-test exposure to the heroin-associated context increased DA only in FDR rats; but in the NAc core, DA increased regardless of feeding condition. Food restriction significantly augmented heroin seeking and increased DA in the NAc shell and core during the test. Intra-NAc shell administration of SCH39166 decreased heroin seeking in all rats. In contrast, in the NAc core, SCH39166 selectively decreased the augmentation of heroin-seeking induced by chronic food restriction. Taken together, these results suggest that activation of the DA D1-like receptor in the NAc core is important for food restriction-induced augmentation of heroin seeking.
Project description:BackgroundCocaine-induced plasticity in the nucleus accumbens shell of males occurs primarily in dopamine D1 receptor-expressing medium spiny neurons (D1R-MSNs), with little if any impact on dopamine D2 receptor-expressing medium spiny neurons (D2R-MSNs). In females, the effect of cocaine on accumbens shell D1R- and D2R-MSN neurophysiology has yet to be reported, nor have estrous cycle effects been accounted for.MethodsWe used a 5-day locomotor sensitization paradigm followed by a 10- to 14-day drug-free abstinence period. We then obtained ex vivo whole-cell recordings from fluorescently labeled D1R-MSNs and D2R-MSNs in the nucleus accumbens shell of male and female mice during estrus and diestrus. We examined accumbens shell neuronal excitability as well as miniature excitatory postsynaptic currents (mEPSCs).ResultsIn females, we observed alterations in D1R-MSN excitability across the estrous cycle similar in magnitude to the effects of cocaine in males. Furthermore, cocaine shifted estrous cycle-dependent plasticity from intrinsic excitability changes in D1R-MSNs to D2R-MSNs. In males, cocaine treatment produced the anticipated drop in D1R-MSN excitability with no effect on D2R-MSN excitability. Cocaine increased mEPSC frequencies and amplitudes in D2R-MSNs from females in estrus and mEPSC amplitudes of D2R-MSNs from females in diestrus. In males, cocaine increased both D1R- and D2R-MSN mEPSC amplitudes with no effect on mEPSC frequencies.ConclusionsOverall, while there are similar cocaine-induced disparities regarding the relative excitability of D1R-MSNs versus D2R-MSNs between the sexes, this is mediated through reduced D1R-MSN excitability in males, whereas it is due to heightened D2R-MSN excitability in females.
Project description:Protein translation is essential for some forms of synaptic plasticity. We used nucleus accumbens (NAc) medium spiny neurons (MSN), co-cultured with cortical neurons to restore excitatory synapses, to examine whether dopamine modulates protein translation in NAc MSN. FUNCAT was used to measure translation in MSNs under basal conditions and after disinhibiting excitatory transmission using the GABAA receptor antagonist bicuculline (2 hr). Under basal conditions, translation was not altered by the D1-class receptor (D1R) agonist SKF81297 or the D2-class receptor (D2R) agonist quinpirole. Bicuculline alone robustly increased translation. This was reversed by quinpirole but not SKF81297. It was also reversed by co-incubation with the D1R antagonist SCH23390, but not the D2R antagonist eticlopride, suggesting dopaminergic tone at D1Rs. This was surprising because no dopamine neurons are present. An alternative explanation is that bicuculline activates translation by increasing glutamate tone at NMDA receptors (NMDAR) within D1R/NMDAR heteromers, which have been described in other cell types. Supporting this, immunocytochemistry and proximity ligation assays revealed D1/NMDAR heteromers on NAc cells both in vitro and in vivo. Further, bicuculline's effect was reversed to the same extent by SCH23390 alone, the NMDAR antagonist APV alone, or SCH23390+APV. These results suggest that: 1) excitatory synaptic transmission stimulates translation in NAc MSNs, 2) this is opposed when glutamate activates D1R/NMDAR heteromers, even in the absence of dopamine, and 3) antagonist occupation of D1Rs within the heteromers prevents their activation. Our study is the first to suggest a role for D2 receptors and D1R/NMDAR heteromers in regulating protein translation.
Project description:Varenicline, a pharmacotherapy for tobacco addiction, reduces alcohol consumption in humans and rodents. The therapeutic potential of varenicline would escalate if it also diminished conditioned responses elicited by alcohol-predictive cues, which can precipitate relapse in abstinent individuals. We investigated this application, along with the underlying neural substrates, using a robust preclinical assay in which relapse to alcohol-seeking was triggered by re-exposure to an alcohol-associated environmental context. Male, Long-Evans rats received Pavlovian conditioning sessions in which one auditory conditioned stimulus (CS+) was paired with 15% ethanol and a second conditioned stimulus (CS-) was not. Ethanol was delivered into a port for oral consumption and port entries triggered by each CS were recorded. Extinction was then conducted in a different context where the CS+ and CS- were presented without ethanol. To stimulate relapse, both cues were subsequently presented without ethanol in the prior conditioning context. Systemic varenicline (0, 0.5 or 2.5 mg/kg; intraperitoneal) blocked context-induced relapse to alcohol-seeking without affecting the ability to make a port entry. It also reduced context-induced relapse to sucrose-seeking, but only at the 2.5 mg/kg dose. Neuropharmacological studies showed that context-induced relapse to alcohol-seeking was attenuated by bilateral microinfusion of varenicline (0.3 μl/side) into the nucleus accumbens (NAc; 0 or 3.5 μg), but not the ventral tegmental area (0, 2 or 4 μg). These data show for the first time that varenicline reduces relapse triggered by contexts that predict alcohol, and suggest that nicotinic acetylcholine receptors in the NAc are critical for this effect.
Project description:Dopamine D1 receptor-expressing medium spiny neurons (D1R-MSNs) and dopamine D2 receptor-expressing MSNs (D2R-MSNs) in nucleus accumbens (NAc) have been demonstrated to show different effects on reward and memory of abstinence. A-kinase anchoring protein 150 (AKAP150) expression in NAc is significantly upregulated and contributes to the morphine withdrawal behavior. However, the underlying mechanism of AKAP150 under opioid withdrawal remains unclear. In this study, AKAP150 expression in NAc is upregulated in naloxone-precipitated morphine withdrawal model, and knockdown of AKAP150 alleviates morphine withdrawal somatic signs and improves the performance of conditioned place aversion (CPA) test. AKAP150 in NAc D1R-MSNs is related to modulation of the performance of morphine withdrawal CPA test, while AKAP150 in NAc D2R-MSNs is relevant to the severity of somatic responses. Our results suggest that AKAP150 from D1R-MSNs or D2R-MSNs in NAc contributes to the developmental process of morphine withdrawal but plays different roles in aspects of behavior or psychology.
Project description:The α1-adrenergic receptors (α1ARs) have been implicated in numerous actions of the brain, including attention and wakefulness. Additionally, they have been identified as contributing to disorders of the brain, such as drug addiction, and recent work has shown a role of these receptors in relapse to psychostimulants. While some functionality is known, the actual subcellular localization of the subtypes of the α1ARs remains to be elucidated. Further, their anatomical relationship to receptors for other neurotransmitters, such as dopamine (DA), remains unclear. Therefore, using immunohistochemistry and electron microscopy techniques, this study describes the subcellular localization of the α1b-adrenergic receptor (α1bAR), the subtype most tied to relapse behaviors, as well as its relationship to the D1-dopamine receptor (D1R) in both the shell and core of the rat nucleus accumbens (NAc). Overall, α1bARs were found in unmyelinated axons and axon terminals with some labeling in dendrites. In accordance with other studies of the striatum, the D1R was found mainly in dendrites and spines; therefore, colocalization of the D1R with the α1bAR was rare postsynaptically. However, in the NAc shell, when the receptors were co-expressed in the same neuronal elements there was a trend for both receptors to be found on the plasma membrane, as opposed to the intracellular compartment. This study provides valuable anatomical information about the α1bAR and its relationship to the D1R and the regulation of DA and norepinephrine (NE) neurotransmission in the brain which have been examined previously.