Dopamine D3 receptors in the basolateral amygdala and the lateral habenula modulate cue-induced reinstatement of nicotine seeking.
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ABSTRACT:
SUBMITTER: Khaled MA
PROVIDER: S-EPMC4229576 | biostudies-other | 2014 Dec
REPOSITORIES: biostudies-other
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Project description:Women report greater craving during certain phases of the menstrual cycle. As well, research indicates that pharmacotherapies for smoking may be less efficacious in women compared with men, which may be due to interactions with natural fluctuations in ovarian hormone levels. N-Acetylcysteine (NAC) is a glutamatergic compound that has shown some efficacy in treating substance use disorders and aids in the prevention of relapse. However, it is unclear whether NAC has sex-specific effectiveness for nicotine relapse treatment. Given that NAC has shown promise to reduce nicotine reinstatement in preclinical models using male rats, the exploration of potential sex differences in the efficacy of NAC is warranted. Using a rat model, we first investigated the ability of NAC treatment (100 mg/kg, ip) during nicotine withdrawal with extinction training to reduce cue-induced nicotine seeking in male and female rats. Next, we assessed whether NAC's effects were estrous cycle-dependent for female rats. Results show that following NAC treatment during extinction, reinstatement of nicotine seeking was significantly decreased in males but not females, indicating a sex-specific effect of NAC. Furthermore, for females, both vehicle- and NAC-treated groups significantly reinstated nicotine-seeking behavior compared with extinction, regardless of estrous cycle phase. These results suggest that NAC is inefficacious in reducing nicotine relapse in females regardless of estrous cycle phase at the dose evaluated here. These collective findings could have important clinical implications for use and efficacy of NAC as a pharmacotherapy for freely cycling women smokers.
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Project description:The dynorphin (DYN)/kappa-opioid receptor (KOR) system plays a conserved role in stress-induced reinstatement of drug seeking for prototypical substances of abuse. Due to nicotine's high propensity for stress-induced relapse, we hypothesized that stress would induce reinstatement of nicotine seeking-like behavior in a KOR-dependent manner. Using a conditioned place preference (CPP) reinstatement procedure in mice, we show that both foot-shock stress and the pharmacological stressor yohimbine (2 mg/kg, i.p.) induce reinstatement of nicotine CPP in a norbinaltorphimine (norBNI, a KOR antagonist)-sensitive manner, indicating that KOR activity is necessary for stress-induced nicotine CPP reinstatement. After reinstatement testing, we visualized robust c-fos expression in the basolateral amygdala (BLA), which was reduced in mice pretreated with norBNI. We then used several distinct but complementary approaches of locally disrupting BLA KOR activity to assess the role of KORs and KOR-coupled intracellular signaling cascades on reinstatement of nicotine CPP. norBNI injected locally into the BLA prevented yohimbine-induced nicotine CPP reinstatement without affecting CPP acquisition. Similarly, selective deletion of BLA KORs in KOR conditional knock-out mice prevented foot-shock-induced CPP reinstatement. Together, these findings strongly implicate BLA KORs in stress-induced nicotine seeking-like behavior. In addition, we found that chemogenetic activation of G?i signaling within CaMKII? BLA neurons was sufficient to induce nicotine CPP reinstatement, identifying an anatomically specific intracellular mechanism by which stress leads to reinstatement. Considered together, our findings suggest that activation of the DYN/KOR system and G?i signaling within the BLA is both necessary and sufficient to produce reinstatement of nicotine preference.Considering the major impact of nicotine use on human health, understanding the mechanisms by which stress triggers reinstatement of drug-seeking behaviors is particularly pertinent to nicotine. The dynorphin (DYN)/kappa-opioid receptor (KOR) system has been implicated in stress-induced reinstatement of drug seeking for other commonly abused drugs. However, the specific role, brain region, and mechanisms that this system plays in reinstatement of nicotine seeking has not been characterized. Here, we report region-specific engagement of the DYN/KOR system and subsequent activation of inhibitory (Gi-linked) intracellular signaling pathways within the basolateral amygdala during stress-induced reinstatement of nicotine preference. We show that the DYN/KOR system is necessary to produce this behavioral state. This work may provide novel insight for the development of therapeutic approaches to prevent stress-related nicotine relapse.
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Project description:Hypocretin/orexin signaling is critically involved in relapse to drug-seeking behaviors. In this study, we investigated the involvement of the hypocretin system in the reinstatement of nicotine-seeking behavior induced by nicotine-associated cues. Pretreatment with the hypocretin receptor-1 antagonist SB334867, but not with the hypocretin receptor-2 antagonist TCSOX229, attenuated cue-induced reinstatement of nicotine-seeking, which was associated with an activation of hypocretin neurons of the lateral and perifornical hypothalamic areas. In addition, relapse to nicotine-seeking increased the phosphorylation levels of GluR2-Ser880, NR1-Ser890, and p38 MAPK in the nucleus accumbens (NAc), but not in the prefrontal cortex. Notably, phosphorylation levels of NR1-Ser890 and p38 MAPK, but not GluR2-Ser880, were dependent on hypocretin receptor-1 activation. The intra-accumbens infusion of the protein kinase C (PKC) inhibitor NPC-15437 reduced nicotine-seeking behavior elicited by drug-paired cues consistent with the PKC-dependent phosphorylations of GluR2-Ser880 and NR1-Ser890. SB334867 failed to modify cue-induced reinstatement of food-seeking, which did not produce any biochemical changes in the NAc. These data identify hypocretin receptor-1 and PKC signaling as potential targets for the treatment of relapse to nicotine-seeking induced by nicotine-associated cues.
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Project description:Cocaine addiction is a disease characterized by chronic relapse despite long periods of abstinence. The lateral orbitofrontal cortex (lOFC) and basolateral amygdala (BLA) promote cocaine-seeking behavior in response to drug-associated conditioned stimuli (CS) and share dense reciprocal connections. Hence, we hypothesized that monosynaptic projections between these brain regions mediate CS-induced cocaine-seeking behavior. Male Sprague-Dawley rats received bilateral infusions of a Cre-dependent adeno-associated viral (AAV) vector expressing enhanced halorhodopsin 3.0 fused with a reporter protein (NpHR-mCherry) or a control AAV (mCherry) plus optic fiber implants into the lOFC (Experiment 1) or BLA (Experiment 2). The same rats also received bilateral infusions of a retrogradely transported AAV vector expressing Cre recombinase (Retro-Cre-GFP) into the BLA (Experiment 1) or lOFC (Experiment 2). Thus, NpHR-mCherry or mCherry expression was targeted to lOFC neurons that project to the BLA or to BLA neurons that project to the lOFC in different groups. Rats were trained to lever press for cocaine infusions paired with 5-s CS presentations. Responding was then extinguished. At test, response-contingent CS presentation was discretely coupled with optogenetic inhibition (5-s laser activation) or no optogenetic inhibition while lever responding was assessed without cocaine/food reinforcement. Optogenetic inhibition of lOFC to BLA, but not BLA to lOFC, projections in the NpHR-mCherry groups disrupted CS-induced reinstatement of cocaine-seeking behavior relative to (i) no optogenetic inhibition or (ii) manipulations in mCherry control or (iii) NpHR-mCherry food control groups. These findings suggest that the lOFC sends requisite input to the BLA, via monosynaptic connections, to promote CS-induced cocaine-seeking behavior.
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Project description:The ability to inhibit drinking is a significant challenge for recovering alcoholics, especially in the presence of alcohol-associated cues. Previous studies have demonstrated that the regulation of cue-guided alcohol seeking is mediated by the basolateral amygdala (BLA), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC). However, given the high interconnectivity between these structures, it is unclear how mPFC projections to each subcortical structure, as well as projections between BLA and NAc, mediate alcohol-seeking behaviors. Here, we evaluate how cortico-striatal, cortico-amygdalar, and amygdalo-striatal projections control extinction and relapse in a rat model of alcohol seeking. Specifically, we used a combinatorial viral technique to express diphtheria toxin receptors in specific neuron populations based on their projection targets. We then used this strategy to create directionally selective ablations of three distinct pathways after acquisition of ethanol self-administration but before extinction and reinstatement. We demonstrate that ablation of mPFC neurons projecting to NAc, but not BLA, blocks cue-induced reinstatement of alcohol seeking and neither pathway is necessary for extinction of responding. Further, we show that ablating BLA neurons that project to NAc disrupts extinction of alcohol approach behaviors and attenuates reinstatement. Together, these data provide evidence that the mPFC→NAc pathway is necessary for cue-induced reinstatement of alcohol seeking, expand our understanding of how the BLA→NAc pathway regulates alcohol behavior, and introduce a new methodology for the manipulation of target-specific neural projections.SIGNIFICANCE STATEMENT The vast majority of recovering alcoholics will relapse at least once and understanding how the brain regulates relapse will be key to developing more effective behavior and pharmacological therapies for alcoholism. Given the high interconnectivity of cortical, striatal, and limbic structures that regulate alcohol intake, it has been difficult to disentangle how separate projections between them may control different aspects of these complex behaviors. Here, we demonstrate a new approach for noninvasively ablating each of these pathways and testing their necessity for both extinction and relapse. We show that inputs to the nucleus accumbens from medial prefrontal cortex and amygdala regulate alcohol-seeking behaviors differentially, adding to our understanding of the neural control of alcoholism.
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Project description:In humans, relapse to unhealthy eating habits following dieting is a significant impediment to obesity treatment. Food-associated cues are one of the main triggers of relapse to unhealthy eating during self-imposed abstinence. Here we report a behavioral method examining cue-induced relapse to food seeking following punishment-induced suppression of food taking. We trained male rats to lever press for food pellets that were delivered after a 10-s conditional stimulus (CS) (appetitive). Following training, 25% of reinforced lever presses resulted in the presentation of a compound stimulus consisting of a novel CS (aversive) and the appetitive CS followed by a pellet and footshock. After punishment-imposed abstinence, we tested the rats in an extinction test where lever pressing resulted in the presentation of either the appetitive or aversive CS. We then compared activity of lateral hypothalamus (LH) and associated extrahypothalamic regions following this test. We also assessed Fos expression in LH orexin and GABA neurons. We found that cue-induced relapse of food seeking on test was higher in rats tested with the appetitive CS compared to the aversive CS. Relapse induced by the appetitive CS was associated with increased Fos expression in LH, caudal basolateral amygdala (BLA), and medial amygdala (MeA). This relapse was also associated with increased Fos expression in LH orexin and VGAT-expressing neurons. These data show that relapse to food seeking can be induced by food-associated cues after punishment-imposed abstinence, and this relapse is associated with increased activity in LH, caudal BLA, and MeA. (PsycINFO Database Record
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