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Drugs of abuse induce cell type-specific adaptations in D1- and D2-medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore) that can bias signalling towards D1-MSNs and enhance relapse vulnerability. Whether Δ9 -tetrahydrocannabinol (THC) use initiates similar neuroadaptations is unknown. D1- and D2-Cre transgenic rats were transfected with Cre-dependent reporters and trained to self-administer THC + cannabidiol (THC + CBD). After extinction training spine morphology, glutamate transmission, CB1R function and cFOS expression were quantified. We found that extinction from THC + CBD induced a loss of large spine heads in D1- but not D2-MSNs and commensurate reductions in glutamate synaptic transmission. Also, presynaptic CB1R function was impaired selectively at glutamatergic synapses on D1-MSNs, which augmented the capacity to potentiate glutamate transmission. Using cFOS expression as an activity marker, we found no change after extinction but increased cFOS expression in D1-MSNs after cue-induced drug seeking. Contrasting D1-MSNs, CB1R function and glutamate synaptic transmission on D2-MSN synapses were unaffected by THC + CBD use. However, cFOS expression was decreased in D2-MSNs of THC + CBD-extinguished rats and was restored after drug seeking. Thus, CB1R adaptations in D1-MSNs partially predicted neuronal activity changes, posing pathway specific modulation of eCB signalling in D1-MSNs as a potential treatment avenue for cannabis use disorder (CUD).
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Dronabinol , Núcleo Accumbens , Ratas , Animales , Ratones , Núcleo Accumbens/metabolismo , Dronabinol/farmacología , Dronabinol/metabolismo , Neuronas/metabolismo , Transmisión Sináptica , Ratas Transgénicas , Glutamatos/metabolismo , Receptores de Dopamina D1/metabolismo , Ratones Transgénicos , Ratones Endogámicos C57BLRESUMEN
Nicotine addiction is a chronic relapsing brain disorder, and cigarette smoking is the leading cause of preventable death in the United States. Currently, the most effective pharmacotherapy for smoking cessation is Varenicline (VRN), which reduces both positive and negative reinforcement by nicotine. Clinically, VRN attenuates withdrawal symptoms and promotes abstinence, but >50% of smokers relapse within 3 months following a quit attempt. This may indicate that VRN fails to ameliorate components of nicotine-induced neuroplasticity that promote relapse vulnerability. Animal models reveal that glutamate dysregulation in the nucleus accumbens is associated with nicotine relapse. N-acetylcysteine (NAC) normalizes glutamate transmission and prolongs cocaine abstinence. Thus, combining VRN and NAC may promote and maintain, respectively, nicotine abstinence. In rats, we found that VRN effectively reduced nicotine self-administration and seeking in early abstinence, but not seeking later in abstinence. In contrast, NAC reduced seeking only later in abstinence. Because VRN and NAC are sometimes associated with mild adverse effects, we also evaluated a sequential approach combining subthreshold doses of VRN during self-administration and early abstinence with subthreshold doses of NAC during late abstinence. As expected, subthreshold VRN did not reduce nicotine intake. However, subthreshold VRN and NAC reduced seeking in late abstinence, suggesting a combined effect. Overall, our results suggest that combining subthreshold VRN and NAC is a viable and drug-specific approach to promote abstinence and reduce relapse while minimizing adverse effects. Our data also suggest that different components and time points in addiction engage the different neurocircuits targeted by VRN and NAC.
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Cese del Hábito de Fumar , Tabaquismo , Acetilcisteína/farmacología , Acetilcisteína/uso terapéutico , Animales , Nicotina/farmacología , Ratas , Tabaquismo/tratamiento farmacológico , Tabaquismo/prevención & control , Vareniclina/farmacología , Vareniclina/uso terapéuticoRESUMEN
Glutamatergic plasticity in the nucleus accumbens core (NAcore) is a key neuronal process in appetitive learning and contributes to pathologies such as drug addiction. Understanding how this plasticity factors into cannabis addiction and relapse has been hampered by the lack of a rodent model of cannabis self-administration. We used intravenous self-administration of two constituents of cannabis, Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD) to examine how contingent cannabis use and cue-induced cannabinoid-seeking alters glutamatergic neurotransmission and synaptic plasticity in NAcore. NMDA receptor (NMDAR)-dependent long-term depression (LTD) in the NAcore was lost after cannabinoid, but not sucrose self-administration. Surprisingly, when rats underwent cue-induced cannabinoid seeking, LTD was restored. Loss of LTD was accompanied by desensitization of cannabinoid receptor 1 (CB1R). CB1R are positioned to regulate synaptic plasticity by being expressed on glutamatergic terminals and negatively regulating presynaptic excitability and glutamate release. Supporting this possibility, LTD was restored by promoting CB1R signaling with the CB1 positive allosteric modulator GAT211. These data implicate NAcore CB1R as critical regulators of metaplasticity induced by cannabis self-administration and the cues predicting cannabis availability.
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Cannabidiol/farmacología , Cannabinoides/farmacología , Dronabinol/farmacología , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Receptor Cannabinoide CB1/agonistas , Receptores de N-Metil-D-Aspartato/fisiología , Regulación Alostérica/efectos de los fármacos , Animales , Conducta Adictiva/inducido químicamente , Cannabidiol/administración & dosificación , Agonistas de Receptores de Cannabinoides/administración & dosificación , Agonistas de Receptores de Cannabinoides/farmacología , Cannabinoides/administración & dosificación , Dronabinol/administración & dosificación , Ácido Glutámico/metabolismo , Indoles/administración & dosificación , Indoles/farmacología , Depresión Sináptica a Largo Plazo/fisiología , Masculino , Núcleo Accumbens/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Autoadministración , Transmisión Sináptica/efectos de los fármacosRESUMEN
UNLABELLED: Experience with sexual behavior causes cross-sensitization of amphetamine reward, an effect dependent on a period of sexual reward abstinence. We previously showed that ΔFosB in the nucleus accumbens (NAc) is a key mediator of this cross-sensitization, potentially via dopamine receptor activation. However, the role of mesolimbic dopamine for sexual behavior or cross-sensitization between natural and drug reward is unknown. This was tested using inhibitory designer receptors exclusively activated by designer drugs in ventral tegmental area (VTA) dopamine cells. rAAV5/hSvn-DIO-hm4D-mCherry was injected into the VTA of TH::Cre adult male rats. Males received clozapine N-oxide (CNO) or vehicle injections before each of 5 consecutive days of mating or handling. Following an abstinence period of 7 d, males were tested for amphetamine conditioned place preference (CPP). Next, males were injected with CNO or vehicle before mating or handling for analysis of mating-induced cFos, sex experience-induced ΔFosB, and reduction of VTA dopamine soma size. Results showed that CNO did not affect mating behavior. Instead, CNO prevented sexual experience-induced cross-sensitization of amphetamine CPP, ΔFosB in the NAc and medial prefrontal cortex, and decreases in VTA dopamine soma size. Expression of hm4D-mCherry was specific to VTA dopamine cells and CNO blocked excitation and mating-induced cFos expression in VTA dopamine cells. These findings provide direct evidence that VTA dopamine activation is not required for initiation or performance of sexual behavior. Instead, VTA dopamine directly contributes to increased vulnerability for drug use following loss of natural reward by causing neuroplasticity in the mesolimbic pathway during the natural reward experience. SIGNIFICANCE STATEMENT: Drugs of abuse act on the neural pathways that mediate natural reward learning and memory. Exposure to natural reward behaviors can alter subsequent drug-related reward. Specifically, experience with sexual behavior, followed by a period of abstinence from sexual behavior, causes increased reward for amphetamine in male rats. This study demonstrates that activation of ventral tegmental area dopamine neurons during sexual experience regulates cross-sensitization of amphetamine reward. Finally, ventral tegmental area dopamine cell activation is essential for experience-induced neural adaptations in the nucleus accumbens, prefrontal cortex, and ventral tegmental area. These findings demonstrate a role of mesolimbic dopamine in the interaction between natural and drug rewards, and identify mesolimbic dopamine as a key mediator of changes in vulnerability for drug use after loss of natural reward.
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Anfetamina/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Conducta Sexual Animal/efectos de los fármacos , Área Tegmental Ventral/citología , Animales , Clozapina/análogos & derivados , Clozapina/farmacología , Condicionamiento Operante/efectos de los fármacos , Drogas de Diseño/farmacología , Femenino , Regulación de la Expresión Génica/fisiología , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Plasticidad Neuronal/fisiología , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Recompensa , Transducción Genética , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Proteína Fluorescente RojaRESUMEN
Natural reward and drugs of abuse converge on the mesolimbic pathway and activate common mechanism of neural plasticity in the nucleus accumbens. Chronic exposure to opiates induces plasticity in dopaminergic neurons of the ventral tegmental area (VTA), which regulates morphine reward tolerance. Here, we test the hypotheses that mating-induced release of endogenous opioids in the VTA causes morphological changes of VTA dopamine cells in male rats, which in-turn regulate the long-term expression of experience-induced reinforcement of sexual behavior. First, sexual experience decreased VTA dopamine soma size 1 and 7 days, but not 30 days after the last mating session. This effect was blocked with naloxone before each mating session; thus, VTA dopamine cell plasticity was dependent on action of endogenous opioids. In turn, VTA plasticity was associated with altered opiate reward, as sexually experienced males did not form conditioned place preference for 0.5 mg/kg morphine. Next, it was determined whether endogenous opioid action mediates sexual reward and memory in male rats treated with naloxone during mating experience, either systemically or intra-VTA. Naloxone did not prevent the initial experience-induced facilitation of sexual behavior over repeated mating sessions, or conditioned place preference for mating. However, naloxone treatment attenuated the longer-term expression of experience-induced facilitation of sexual behavior and neural activation in mesolimbic areas induced by mating-associated conditioned cues. Together, these data demonstrate that endogenous opioids during mating induce neural plasticity in VTA dopamine neurons that appear critical for morphine reward and long-term memory for natural reward behavior.
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Copulación/fisiología , Neuronas Dopaminérgicas/fisiología , Plasticidad Neuronal/fisiología , Recompensa , Área Tegmental Ventral/fisiología , Animales , Aprendizaje por Asociación/efectos de los fármacos , Aprendizaje por Asociación/fisiología , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Neuronas Dopaminérgicas/efectos de los fármacos , Masculino , Morfina/farmacología , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Plasticidad Neuronal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Área Tegmental Ventral/efectos de los fármacosRESUMEN
Introduction: Chemogenetic techniques, specifically the use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), have become invaluable tools in neuroscience research. Yet, the understanding of how Gq- and Gicoupled DREADDs alter local field potential (LFP) oscillations in vivo remains incomplete. Methods: This study investigates the in vivo electrophysiological effects of DREADD actuation by deschloroclozapine, on spontaneous firing rate and LFP oscillations recorded from the anterior cingulate cortex in lightly anesthetized male rats. Results: Unexpectedly, in response to the administration of deschloroclozapine, we observed inhibitory effects with pan-neuronal hM3D(Gq) stimulation, and excitatory effects with pan-neuronal hM4D(Gi) stimulation in a significant portion of neurons. These results emphasize the need to account for indirect perturbation effects at the local neuronal network level in vivo, particularly when not all neurons express the chemogenetic receptors uniformly. In the current study, for instance, the majority of cells that were transduced with both hM3D(Gq) and hM4D(Gi) were GABAergic. Moreover, we found that panneuronal cortical chemogenetic modulation can profoundly alter oscillatory neuronal activity, presenting a potential research tool or therapeutic strategy in several neuropsychiatric models and diseases. Discussion: These findings help to optimize the use of chemogenetic techniques in neuroscience research and open new possibilities for novel therapeutic strategies.
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Simultaneously manipulating and monitoring both microscopic and macroscopic brain activity in vivo and identifying the linkage to behavior are powerful tools in neuroscience research. These capabilities have been realized with the recent technical advances of optogenetics and its combination with fMRI, here termed "opto-fMRI." Opto-fMRI allows for targeted brain region-, cell-type-, or projection-specific manipulation and targeted Ca 2 + activity measurement to be linked with global brain signaling and behavior. We cover the history, technical advances, applications, and important considerations of opto-fMRI in anesthetized and awake rodents and the future directions of the combined techniques in neuroscience and neuroimaging.
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Recent proteome and transcriptome profiling of Alzheimer's disease (AD) brains reveals RNA splicing dysfunction and U1 small nuclear ribonucleoprotein (snRNP) pathology containing U1-70K and its N-terminal 40-KDa fragment (N40K). Here we present a causative role of U1 snRNP dysfunction to neurodegeneration in primary neurons and transgenic mice (N40K-Tg), in which N40K expression exerts a dominant-negative effect to downregulate full-length U1-70K. N40K-Tg recapitulates N40K insolubility, erroneous splicing events, neuronal degeneration and cognitive impairment. Specifically, N40K-Tg shows the reduction of GABAergic synapse components (e.g., the GABA receptor subunit of GABRA2), and concomitant postsynaptic hyperexcitability that is rescued by a GABA receptor agonist. Crossing of N40K-Tg and the 5xFAD amyloidosis model indicates that the RNA splicing defect synergizes with the amyloid cascade to remodel the brain transcriptome and proteome, deregulate synaptic proteins, and accelerate cognitive decline. Thus, our results support the contribution of U1 snRNP-mediated splicing dysfunction to AD pathogenesis.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Animales , Ratones , Ribonucleoproteína Nuclear Pequeña U1/genética , Enfermedad de Alzheimer/genética , Proteoma/genética , Empalme del ARN/genética , Disfunción Cognitiva/genéticaRESUMEN
Vulnerability to develop addiction is influenced by numerous factors, including social behavior. Specifically, in human users, drug taking in a socio-sexual context appears to enhance further drug-seeking behavior. Users report heightened sexual pleasure as a motivation for further drug use and display risk behaviors even when tested in drug-free state. Here, using a preclinical model of limited voluntary drug use in rats, the hypothesis was tested that methamphetamine (Meth)-taking concurrently with socio-sexual experience increases vulnerability to addiction. Male Sprague Dawley rats were socially housed and underwent limited-access Meth self-administration (maximum 1 mg/kg/session). Meth-taking was either concurrent or non-concurrent with sexual behavior: concurrent animals were mated with a receptive female immediately after each session, while non-concurrent animals gained equivalent sexual experience the week prior. Next, drug-seeking behaviors were measured during cue reactivity, extinction, and reinstatement sessions using different extinction and reinstatement protocols in 4 separate studies. Both groups equally acquired Meth self-administration and did not differ in total Meth intake. However, drug-seeking behavior was significantly higher in concurrent animals during cue reactivity tasks, extinction sessions, and cue- or Meth-induced reinstatement tests. In addition, sexual behavior in the absence of Meth triggered reinstatement of drug-seeking in concurrent animals. These results indicate that Meth-taking in a socio-sexual context significantly enhances vulnerability for drug addiction in male rats. This preclinical paradigm of drug self-administration concurrent with socio-sexual behavior provides a useful model for studying the underlying neurobiology of socially driven vulnerability to drug addiction.
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Conducta Adictiva , Estimulantes del Sistema Nervioso Central/administración & dosificación , Metanfetamina/administración & dosificación , Conducta Sexual Animal , Conducta Social , Animales , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Sprague-Dawley , AutoadministraciónRESUMEN
Many factors, including social elements, influence drug addiction in humans and can be modeled in laboratory rodents. In general, the presence of social reward is protective against drug abuse and the absence or removal of social reward in both humans and rodents increases vulnerability to drug addiction. The current review chapter is focused on studies from our lab that have examined the effects of sociosexual behavior in male rats on drug-induced behaviors, including changes in both psychostimulant and opiate behavior. Furthermore, we review the underlying neural mechanisms by which these effects occur. Together, these results may help elucidate the neural mechanisms underlying the interaction between social and drug rewards and the mechanisms by which a loss of social rewards increase the vulnerability to drug addiction development.
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Conducta Adictiva/fisiopatología , Conducta Animal/fisiología , Estimulantes del Sistema Nervioso Central/farmacología , Neuronas Dopaminérgicas/metabolismo , Núcleo Accumbens/metabolismo , Alcaloides Opiáceos/farmacología , Refuerzo en Psicología , Conducta Sexual Animal/fisiología , Transducción de Señal/fisiología , Conducta Social , Área Tegmental Ventral/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Neuronas Dopaminérgicas/citología , Neuronas Dopaminérgicas/efectos de los fármacos , Masculino , Núcleo Accumbens/citología , Núcleo Accumbens/efectos de los fármacos , Ratas , Transducción de Señal/efectos de los fármacos , Área Tegmental Ventral/citología , Área Tegmental Ventral/efectos de los fármacosRESUMEN
Different factors influence the development of drug addiction in humans, including social reward experiences. In animals, experience with social rewards, such as sexual behavior, pair bonding, social and environmental enrichment, can be protective. However, loss or lack of social rewards can lead to a vulnerability to drug-seeking behavior. The effects of social reward experience on drug-seeking behavior are associated with changes in the neural pathways that control drug-related behavior. This review will provide an introduction and overview of the mesolimbic pathway and the influence of social reward experience on drug-seeking behavior in rodents. Moreover, the research from our laboratory on effects of sexual experience and loss of sex reward on psychostimulant and opiate reward will be reviewed. Finally, we will review current knowledge of the neural mechanisms that underlie these interactions. Investigations of the neural underpinnings by which social and drug rewards interact contribute to improved understanding of the neural basis of vulnerability for drug addiction and reward-related behaviors in general.
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Plasticidad Neuronal/fisiología , Recompensa , Conducta Sexual , Conducta Social , Trastornos Relacionados con Sustancias , Animales , Encéfalo/patología , Encéfalo/fisiopatología , Comportamiento de Búsqueda de Drogas/fisiología , Femenino , Humanos , Masculino , Trastornos Relacionados con Sustancias/patología , Trastornos Relacionados con Sustancias/fisiopatología , Trastornos Relacionados con Sustancias/psicologíaRESUMEN
The mineralocorticoid receptor (MR) is a member of the steroid-thyroid hormone receptor superfamily of ligand-dependent transcription factors with diverse functions including the biological actions of aldosterone. Identification of the various transcriptional coregulators of MR is essential for understanding the complexity of MR signaling pathways under physiological and pathological conditions. We used a yeast two-hybrid system to find proteins that interact with a full-length MR and found, among other proteins, that MR interacted specifically with receptor for activated C kinase 1 (RACK1), a scaffolding protein. Overexpression of RACK1 using a tetracycline-inducible lentivirus in mouse cortical collecting duct M1 cells stably expressing the rat MR and a Gaussia luciferase gene reporter under a hormone-response element promoter resulted in enhanced agonist-dependent MR transactivation. Knockdown of RACK1 protein expression by short hairpin RNAs led to a significant reduction in MR activation of the reporter gene and the endogenous genes Ctla2α and Psca. We also demonstrated that RACK1 regulation of MR action is mediated through phosphorylation by the PKC-ß signaling pathway. MR and RACK1 were coimmunoprecipitated using an MR antibody in male Sprague-Dawley brain tissue and M1-rMR cells, and colocalization in M1-rMR cells and male rat brains was confirmed by immunofluorescence and immunohistochemistry. The scaffolding protein RACK1 is associated with MR under basal and agonist-stimulated conditions and facilitates agonist-stimulated MR actions through PKC-ß. These findings indicate that RACK1 is a newly described coactivator of MR.
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Aldosterona/metabolismo , Proteínas de Unión al GTP/metabolismo , Receptores de Mineralocorticoides/metabolismo , Animales , Células Cultivadas , Proteínas de Unión al GTP/genética , Masculino , Regiones Promotoras Genéticas , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores de Cinasa C Activada , Receptores de Mineralocorticoides/genética , Transducción de Señal/genética , Activación TranscripcionalRESUMEN
Sexual experience in male rats followed by a period of abstinence causes sensitization to d-Amphetamine (Amph) reward, evidenced by an increased conditioned place preference (CPP) for low doses of Amph. Moreover, sexual experience induces neural plasticity within the nucleus accumbens (NAc), including induction of deltaFosB, which plays a key role in Amph reward cross-sensitization. The NMDA receptor subunit NR1 is also upregulated by mating, but the functional relevance of NMDA receptors in sex experience-induced effects is unknown. Here, we examined the influence of intra-NAc MK 801 infusions on sex experience-induced NAc deltaFosB and cFos expression, as well as mating- and Amph-induced CPP in adult male rats. In experiment 1, males received MK 801 or saline into the NAc during each of 4 consecutive days of mating or handling and were tested for Amph CPP and experience-induced deltaFosB 10 days later. Intra-NAc MK 801 during sexual behavior prevented experience-induced increases in Amph CPP and NAc deltaFosB expression without affecting sexual behavior. In experiment 2, the effects of intra-NAc MK 801 on mating-induced CPP were examined by intra-NAc infusion of MK 801 or saline prior to mating on conditioning days. Intra-NAc MK 801 did not affect mating-induced CPP. Next, effects of intra-NAc MK 801 on mating-induced cFos immunoreactivity were examined. MK 801 prevented mating-induced cFos expression in NAc shell and core. Together, these results provide evidence that NAc NMDA receptor activation during sexual behavior plays a key role in mating-induced cFos and deltaFosB expression and subsequent experience-induced cross-sensitization to Amph reward.
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Estimulantes del Sistema Nervioso Central/farmacología , Núcleo Accumbens/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Conducta Sexual Animal/fisiología , Anfetamina/farmacología , Análisis de Varianza , Animales , Condicionamiento Operante/efectos de los fármacos , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Núcleo Accumbens/efectos de los fármacos , Ratas , Tiempo de Reacción/efectos de los fármacos , RecompensaRESUMEN
Obesity is associated with abnormal brain reactivity in response to palatable food consumption, a factor that may contribute to non-homeostatic eating. However, little is known about how obesity interacts with the reinforcing effects of highly palatable constituents of food (e.g., fat), and if altered reinforcement processes associated with obesity generalize to non-food reinforcers. The current study compared the reinforcing effects of a fat (corn oil) and a drug of abuse (cocaine) in obese and lean Zucker rats. Specifically, obese and lean Zucker rats self-administered corn oil or intravenous cocaine in a behavioral economic demand procedure. For corn oil, maximum demand was higher and demand elasticity was lower in the obese rats compared to their lean counterparts. However, there were no differences in demand for cocaine between the obese and lean rats. These results demonstrate that a fat in the form of corn oil is a more effective reinforcer in obese Zucker rats. However, the fact that demand for cocaine was not different between the obese and lean rats suggests that differences in reward mechanisms may be reinforcer-specific and do not necessarily generalize to non-food reinforcers.