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1.
J Neurosci ; 40(33): 6409-6427, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32669355

RESUMO

The mesolimbic dopamine system comprises distinct compartments supporting different functions in learning and motivation. Less well understood is how complex addiction-related behaviors emerge from activity patterns across these compartments. Here we show how different forms of relapse to alcohol-seeking in male rats are assembled from activity across the VTA and the nucleus accumbens. First, we used chemogenetic approaches to show a causal role for VTA TH neurons in two forms of relapse to alcohol-seeking: renewal (context-induced reinstatement) and reacquisition. Then, using gCaMP fiber photometry of VTA TH neurons, we identified medial and lateral VTA TH neuron activity profiles during self-administration, renewal, and reacquisition. Next, we used optogenetic inhibition of VTA TH neurons to show distinct causal roles for VTA subregions in distinct forms of relapse. We then used dLight fiber photometry to measure dopamine binding across the ventral striatum (medial accumbens shell, accumbens core, lateral accumbens shell) and showed complex and heterogeneous profiles of dopamine binding during self-administration and relapse. Finally, we used representational similarity analysis to identify mesolimbic dopamine signatures of self-administration, extinction, and relapse. Our results show that signatures of relapse can be identified from heterogeneous activity profiles across the mesolimbic dopamine system and that these signatures are unique for different forms of relapse.SIGNIFICANCE STATEMENT It is axiomatic that the actions of dopamine are critical to drug addiction. Yet how relapse to drug-seeking is assembled from activity across the mesolimbic dopamine system is poorly understood. Here we show how relapse to alcohol-seeking relates to activity in specific VTA and accumbens compartments, how these change for different forms of relapse, and how relapse-associated activity relates to activity during self-administration and extinction. We report the mesolimbic dopamine activity signatures for relapse and show that these signatures are unique for different forms of relapse.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Comportamento de Procura de Droga/fisiologia , Etanol/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologia , Animais , Comportamento Aditivo/fisiopatologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Dopamina/metabolismo , Masculino , Potenciais da Membrana , Optogenética , Ratos Long-Evans , Recidiva , Tirosina 3-Mono-Oxigenase/metabolismo
2.
J Neurosci ; 40(33): 6379-6388, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32493711

RESUMO

The perception of time is critical to adaptive behavior. While prefrontal cortex and basal ganglia have been implicated in interval timing in the seconds to minutes range, little is known about the role of the mediodorsal thalamus (MD), which is a key component of the limbic cortico-basal ganglia-thalamocortical loop. In this study, we tested the role of the MD in timing, using an operant temporal production task in male mice. In this task, that the expected timing of available rewards is indicated by lever pressing. Inactivation of the MD with muscimol produced rightward shifts in peak pressing on probe trials as well as increases in peak spread, thus significantly altering both temporal accuracy and precision. Optogenetic inhibition of glutamatergic projection neurons in the MD also resulted in similar changes in timing. The observed effects were found to be independent of significant changes in movement. Our findings suggest that the MD is a critical component of the neural circuit for interval timing, without playing a direct role in regulating ongoing performance.SIGNIFICANCE STATEMENT The mediodorsal nucleus (MD) of the thalamus is strongly connected with the prefrontal cortex and basal ganglia, areas which have been implicated in interval timing. Previous work has shown that the MD contributes to working memory and learning of action-outcome contingencies, but its role in behavioral timing is poorly understood. Using an operant temporal production task, we showed that inactivation of the MD significantly impaired timing behavior.


Assuntos
Condicionamento Operante/fisiologia , Núcleo Mediodorsal do Tálamo/fisiologia , Desempenho Psicomotor/fisiologia , Percepção do Tempo/fisiologia , Animais , Condicionamento Operante/efeitos dos fármacos , Agonistas de Receptores de GABA-A/administração & dosagem , Masculino , Núcleo Mediodorsal do Tálamo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Muscimol/administração & dosagem , Optogenética , Desempenho Psicomotor/efeitos dos fármacos , Recompensa , Percepção do Tempo/efeitos dos fármacos
3.
Psychopharmacology (Berl) ; 237(9): 2845-2854, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32561947

RESUMO

RATIONALE: Effort-based decision-making tasks allow animals to choose between preferred reinforcers that require high effort to obtain vs. low-effort/low reward options. Mesolimbic dopamine (DA) and related neural systems regulate effort-based choice. Tetrabenazine (TBZ) is a vesicular monoamine transport type-2 inhibitor that blocks DA storage and depletes DA. In humans, TBZ induces motivational dysfunction and depression. TBZ has been shown reliably to induce a low-effort bias in rats, but there are fewer mouse studies. OBJECTIVES: The present studies used touchscreen operant procedures (Bussey-Saksida chambers) to assess the effects of TBZ on effort-based choice in mice. METHODS: C57BL6 mice were trained to press an elevated lit panel on the touchscreen on a fixed ratio 1 schedule reinforced by strawberry milkshake, vs. approaching and consuming a concurrently available but less preferred food pellets (Bio-serv). RESULTS: TBZ (2.0-8.0 mg/kg IP) shifted choice, producing a dose-related decrease in panel pressing but an increase in pellet intake. In contrast, reinforcer devaluation by pre-feeding substantially decreased both panel pressing and pellet intake. In free-feeding choice tests, mice strongly preferred the milkshake vs. the pellets, and TBZ had no effect on milkshake intake or preference, indicating that the TBZ-induced low-effort bias was not due to changes in primary food motivation or preference. TBZ significantly decreased tissue levels of nucleus accumbens DA. CONCLUSION: The DA depleting agent TBZ induced an effort-related motivational dysfunction in mice, which may have clinical relevance for assessing novel drug targets for their potential use as therapeutic agents in patients with motivation impairments.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Dopamina/metabolismo , Motivação/efeitos dos fármacos , Reforço Psicológico , Tetrabenazina/farmacologia , Animais , Comportamento de Escolha/fisiologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Motivação/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos Sprague-Dawley , Recompensa
4.
Psychopharmacology (Berl) ; 237(8): 2395-2404, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32448943

RESUMO

RATIONALE: Menthol is a widely used tobacco constituent that has shown to enhance nicotine's reinforcing effects. OBJECTIVE: To determine whether injected menthol also alters nicotine's stimulus effects, we used a drug discrimination task. METHODS: A total of 57 adult Sprague-Dawley rats (28M, 29F) received 20 positive and 20 negative days (intermixed) of discrimination training. On positive days, rats received a group-specific menthol and nicotine injection (VEH + 0.1 NIC, 1 M + 0.1 NIC, 5 M + 0.1 NIC, VEH + 0.4 NIC, 1 M + 0.4 NIC, 5 M + 0.4 NIC; mg/kg) before eight 15-s cue light presentations (conditioned stimulus (CS)), each followed by 4-s sucrose access. On negative days, all rats were injected with vehicle and saline before eight non-reinforced CS presentations. Next, rats underwent generalization testing with 30 dose combinations of menthol and nicotine. The change in drug-mediated anticipatory goal tracking during the CS was calculated as a difference score (CS minus pre-CS responding). RESULTS: All groups readily acquired drug discrimination. However, difference scores for the 5M + 0.1 NIC group were lower for females. Additionally, females had lower scores for 0.05, 0.1, and 0.4 mg/kg nicotine generalization tests. The lowest nicotine dose discriminable from saline was 0.05 mg/kg for females but 0.025 mg/kg for males. Co-administration with 5 or 10 mg/kg menthol weakened discrimination performance between 0.1 and 0.4 mg/kg and between 0.1 and 0.05 mg/kg nicotine for 0.1 mg/kg nicotine training groups. CONCLUSIONS: Female rats that were trained with 0.1 mg/kg nicotine were more sensitive to menthol's modulatory effects on nicotine's stimulus effects. This highlights the importance of taking sex and training dose into account when evaluating the interoceptive stimulus effects of nicotine and menthol.


Assuntos
Aprendizagem por Discriminação/efeitos dos fármacos , Mentol/administração & dosagem , Nicotina/administração & dosagem , Reforço Psicológico , Caracteres Sexuais , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Aprendizagem por Discriminação/fisiologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Sacarose/administração & dosagem
5.
Brain Struct Funct ; 225(3): 1073-1088, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32246242

RESUMO

This study sought to determine if reducing dopamine D1 receptor (D1R) expression in the dorsal striatum (DS) via RNA-interference alters methamphetamine self-administration. A lentiviral construct containing a short hairpin RNA (shRNA) was used to knock down D1R expression (D1RshRNA). D1RshRNA in male rats increased responding for methamphetamine (i.v.) under a fixed-ratio schedule in an extended access paradigm, compared to D1R-intact rats. D1RshRNA also produced a vertical shift in a dose-response paradigm and enhanced responding for methamphetamine in a progressive-ratio schedule, generating a drug-vulnerable phenotype. D1RshRNA did not alter responding for sucrose (oral) under a fixed-ratio schedule compared to D1R-intact rats. Western blotting confirmed reduced D1R expression in methamphetamine and sucrose D1RshRNA rats. D1RshRNA reduced the expression of PSD-95 and MAPK-1 and increased the expression of dopamine transporter (DAT) in the DS from methamphetamine, but not sucrose rats. Sucrose density gradient fractionation was performed in behavior-naïve controls, D1RshRNA- and D1R-intact rats to determine the subcellular localization of D1Rs, DAT and D1R signaling proteins. D1Rs, DAT, MAPK-1 and PSD-95 predominantly localized to heavy fractions, and the membrane/lipid raft protein caveolin-1 (Cav-1) and flotillin-1 were distributed equally between buoyant and heavy fractions in controls. Methamphetamine increased localization of PSD-95, Cav-1, and flotillin-1 in D1RshRNA and D1R-intact rats to buoyant fractions. Our studies indicate that reduced D1R expression in the DS increases vulnerability to methamphetamine addiction-like behavior, and this is accompanied by striatal alterations in the expression of DAT and D1R signaling proteins and is independent of the subcellular localization of these proteins.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Corpo Estriado/metabolismo , Comportamento de Procura de Droga/fisiologia , Metanfetamina/administração & dosagem , Receptores de Dopamina D1/metabolismo , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Corpo Estriado/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Comportamento de Procura de Droga/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Masculino , RNA Interferente Pequeno/administração & dosagem , Ratos Long-Evans , Receptores de Dopamina D2/metabolismo
6.
J Neurosci ; 40(17): 3465-3477, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32184221

RESUMO

Nicotine addiction, through smoking, is the principal cause of preventable mortality worldwide. Human genome-wide association studies have linked polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster, coding for the α5, α3, and ß4 nicotinic acetylcholine receptor (nAChR) subunits, to nicotine addiction. ß4*nAChRs have been implicated in nicotine withdrawal, aversion, and reinforcement. Here we show that ß4*nAChRs also are involved in non-nicotine-mediated responses that may predispose to addiction-related behaviors. ß4 knock-out (KO) male mice show increased novelty-induced locomotor activity, lower baseline anxiety, and motivational deficits in operant conditioning for palatable food rewards and in reward-based Go/No-go tasks. To further explore reward deficits we used intracranial self-administration (ICSA) by directly injecting nicotine into the ventral tegmental area (VTA) in mice. We found that, at low nicotine doses, ß4KO self-administer less than wild-type (WT) mice. Conversely, at high nicotine doses, this was reversed and ß4KO self-administered more than WT mice, whereas ß4-overexpressing mice avoided nicotine injections. Viral expression of ß4 subunits in medial habenula (MHb), interpeduncular nucleus (IPN), and VTA of ß4KO mice revealed dose- and region-dependent differences: ß4*nAChRs in the VTA potentiated nicotine-mediated rewarding effects at all doses, whereas ß4*nAChRs in the MHb-IPN pathway, limited VTA-ICSA at high nicotine doses. Together, our findings indicate that the lack of functional ß4*nAChRs result in deficits in reward sensitivity including increased ICSA at high doses of nicotine that is restored by re-expression of ß4*nAChRs in the MHb-IPN. These data indicate that ß4 is a critical modulator of reward-related behaviors.SIGNIFICANCE STATEMENT Human genetic studies have provided strong evidence for a relationship between variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster and nicotine addiction. Yet, little is known about the role of ß4 nicotinic acetylcholine receptor (nAChR) subunit encoded by this cluster. We investigated the implication of ß4*nAChRs in anxiety-, food reward- and nicotine reward-related behaviors. Deletion of the ß4 subunit gene resulted in an addiction-related phenotype characterized by low anxiety, high novelty-induced response, lack of sensitivity to palatable food rewards and increased intracranial nicotine self-administration at high doses. Lentiviral vector-induced re-expression of the ß4 subunit into either the MHb or IPN restored a "stop" signal on nicotine self-administration. These results suggest that ß4*nAChRs provide a promising novel drug target for smoking cessation.


Assuntos
Condicionamento Operante/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Nicotina/administração & dosagem , Receptores Nicotínicos/metabolismo , Recompensa , Autocontrole , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Motivação/efeitos dos fármacos , Proteínas do Tecido Nervoso/genética , Agonistas Nicotínicos/administração & dosagem , Receptores Nicotínicos/genética , Autoadministração
7.
Behav Neurosci ; 134(2): 101-118, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32175760

RESUMO

Cost-benefit decision making is essential for organisms to adapt to their ever-changing environment. Most studies of cost-benefit decision making involve choice conditions in which effort and value are varied simultaneously. This prevents identification of the aspects of cost-benefit decision making that are affected by experimental manipulations. We developed operant assays to isolate the individual impacts of effort and value manipulations on cost-benefit decision making. In the concurrent effort choice (CEC) task, mice choose between exerting two distinct types of effort: the number of responses and the duration of a response, to earn the same reward. By parametrically varying response cost, psychometric functions are obtained that reflect how the two types of effort scale against one another. Direct manipulations of effort shift the functions. Because reward value is held constant in this task, differences in scaling of the two response types must be related to the effort manipulations. In the concurrent value choice (CVC) task, mice make the same type of response to earn rewards of different value (e.g., pellets vs. sucrose solutions). Here the effort required to earn one reward type is parametrically varied to obtain the psychometric function that scales the value of the two rewards into the number of responses subjects will pay to earn one reward over the other. Direct value manipulations shift these functions. We tested the effect of the dopamine D2 receptor antagonist, haloperidol, on performance in the CEC and CVC assays and found that D2R signaling is important for effort-based, but not value-based decision making. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


Assuntos
Condicionamento Operante , Tomada de Decisões/fisiologia , Esforço Físico , Receptores de Dopamina D2/fisiologia , Recompensa , Animais , Condicionamento Operante/efeitos dos fármacos , Tomada de Decisões/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/administração & dosagem , Haloperidol/administração & dosagem , Masculino , Camundongos Endogâmicos C57BL , Esforço Físico/efeitos dos fármacos
8.
Behav Pharmacol ; 31(2&3): 207-215, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32058349

RESUMO

Previous research demonstrated that a remifentanil-associated stimulus facilitated the acquisition of a previously unlearned response; however, it is unclear how long a remifentanil-associated stimulus maintains conditioned reinforcing properties under conditions of daily testing. To address this gap, we exposed adult male rats to response-independent stimulus presentations and deliveries of remifentanil (1.0, 3.2, or 10.0 µg/kg/infusion). Rats either received the stimulus presentations and remifentanil deliveries together (Paired Pavlovian conditioning) or according to separate clocks (Random control group). In the sessions following Pavlovian conditioning, we allowed rats to emit nose-poke responses for the presentation of the stimulus alone and measured the extent to which the stimulus facilitated and maintained a previously unlearned response. We tested responding for the stimulus presentations across 28 daily sessions to assess the Pavlovian extinction (degradation of the drug-stimulus association) of the conditioned reinforcing properties of the remifentanil-associated stimulus. We observed the highest and most persistent levels of responding in rats with a Paired Pavlovian conditioning history at 3.2 and 10.0 µg/kg/infusion. In addition, we included analyses of the variability in responding for each group, which revealed individual differences in the susceptibility of the remifentanil-associated stimulus acting as a conditioned reinforcer. These findings demonstrate that a remifentanil-associated stimulus has the ability to sustain drug-seeking behavior and underscores the importance of Pavlovian conditioning in promoting drug abuse.


Assuntos
Condicionamento Operante/efeitos dos fármacos , Remifentanil/farmacologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Comportamento de Procura de Droga/fisiologia , Extinção Psicológica/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , Remifentanil/metabolismo
9.
Toxicol Lett ; 325: 34-42, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32070766

RESUMO

Carfentanil is an ultra-potent opioid with an analgesic potency 10,000 times that of morphine but has received little scientific investigation. Three experiments were conducted to evaluate the toxicity of carfentanil and the efficacy of naloxone in adult male African green monkeys. The first experiment determined the ED50 (found to be 0.71 µg/kg) of subcutaneous carfentanil for inducing bradypnea and/or loss of posture. Experiment 2 attempted to establish the ED50 of naloxone for rapidly reversing the bradypnea/loss of posture induced by carfentanil (1.15 µg/kg). Experiment 3 evaluated the effects of carfentanil (0.575 µg/kg) alone, the safety of naloxone (71-2841 µg/kg), and the efficacy of naloxone (71-710 µg/kg) administration at two time points following carfentanil (1.15 µg/kg) on operant choice reaction time. Collectively, these experiments characterized the temporal progression of carfentanil-induced toxic signs, determined the range of naloxone doses that restored respiratory and gross behavioral function, and determined the time course and range of naloxone doses that partially or completely reversed the effects of carfentanil on operant choice reaction time performance in African green monkeys. These results have practical relevance for the selection of opioid antagonists, initial doses, and expected functional outcomes following treatment of synthetic opioid overdose in a variety of operational/emergency response contexts.


Assuntos
Analgésicos Opioides/toxicidade , Fentanila/análogos & derivados , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Analgésicos Opioides/antagonistas & inibidores , Animais , Apneia/induzido quimicamente , Apneia/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Chlorocebus aethiops , Condicionamento Operante/efeitos dos fármacos , Overdose de Drogas/tratamento farmacológico , Fentanila/antagonistas & inibidores , Fentanila/toxicidade , Masculino , Naloxona/toxicidade , Antagonistas de Entorpecentes/toxicidade , Tempo de Reação/efeitos dos fármacos
10.
Pharmacol Biochem Behav ; 190: 172874, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32084492

RESUMO

Environmental enrichment (EE) for rodents is generally defined as providing subjects with an environment enhanced with access to conspecifics, novel and tactile stimuli, and in many preparations, more space. EE exposure, in particular as an "intervention" in adult rodents, decreases food and drug seeking and taking. This review focuses on the reduction of sucrose seeking and taking in rats assessed in operant-based procedures. The operant-based model provides a means to evaluate addiction-related behaviors. Findings using the model might translate to clinically-relevant addiction behaviors directed towards both drugs and food. Both overnight (acute) and one month (chronic) EE effects on behavior are described, including a recent evaluation of the persistence of EE effects following its removal. EE effects on neurobiology related to sucrose seeking using the model are outlined, with a special emphasis on meso-cortico-limbic terminals. Overall, our working hypothesis for how EE reduces sucrose seeking and taking is that EE alters processing of incentive valence. This may also be accompanied by changes in learning and affect. Anti-seeking and anti-taking effects of EE have translational implications for the prevention and treatment of both drug addiction and food-focused behaviors ("food addiction").


Assuntos
Comportamento Apetitivo/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Comportamento de Procura de Droga/efeitos dos fármacos , Alimentos , Sacarose/farmacologia , Animais , Comportamento Aditivo , Fissura/efeitos dos fármacos , Sinais (Psicologia) , Dependência de Alimentos , Masculino , Ratos , Ratos Long-Evans , Autoadministração , Sacarose/administração & dosagem
11.
Pharmacol Biochem Behav ; 191: 172879, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32088359

RESUMO

Many adolescents use amphetamines which are the second most common abused illegal drugs. Methamphetamine (Meth), as a potent amphetamine affects attentional functions. However, the most significant factor for susceptibility to Meth is the age of exposure, most studies have examined the effects of Meth after early adolescence stage. The present experiment was aimed to investigate some possible short- and long-term effects of Meth at two distinct points of adolescence stage (early versus late) on 1) locomotor activity in adolescent rats and 2) attentional functions in their adulthood. Rats received Meth (5 mg/kg, i.p., for consecutive 10 days) during early adolescence (postnatal days (PND) 30-39) or late adolescence (PND 50-59). Locomotor activity was assessed after the first and tenth injections. Then, in adulthood, rats were trained and tested on the Five-choice serial reaction time task (5-CSRTT) to display possible attentional impairments. The first Meth administration in early exposed adolescent (EEA) group produced the highest level of activity, compared with the first exposure in late exposed adolescent (LEA) group and tenth administrations in both groups. In adulthood, LEA group significantly delayed learning the 5-CSRTT and exhibited attentional impairments, as demonstrated by significant reduced response accuracy and increased omission errors under pharmacological challenge, compared with control group. The susceptibility to Meth depends on the age of exposure and Meth administration during late adolescence stage may cause prolonged attentional deficits in adulthood.


Assuntos
Atenção/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Drogas Ilícitas/farmacologia , Locomoção/efeitos dos fármacos , Metanfetamina/farmacologia , Fatores Etários , Animais , Condicionamento Operante/efeitos dos fármacos , Dextroanfetamina/farmacologia , Masculino , Ratos , Tempo de Reação
12.
J Neurosci ; 40(13): 2695-2707, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32066582

RESUMO

Nonmuscle myosin II inhibition (NMIIi) in the basolateral amygdala (BLA), but not dorsal hippocampus (CA1), selectively disrupts memories associated with methamphetamine (METH) days after learning, without retrieval. However, the molecular mechanisms underlying this selective vulnerability remain poorly understood. A known function of NMII is to transiently activate synaptic actin dynamics with learning. Therefore, we hypothesized that METH-associated learning perpetuates NMII-driven actin dynamics in synapses, leading to an extended window of vulnerability for memory disruption. We used time-lapse two-photon imaging of dendritic spine motility in acutely prepared brain slices from female and male mice following METH-associated learning as a readout of actin-myosin dynamics. Spine motility was persistently increased in the BLA, but not in CA1. Consistent with the memory disrupting effect of intra-BLA NMII inhibition, METH-induced changes to BLA spine dynamics were reversed by a single systemic injection of an NMII inhibitor. Intra-CA1 NMII inhibition, on the other hand, did not disrupt METH-associated memory. Thus, we report identification of a previously unknown ability for spine actin dynamics to persist days after stimulation and that this is under the control of NMII. Further, these perpetual NMII-driven spine actin dynamics in BLA neurons may contribute to the unique susceptibility of METH-associated memories.SIGNIFICANCE STATEMENT There are no Food and Drug Administration-approved pharmacotherapies to prevent relapse to the use of stimulants, such as methamphetamine (METH). Environmental cues become associated with drug use, such that the memories can elicit strong motivation to seek the drug during abstinence. We previously reported that the storage of METH-associated memories is uniquely vulnerable to immediate, retrieval-independent, and lasting disruption by direct actin depolymerization or by inhibiting the actin driver nonmuscle myosin II (NMII) in the BLA or systemically. Here we report a potential structural mechanism responsible for the unique vulnerability of METH-associated memories and METH-seeking behavior to NMII inhibition within the BLA.


Assuntos
Aprendizagem por Associação/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Espinhas Dendríticas/metabolismo , Metanfetamina/farmacologia , Neurônios/metabolismo , Miosina não Muscular Tipo IIB/metabolismo , Animais , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Feminino , Masculino , Camundongos , Neurônios/efeitos dos fármacos
13.
Behav Pharmacol ; 31(2&3): 168-173, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31972623

RESUMO

Developing effective analgesics with fewer unwanted side effects is a pressing concern. Due to a lack of effective nonopioid options currently available, an alternative approach termed opioid-sparing evaluates the ability of a coadministered drug to reduce the amount of opioid needed to produce an antinociceptive effect. Opioids and benzodiazepines are often coprescribed. Although this approach is theoretically rational given the prevalent comorbidity of chronic pain and anxiety, it also has inherent risks of respiratory depression, which is likely responsible for the substantial percentage of fatal opioid overdoses that have involved benzodiazepines. Moreover, there have been no clinical trials to support the effectiveness of this drug combination nor has there been corroborative preclinical evidence using traditional animal models of nociception. The present studies examined the prescription µ-opioid analgesic oxycodone (0.003-0.1 mg/kg) and the prototypical benzodiazepine anxiolytic diazepam (0.03-1.0 mg/kg), alone and in combination, using an animal model of pain that examines the restoration of conflict-related operant behavior as evidence of analgesia. Results documented significant dose-related increases in thermal threshold following oxycodone treatment. Diazepam treatment alone did not produce significant antinociception. In combination, diazepam pretreatment shifted oxycodone functions upward in a dose-dependent manner, but the additive effects were limited to a narrow dose range. In addition, combinations of diazepam and oxycodone at higher doses abolished responding. Taken together, though intriguing, these findings do not provide sufficient evidence that coadministration of an anxiolytic will result in clinically relevant opioid-sparing for pain management, especially when considering the inherent risks of this drug class combination.


Assuntos
Diazepam/farmacologia , Nociceptividade/efeitos dos fármacos , Oxicodona/farmacologia , Analgésicos/farmacologia , Animais , Condicionamento Operante/efeitos dos fármacos , Quimioterapia Combinada/métodos , Masculino , Modelos Animais , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Dor/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Saimiri
14.
J Neurosci ; 40(9): 1897-1908, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-31953372

RESUMO

Recent trends in cannabis legalization have increased the necessity to better understand the effects of cannabis use. Animal models involving traditional cannabinoid self-administration approaches have been notoriously difficult to establish and differences in the drug used and its route of administration have limited the translational value of preclinical studies. To address this challenge in the field, we have developed a novel method of cannabis self-administration using response-contingent delivery of vaporized Δ9-tetrahydrocannabinol-rich (CANTHC) or cannabidiol-rich (CANCBD) whole-plant cannabis extracts. Male Sprague-Dawley rats were trained to nose-poke for discrete puffs of CANTHC, CANCBD, or vehicle (VEH) in daily 1 h sessions. Cannabis vapor reinforcement resulted in strong discrimination between active and inactive operanda. CANTHC maintained higher response rates under fixed ratio schedules and higher break points under progressive ratio schedules compared with CANCBD or VEH, and the number of vapor deliveries positively correlated with plasma THC concentrations. Moreover, metabolic phenotyping studies revealed alterations in locomotor activity, energy expenditure, and daily food intake that are consistent with effects in human cannabis users. Furthermore, both cannabis regimens produced ecologically relevant brain concentrations of THC and CBD and CANTHC administration decreased hippocampal CB1 receptor binding. Removal of CANTHC reinforcement (but not CANCBD) resulted in a robust extinction burst and an increase in cue-induced cannabis-seeking behavior relative to VEH. These data indicate that volitional exposure to THC-rich cannabis vapor has bona fide reinforcing properties and collectively support the utility of the vapor self-administration model for the preclinical assessment of volitional cannabis intake and cannabis-seeking behaviors.SIGNIFICANCE STATEMENT The evolving legal landscape concerning recreational cannabis use has increased urgency to better understand its effects on the brain and behavior. Animal models are advantageous in this respect; however, current approaches typically used forced injections of synthetic cannabinoids or isolated cannabis constituents that may not capture the complex effects of volitional cannabis consumption. We have developed a novel model of cannabis self-administration using response-contingent delivery of vaporized cannabis extracts containing high concentrations of Δ9 tetrahydrocannabinol (THC) or cannabidiol. Our data indicate that THC-rich cannabis vapor has reinforcing properties that support stable rates of responding and conditioned drug-seeking behavior. This approach will be valuable for interrogating effects of cannabis and delineating neural mechanisms that give rise to aberrant cannabis-seeking behavior.


Assuntos
Cannabis , Condicionamento Operante/efeitos dos fármacos , Comportamento de Procura de Droga/efeitos dos fármacos , Extratos Vegetais/farmacologia , Reforço Psicológico , Animais , Encéfalo/metabolismo , Dronabinol/farmacocinética , Dronabinol/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Alucinógenos/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Fumar Maconha , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/efeitos dos fármacos
15.
Pharmacol Biochem Behav ; 189: 172851, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31931017

RESUMO

Diets high in sugar or fat are associated with multiple health conditions, including binge eating disorder (BED). BED affects approximately 2% of the US adult population, and occurs more frequently in females. It is important to develop animal models of palatable food consumption and food seeking that may have relevance for BED and other conditions associated with excessive food intake. The catecholamine uptake blocker and d-amphetamine prodrug lisdexamfetamine is used to treat BED. The present experiments studied the effect of lisdexamfetamine on food intake and food-reinforced effort-based choice in female Wistar rats. Three groups of rats received different food exposure conditions in the home cage randomly spread over several weeks: a chocolate exposure group (CE; brief access of chocolate and additional lab chow, n = 15), a lab chow exposure (LChE) group given additional access to lab chow (n = 8), and a third group given empty food dishes (n = 7). In tests of food intake under non-restricted conditions, lisdexamfetamine (0.1875-1.5 mg/kg IP) significantly reduced intake of both chocolate and chow in the CE group. In the LChE group, there was a trend towards reduced chow intake induced by lisdexamfetamine. All rats were trained on a Progressive Ratio/chow feeding choice task, in which they had a choice between working for high carbohydrate chocolate flavored pellets by lever pressing vs. approaching and consuming a concurrently available lab chow. The LChE group and the empty food dish group were combined to create one control group (n = 15). There was a significant overall dose-related suppressive effect of lisdexamfetamine on lever pressing but no group difference, and no dose x group interaction. Lisdexamfetamine significantly decreased chow intake in the CE group, but not in the control group. In conclusion, lisdexamfetamine affected both food intake and food-reinforced operant behavior, with larger effects seen in the group exposed to chocolate.


Assuntos
Transtorno da Compulsão Alimentar/tratamento farmacológico , Bulimia/tratamento farmacológico , Comportamento Consumatório/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Dimesilato de Lisdexanfetamina/administração & dosagem , Animais , Peso Corporal/efeitos dos fármacos , Chocolate , Condicionamento Operante/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Preferências Alimentares/efeitos dos fármacos , Pró-Fármacos/administração & dosagem , Ratos , Ratos Wistar , Recompensa , Resultado do Tratamento
16.
Behav Pharmacol ; 31(2&3): 221-232, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31922965

RESUMO

Opioid addiction/dependence is associated with impulsive and risky behavior. Moreover, opioids can increase impulsive choice in preclinical studies with nonhumans. The objective of this study was to investigate a potential behavioral mechanism of opioids: a change in the impact of reinforcement magnitude on choice. Rats (n = 7) chose between smaller and larger reinforcers under a continuous-choice (concurrent-chains) procedure. The levers associated with the smaller and larger reinforcers alternated every five sessions. During baseline under this procedure, rats showed a reliable preference for the larger reinforcer. Effects of several doses (0.1-1.7 mg/kg, s.c.) of the prescription opioid, oxycodone, were examined on preference based upon reinforcement magnitude. Oxycodone dose-dependently decreased preference for the larger reinforcer (i.e. decreased sensitivity to reinforcement magnitude). The decrease in sensitivity to reinforcement magnitude was selective in that the intermediate doses did not affect, or had minimal impact on, other measures of performance (e.g. on general motivation to respond). These data suggest that a decrease in the sensitivity to reinforcement magnitude is a reliable outcome of µ-opioid administration, an effect that has important implications for the impact of these drugs on both impulsive and risky behavior.


Assuntos
Comportamento Aditivo/fisiopatologia , Comportamento de Escolha/efeitos dos fármacos , Comportamento Impulsivo/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Animais , Condicionamento Operante/efeitos dos fármacos , Desvalorização pelo Atraso/efeitos dos fármacos , Masculino , Motivação , Oxicodona/farmacologia , Ratos , Ratos Sprague-Dawley , Esquema de Reforço , Reforço Psicológico , Assunção de Riscos
17.
Psychopharmacology (Berl) ; 237(4): 1147-1160, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31915862

RESUMO

RATIONALE: Cocaine addiction is a chronic brain disease characterized by compulsive drug intake and dysregulation of brain reward systems. Few preclinical studies have modeled the natural longitudinal course of cocaine addiction. Extended access self-administration protocols are powerful tools for modeling the advanced stages of addiction; however, few studies have duration of drug access longer than 12 h/session, potentially limiting their construct validity. Identification of changes in cocaine intake patterns during the development of addictive-like states may allow better treatments for vulnerable subjects. The kappa opioid receptor (KOPr) system has been implicated in the neurobiological regulation of addictive states as well as mood and stress disorders, with selective KOPr antagonists proposed as possible pharmacotherapeutic agents. Chronic cocaine exposure increases the expression of KOPr and its endogenous agonists, the dynorphins, in several brain areas in rodents. OBJECTIVES: To examine the behavioral pattern of intake during chronic (14 days) 18 h intravenous cocaine self-administration (0.5 mg/kg/infusion) and the effect of a novel short-acting KOPr antagonist LY2444296 HCl (3 mg/kg) administered during sessions 8 to 14 of chronic 18 h/day cocaine self-administration and prior to a single re-exposure session after 2 cocaine-free withdrawal days. RESULTS: Both daily and hourly cocaine intake patterns changed over 14 days of 18 h self-administration. LY pretreatment affected the pattern of self-administration across the second week of extended access cocaine self-administration and prevented the increase in cocaine intake during re-exposure. CONCLUSIONS: Overall, the KOPr antagonist attenuated escalated cocaine consumption in a rat model of extended access cocaine self-administration.


Assuntos
Comportamento Aditivo/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Cocaína/administração & dosagem , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides kappa/antagonistas & inibidores , Animais , Comportamento Aditivo/metabolismo , Encéfalo/metabolismo , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Inibidores da Captação de Dopamina/administração & dosagem , Masculino , Antagonistas de Entorpecentes/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores Opioides kappa/metabolismo , Autoadministração , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/metabolismo
18.
Psychopharmacology (Berl) ; 237(3): 855-867, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31832720

RESUMO

RATIONALE: Kratom is proposed to exhibit therapeutic potential as an opium substitute, but little is known about its dependence-producing profile, particularly of its main psychoactive compound, mitragynine (MG). OBJECTIVES: This study examined the dependence-producing effects of MG using operant-scheduled behaviour in rats and investigated the potential therapeutic effect of MG by comparing effects to buprenorphine in morphine-dependent rats using the same schedule-controlled behavioural task. METHODS: The effects of acutely administered MG and morphine were determined in rats trained to respond under fixed-ratio (FR) 10 schedule of food reinforcement. Next, the rats were administered MG and morphine twice daily for 14 consecutive days to determine if physiological dependence would develop by examining cessation of drug treatment and following antagonist-precipitated withdrawal. The study then examined the effects of MG substitution to suppress naloxone-precipitated morphine withdrawal effects on scheduled responding. RESULTS: Acute doses of MG did not produce dose-related decreases on FR schedules of responding compared to morphine. Unlike morphine, MG-treated rats showed no suppression of response rates following cessation of MG treatment. However, withdrawal effects were evident for MG after precipitation by either naloxone or SR141716A (rimonabant), similar to morphine-treated rats. MG in higher doses (10 and 30 mg/kg) attenuated the naloxone-precipitated morphine withdrawal effects while smaller doses of buprenorphine (0.3 and 1.0 mg/kg) were necessary to alleviate these effects. CONCLUSION: The findings suggest that MG does not induce physiological dependence but can alleviate the physical symptoms associated with morphine withdrawal which represent the desired characteristics of novel pharmacotherapeutic interventions for managing opioid use disorder (OUD).


Assuntos
Esquema de Reforço , Reforço Psicológico , Alcaloides de Triptamina e Secologanina/efeitos adversos , Síndrome de Abstinência a Substâncias/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Relação Dose-Resposta a Droga , Masculino , Antagonistas de Entorpecentes/efeitos adversos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia
19.
Psychopharmacology (Berl) ; 237(3): 801-809, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31858159

RESUMO

RATIONALE: Cannabis use is typically initiated during adolescence, and different studies suggest that adolescent cannabinoid exposure may increase the risk for drug addiction in adulthood. OBJECTIVES: This study investigated the effects of adolescent exposure to the main psychoactive component of cannabis, ∆9-tetrahydrocannabinol (THC), in the reinforcing properties of nicotine in adult male mice. Possible alterations in relapse to nicotine-seeking behaviour in adult animals due to THC adolescent exposure were also evaluated. METHODS: Adolescent mice were exposed to escalating doses of THC from PND35 to PND49. When mice reached adulthood (PND70), surgical procedures were applied for further behavioural evaluation. Nicotine self-administration sessions were conducted consecutively for 10 days. Following extinction, mice were tested for cue- and stress-induced reinstatement of nicotine-seeking behaviour. RESULTS: Adolescent THC treatment did not modify acquisition and extinction of nicotine self-administration in adulthood. Moreover, THC exposure did not alter relapse to nicotine seeking induced by stress or nicotine-associated cues. CONCLUSIONS: These results suggest that a history of exposure to THC during adolescence under these particular conditions does not modify the reinforcing effects and seeking behaviour of nicotine in the adult period.


Assuntos
Condicionamento Operante/efeitos dos fármacos , Dronabinol/administração & dosagem , Alucinógenos/administração & dosagem , Nicotina/administração & dosagem , Reforço Psicológico , Fatores Etários , Animais , Condicionamento Operante/fisiologia , Sinais (Psicologia) , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Recidiva , Autoadministração
20.
J Neurosci ; 40(4): 825-842, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31801810

RESUMO

The extracellular glycan polysialic acid linked to neural cell adhesion molecule (PSA-NCAM) is principally expressed in the developing brain and the adult neurogenic regions. Although colocalization of PSA-NCAM with cholecystokinin (CCK) was found in the adult brain, the role of PSA-NCAM remains unclear. In this study, we aimed to elucidate the functional significance of PSA-NCAM in the CA1 region of the male mouse hippocampus. Combined fluorescence in situ hybridization and immunohistochemistry showed that few vesicular glutamate transporter 3-negative/CCK-positive (VGluT3-/CCK+) cells were colocalized with PSA-NCAM, but most of the VGluT3+/CCK+ cells were colocalized with PSA-NCAM. The somata of PSA-NCAM+/CCK+ cells were highly innervated by serotonergic boutons than those of PSA-NCAM-/CCK+ cells. The expression ratios of 5-HT3A receptors and p11, a serotonin receptor-interacting protein, were higher in PSA-NCAM+/CCK+ cells than in PSA-NCAM-/CCK+ cells. Pharmacological digestion of PSA-NCAM impaired the efficacy of antidepressant fluoxetine (FLX), a selective serotonin reuptake inhibitor, but not the efficacy of benzodiazepine anxiolytic diazepam. A Western blot showed that restraint stress decreased the expressions of p11 and mature brain-derived neurotrophic factor (BDNF), and FLX increased them. Interestingly, the FLX-induced elevation of expression of p11, but not mature BDNF, was impaired by the digestion of PSA-NCAM. Quantitative reverse transcription-polymerase chain reaction showed that restraint stress reduced the expression of polysialyltransferase ST8Sia IV and FLX elevated it. Collectively, PSA-NCAM colocalized with VGluT3+/CCK+ cells in the CA1 region of the hippocampus may play a unique role in the regulation of antidepressant efficacy via the serotonergic pathway.SIGNIFICANCE STATEMENT Polysialic acid (PSA) is composed of eight or more α2,8-linked sialic acids. Here, we examined the functional significance of polysialic acid linked to the neural cell adhesion molecule (PSA-NCAM) in the adult mouse hippocampus. Few vesicular glutamate transporter 3-negative/cholecystokinin-positive (VGluT3-/CCK+) cells were colocalized with PSA-NCAM, but most of the VGluT3+/CCK+ cells were colocalized with PSA-NCAM. The expression ratios of 5-HT3A receptors and p11, a serotonin receptor-interacting protein, were higher in PSA-NCAM+/CCK+ cells than in PSA-NCAM-/CCK+ cells. The efficacy of antidepressants, but not anxiolytics, was impaired by the digestion of PSA-NCAM. The antidepressant-induced increase in p11 expression was inhibited following PSA-NCAM digestion. We hence hypothesize that PSA-NCAM colocalized with VGluT3+/CCK+ cells may play a unique role in regulating antidepressant efficacy.


Assuntos
Antidepressivos/farmacologia , Colecistocinina/metabolismo , Depressão/metabolismo , Hipocampo/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Ácidos Siálicos/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo
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