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1.
Life Sci ; 245: 117386, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32006528

RESUMO

AIMS: Steroid receptor coactivator-1 (SRC-1) is a key coactivator for the efficient transcriptional activity of steroids in the regulation of hippocampal functions. However, the effect of SRC-1 on hippocampal memory processes remains unknown. Our aim was to investigate the roles of hippocampal SRC-1 in the consolidation and reconsolidation of contextual fear memory in mice. MAIN METHODS: Contextual fear conditioning paradigm was constructed in adult male C57BL/6 mice to examine the fear learning and memory processes. Adeno-associated virus (AAV) vector-mediated RNA interference (RNAi) was infused into hippocampus to block hippocampal SRC-1 level. Immunofluorescent staining was used to detect the efficiency of transfection. High plus maze and open field test were used to determine anxiety and locomotor activity. Western blot analyses were used to detect the expression of SRC-1 and synaptic proteins in the hippocampus. KEY FINDINGS: We first showed that the expression of SRC-1 was regulated by fear conditioning training in a time-dependent manner, and knockdown of SRC-1 impaired contextual fear memory consolidation without affecting innate anxiety or locomotor activity. In addition, hippocampal SRC-1 was also regulated by the retrieval of contextual fear memory, and downregulation of SRC-1 disrupted fear memory reconsolidation. Moreover, knockdown of SRC-1 reversed the increased GluR1 and PSD-95 levels induced by contextual fear memory retrieval. SIGNIFICANCE: Our data indicate that hippocampal SRC-1 is required for the consolidation and reconsolidation of contextual fear memory, and SRC-1 may be a potential therapeutic target for mental disorders that are involved in hippocampal memory dysfunction.


Assuntos
Medo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Coativador 1 de Receptor Nuclear/antagonistas & inibidores , Animais , Western Blotting , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Medo/fisiologia , Medo/psicologia , Imunofluorescência , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Coativador 1 de Receptor Nuclear/fisiologia
2.
Pharmacol Biochem Behav ; 185: 172764, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31449820

RESUMO

Zebra finches are songbirds that learn vocal patterns during a sensitive period of development that approximates adolescence. Exposure of these animals to a cannabinoid agonist during their period of sensorimotor vocal learning alters song patterns produced in adulthood. Thus, songbirds have unique value in studying developmental effects of drug exposure on a naturally learned behavior. A missing feature of this animal model has been a method to study drug reinforcement of behavior. To address this gap we have adapted place conditioning methods, used previously to determine that singing behavior is rewarding, to study cocaine reinforcement of behavior. We have found that cocaine dose-dependently reinforces both place conditioning and aversion at potencies consistent with those observed in mammalian species. Use of this place conditioning method has allowed us to determine that, when administered during periods of sensorimotor vocal learning, delta-9-THC, but not nicotine persistently increases sensitivity to cocaine through adulthood. Establishment of this method significantly expands the songbird drug exposure model, and holds promise for better appreciation of mechanisms important to sensorimotor learning that is dependent upon successful progress through sensitive periods of CNS development.


Assuntos
Cocaína/farmacologia , Dronabinol/farmacologia , Tentilhões/crescimento & desenvolvimento , Aprendizagem/efeitos dos fármacos , Vocalização Animal/efeitos dos fármacos , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Cocaína/administração & dosagem , Condicionamento Clássico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Dronabinol/administração & dosagem , Feminino , Masculino , Nicotina/administração & dosagem , Nicotina/farmacologia , Recompensa , Córtex Sensório-Motor/efeitos dos fármacos , Fatores Sexuais
3.
Life Sci ; 233: 116712, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31377325

RESUMO

AIMS: Previous researches demonstrated that genetics and environment are two essential factors to prone individuals to drug abuse. Our previous data showed that dopaminergic system changed in the offspring of morphine-abstinent rats. In the present study, we evaluated whether blocking the D1-like dopamine receptors (DR) in the nucleus accumbens (NAC) affect the rewarding effect of morphine in the offspring of morphine-abstinent rats. MAIN METHODS: In the study, male and female Wistar rats received morphine orally for 21 days. Ten days after last morphine administration, animals prepared to mate either with a morphine abstinent or a drug-naive rat. Adult male offspring were chosen for further evaluation. SCH23390 (0.01 µg/rat) was administrated intra-NAC during the conditioning phase in the CPP paradigm (morphine 7.5 mg/kg). KEY FINDINGS: Obtained data showed that morphine administration (7.5 mg/kg) did not induce conditioning in the offspring of the morphine-abstinent parent(s) (p < 0.001) compared with the control group. However, when SCH23390 injected in the NAC during the induction phase, the offspring of morphine-abstinent rats were conditioned with the same dose of morphine. SIGNIFICANCE: Previous studies showed that the offspring of morphine-abstinent rats are more prone to opioid consumption, and also developed tolerance to the rewarding effect of morphine. Current data indicated that blockade of D1-like DR in the NAC could prevent morphine-induced tolerance in these offspring. Therefore, inhibition of D1-like DR in the NAC might be a new candidate against morphine-reinforcing effect in the offspring of morphine-abstinent parent(s).


Assuntos
Condicionamento Clássico/efeitos dos fármacos , Condicionamento Operante/fisiologia , Dependência de Morfina/metabolismo , Morfina/farmacologia , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Benzazepinas/farmacologia , Condicionamento Operante/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Feminino , Masculino , Morfina/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Dopamina D1/antagonistas & inibidores
4.
Behav Processes ; 166: 103905, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31310793

RESUMO

Globally, native predators and scavengers are threatened through the incidence of illegal poisoning due to increasing human-wildlife conflicts. The use of conditioned taste aversion (CTA) may mitigate such conflicts. CTA is a robust learning paradigm that occurs when animals associate a food with a discomfort induced by a chemical, thereby avoiding that food in subsequent encounters. We reviewed the potential of 167 chemical compounds to be used in CTA, considering effects, margin of safety, accessibility, and detectability. After the review, 15 compounds fulfilled the required characteristics, but only five (thiabendazole, thiram, levamisole, fluconazole and fluralaner) were finally selected to be tested in CTA assays with dogs. Of the tested compounds, thiabendazole, thiram and levamisole caused target food rejection by dogs and reduced the time spent eating during post-conditioning. However, despite being microencapsulated, levamisole appeared to be detectable by dogs, whereas thiram and thiabendazole were not. Fluconazole and fluralaner did not produce any CTA effect. Thiabendazole, thiram and levamisole can therefore induce CTA, and thus are potential candidates as aversive compounds for wildlife management. Thiram is an undetectable, relatively safe and accessible compound that can induce CTA in canids, and opens new possibilities to develop methods of non-lethal predation control.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Predatório/efeitos dos fármacos , Paladar , Animais , Animais Selvagens , Condicionamento Clássico/efeitos dos fármacos , Cães , Fluconazol/farmacologia , Isoxazóis/farmacologia , Levamisol/farmacologia , Masculino , Tiabendazol/farmacologia , Tiram/farmacologia
5.
Brain Stimul ; 12(6): 1448-1455, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31289015

RESUMO

BACKGROUND: Drug use causes the formation of strong cue/reward associations which persist long after cessation of drug-taking and contribute to the long-term risk of relapse. Extinguishing these associations may reduce cue-induced craving and relapse. Previously, we found that pairing vagus nerve stimulation (VNS) with extinction of cocaine self-administration reduces cue-induced reinstatement; however, it remains unclear whether this was primarily caused by extinguishing the context, the instrumental response, or both. OBJECTIVE: Hypothesis: We hypothesized that VNS can facilitate the extinction of both contextual cues and instrumental responding. METHODS: Extinction of context was first tested using Pavlovian conditioned place preference (CPP). Next, the impact of VNS on the extinction of instrumental responding was assessed under ABA and AAA context conditions. In each extinction context separate groups of rats were either provided the opportunity to perform the instrumental response, or the levers were retracted for the duration of extinction training. Reinstatement was induced by reintroduction of the conditioned stimuli and/or the drug-paired context. Data were analyzed using one-way or two-way repeated measures ANOVAs. RESULTS: VNS during extinction reduced reinstatement of CPP. VNS also reduced cue- and context-induced reinstatement of the instrumental response under both AAA and ABA conditions. The subjects' ability to engage with the lever during extinction was crucial for this effect. P values < 0.05 were considered significant. CONCLUSIONS: Craving occurs in response to a range of conditioned stimuli and contexts; VNS may improve outcomes of behavioral therapy by facilitating extinction of both an instrumental response and/or contextual cues.


Assuntos
Cocaína/administração & dosagem , Condicionamento Clássico/fisiologia , Fissura/fisiologia , Extinção Psicológica/fisiologia , Estimulação do Nervo Vago/métodos , Animais , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Fissura/efeitos dos fármacos , Sinais (Psicologia) , Masculino , Ratos , Ratos Sprague-Dawley , Recompensa , Autoadministração , Estimulação do Nervo Vago/tendências
6.
Behav Neurosci ; 133(4): 428-436, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31294591

RESUMO

Previous work from our laboratory has indicated that temporary inactivation of the basolateral amygdala (BLA) with bupivacaine blocks acquisition, consolidation, and retrieval of an amphetamine conditioned place preference (CPP). The present study was designed to extend this line of investigation by examining whether N-methyl-D-aspartate (NMDA) receptors in the BLA mediate acquisition and extinction of an amphetamine CPP. Adult male Long-Evans rats received bilateral intra-BLA injections of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 1.25 µg, 2.5 µg, or 5.0 µg) or saline prior to each session of CPP acquisition (Experiment 1). In addition, separate groups of rats received intra-BLA injections of the sodium channel blocker bupivacaine (Experiment 2), AP5 (1.25 µg, 2.5 µg, or 5.0 µg; Experiment 3), or saline prior to each session of CPP extinction training. Results indicated that intra-BLA injection of bupivacaine or AP5 (2.5 or 5.0 µg) disrupted acquisition of an amphetamine CPP. In addition, neural inactivation of the BLA with bupivacaine blocked extinction of CPP. Finally, intra-BLA AP5 injections (2.5 or 5.0 µg) were sufficient to block CPP extinction. The present findings indicate that NMDA receptor activity in the BLA is critical for acquisition and extinction of an amphetamine CPP and may be relevant to understanding the neural mechanisms underlying some aspects of drug seeking and addiction. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , 2-Amino-5-fosfonovalerato/farmacologia , Anfetamina/metabolismo , Anfetamina/farmacologia , Tonsila do Cerebelo/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Basolateral da Amígdala/fisiologia , Bupivacaína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Extinção Psicológica/fisiologia , Masculino , Memória/fisiologia , Ratos , Ratos Long-Evans , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo
7.
Psychopharmacology (Berl) ; 236(12): 3401-3412, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31243481

RESUMO

RATIONALE: A promising strategy to prevent a return of fear after exposure-based therapy in anxiety disorders is to pharmacologically enhance the extinction memory consolidation presumed to occur after exposure. Accumulating evidence suggests that the effect of a number of pharmacological consolidation enhancers depends on a successful fear reduction during exposure. Here, we employed the dopamine precursor L-DOPA to clarify whether its documented potential to enhance extinction memory consolidation is dependent on successful fear extinction. METHODS: In two double-blind, randomized and placebo-controlled experiments (experiment 1: N = 79, experiment 2: N = 32) comprising fear conditioning (day 1), extinction followed by administration of 150 mg L-DOPA or placebo (day 2) and a memory test (day 3) in healthy male adults, conditioned responses were assessed as differential skin conductance responses. We tested whether the effect of L-DOPA on conditioned responses at test depended on conditioned responses at the end of extinction in an experiment with a short (10 trials, experiment 1) and long (25 trials, experiment 2) extinction session. RESULTS: In both experiments, the effect of L-DOPA was dependent on conditioned responses at the end of extinction. That is, post-extinction L-DOPA compared to placebo administration reduced conditioned responses at test only in participants showing a complete reduction of conditioned fear at the end of extinction. CONCLUSION: The results support the potential use of L-DOPA as a pharmacological adjunct to exposure treatment, but point towards a common boundary condition for pharmacological consolidation enhancers: a successful reduction of fear in the exposure session.


Assuntos
Condicionamento Clássico/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/psicologia , Levodopa/farmacologia , Consolidação da Memória/efeitos dos fármacos , Adulto , Condicionamento Clássico/fisiologia , Dopaminérgicos/farmacologia , Método Duplo-Cego , Extinção Psicológica/fisiologia , Medo/fisiologia , Humanos , Masculino , Consolidação da Memória/fisiologia , Estimulação Luminosa/métodos , Adulto Jovem
8.
Behav Neurosci ; 133(5): 467-477, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31204827

RESUMO

Adolescence is noted as a time of "storm and stress." In this developmental stage both rodents and humans exhibit an impairment in the extinction of learned fear; however, this impairment can be alleviated, at least in rodents, by increasing the amount of extinction training given or by administering the partial NMDA receptor agonist D-Cycloserine. In the present study we explored whether the benefits of these treatments would be reduced by chronic exogenous corticosterone (a commonly studied stress-related hormone). In 2 experiments, adolescent rats were given pairings of a white noise and shock (acquisition) and then given extinction training (white noise presented alone). In Experiment 1, adolescents exhibited impaired extinction retention even after 2 days of extinction training if they had been exposed to corticosterone in adolescence but not if the exposure occurred when they were juveniles. In Experiment 2, exposure to exogenous corticosterone in adolescence, but not during the juvenile period, reduced the efficacy of the pharmacological adjunct D-Cycloserine at enhancing extinction retention after 1 day of extinction training. Taken together, the results support the idea that adolescence is a time of particular susceptibility to elevated levels of the stress hormone corticosterone. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Corticosterona/farmacologia , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Animais , Condicionamento Clássico/efeitos dos fármacos , Corticosterona/metabolismo , Ciclosserina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley
9.
Int J Dev Neurosci ; 75: 19-26, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30959098

RESUMO

Exposure to sevoflurane and other inhalational anesthetics can induce neurodegeneration in the developing brain. Although dexmedetomidine (DEX) has provided neuroprotection against hypoxic ischemic injury, relatively little is known about whether it has the neuroprotective effects against anesthetic-induced neurodegeneration. This study examined whether DEX improves the long-term cognitive dysfunction observed after exposure of neonatal rats to 3% sevoflurane. Seven-day-old rats received intraperitoneal saline (DEX 0) or DEX (6.6, 12.5, 25 µg/kg) 30 min before exposure to 3% sevoflurane with 21% oxygen for 4 h (n = 10 per group). The pups in the control group received only DEX 25 µg/kg without anesthesia. The escape latency in the Morris water maze was significantly increased in the DEX 0 group compared with the sham and control group, and the escape latency, but not the swimming path length, was significantly shorter at post-natal day 47 in the DEX 25 than in the DEX 0 group. The percent time spent in the quadrant was significantly decreased in the DEX 0 group compared with the sham and control group, and the percent time spent in the quadrant was significantly increased in the DEX 25 group compared with the DEX 0 groups. The freezing times of the DEX 0 and 6.6 groups were significantly decreased compared with those in the sham, control and DEX 25 groups. The number of NeuN-positive cells in the CA1 region was significantly decreased in the DEX 0 and 6.6 groups compared with the sham, control and DEX 25 groups. These findings indicate pre-treatment with DEX may improve long-term cognitive function and ameliorate the neuronal degeneration induced by sevoflurane exposure in neonatal rats.


Assuntos
Anestésicos Inalatórios/efeitos adversos , Dexmedetomidina/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Degeneração Neural/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Sevoflurano/efeitos adversos , Animais , Animais Recém-Nascidos , Cognição/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Dexmedetomidina/farmacologia , Medo , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/patologia , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar
10.
Nature ; 569(7754): 116-120, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30944474

RESUMO

A critical period is a developmental epoch during which the nervous system is expressly sensitive to specific environmental stimuli that are required for proper circuit organization and learning. Mechanistic characterization of critical periods has revealed an important role for exuberant brain plasticity during early development, and for constraints that are imposed on these mechanisms as the brain matures1. In disease states, closure of critical periods limits the ability of the brain to adapt even when optimal conditions are restored. Thus, identification of manipulations that reopen critical periods has been a priority for translational neuroscience2. Here we provide evidence that developmental regulation of oxytocin-mediated synaptic plasticity (long-term depression) in the nucleus accumbens establishes a critical period for social reward learning. Furthermore, we show that a single dose of (+/-)-3,4-methylendioxymethamphetamine (MDMA) reopens the critical period for social reward learning and leads to a metaplastic upregulation of oxytocin-dependent long-term depression. MDMA-induced reopening of this critical period requires activation of oxytocin receptors in the nucleus accumbens, and is recapitulated by stimulation of oxytocin terminals in the nucleus accumbens. These findings have important implications for understanding the pathogenesis of neurodevelopmental diseases that are characterized by social impairments and of disorders that respond to social influence or are the result of social injury3.


Assuntos
Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Ocitocina/metabolismo , Recompensa , Envelhecimento/fisiologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Feminino , Depressão Sináptica de Longo Prazo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Transdução de Sinais/efeitos dos fármacos
11.
Artigo em Inglês | MEDLINE | ID: mdl-30953677

RESUMO

Disturbances in fear-evoked signal transduction in the hippocampus (HP), the nuclei of the amygdala (AMY), and the prefrontal cortex (PFC) underlie anxiety-related disorders. However, the molecular mechanisms underlying these effects remain elusive. Heterotrimeric G proteins (GPs) are divided into the following four families based on the intracellular activity of their alpha subunit (Gα): Gα(s) proteins stimulate cyclic AMP (cAMP) generation, Gα(i/o) proteins inhibit the cAMP pathway, Gα(q/11) proteins increase the intracellular Ca++ concentration and the inositol trisphosphate level, and Gα(12/13) proteins activate monomeric GP-Rho. In the present study, we assessed the effects of a fear memory procedure on the mRNA expression of the Gα subunits of all four GP families in the HP, AMY and PFC. C57BL/6 J mice were subjected to a fear conditioning (FC) procedure followed by a contextual or cued fear memory test (CTX-R and CS-R, respectively). Morphine (MOR, 1 mg/kg/ip) was injected immediately after FC to prevent the fear consolidation process. Real-time quantitative PCR was used to measure the mRNA expression levels of Gα subunits at 1 h after FC, 24 h after FC, and 1 h after the CTX-R or CS-R. In the HP, the mRNA levels of Gα(s), Gα(12) and Gα(11) were higher at 1 h after training. Gα(s) levels were slightly lower when consolidation was stabilized and after the CS-R. The mRNA levels of Gα(12) were increased at 1 h after FC, returned to control levels at 24 h after FC and increased again with the CTX-R. The increase in the Gα(11) level persisted at 24 h after FC and after CTX-R. In the AMY, no specific changes were induced by FC. In the PFC, CTX-R was accompanied by a decrease in Gα(i/o) mRNA levels; however, only Gα(i2) downregulation was prevented by MOR treatment. Hence, the FC-evoked changes in Gα mRNA expression were observed mainly in the HP and connected primarily to contextual learning. These results suggest that the activation of signaling pathways by Gα(s) and Gα(12) is required to begin the fear memory consolidation process in the HP, while signal transduction via Gα(11) is implicated in the maintenance of fear consolidation. In the PFC, the downregulation of Gα(i2) appears to be related to the contextual learning of fear.


Assuntos
Encéfalo/metabolismo , Medo , Proteínas de Ligação ao GTP/metabolismo , Memória/efeitos dos fármacos , Morfina/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Sinais (Psicologia) , Medo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo
12.
Pharmacol Biochem Behav ; 181: 9-16, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954637

RESUMO

Learning processes associated with nicotine influence the development of addiction to tobacco products. In the present report, we are interested in the interoceptive stimulus effects of nicotine acquiring control over appetitive behaviors - specifically, reward seeking. Also of interest is the current smoking cessation drug, varenicline (Chantix®). Varenicline, with its nicotine-like stimulus effects, can decrease withdrawal and cravings for a subset of individuals addicted to nicotine, though relapse is still common. We trained rats (N = 48) with nicotine (0.4 mg/kg, SC) as an excitatory stimulus (i.e., paired with sucrose) in a drug-discriminated goal-tracking (DGT) task. There was no access to sucrose on interspersed saline days. After acquisition of the initial nicotine-saline discrimination, rats were separated into four groups to test discrimination reversal and drug substitution. The control group maintained nicotine as the excitatory stimulus (NIC+). The substitution group had varenicline (1 mg/kg) replace nicotine as the stimulus paired with sucrose (VAR+). One reversal group had nicotine signal the absence of sucrose (i.e., now available on intermixed saline sessions; NIC-). The last group was similar to the NIC- group except varenicline replaced nicotine on non-reinforced sessions (VAR-). We found that varenicline fully substituted as the training stimulus when the drug-sucrose relation remained in place (VAR+). Both reversal groups acquired the new discrimination, albeit slowly and more variable for the VAR- group in comparison to NIC-. There was an effect of group during substitution testing. Specifically, nicotine fully substituted for varenicline regardless of condition. However, varenicline only partially substituted for the nicotine stimulus. At the start of extinction, responding mimicked that of the rats training condition. However, by extinction session 12, all groups maintained similarly low levels of responding. These findings show nicotine and varenicline share stimulus elements, yet the conclusion of partial to full substitution depends on the nature of the testing protocol.


Assuntos
Comportamento Apetitivo/efeitos dos fármacos , Interocepção/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Vareniclina/farmacologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Substituição de Medicamentos , Extinção Psicológica/efeitos dos fármacos , Injeções Subcutâneas , Masculino , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Solução Salina/farmacologia , Abandono do Hábito de Fumar , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Sacarose/farmacologia , Vareniclina/administração & dosagem
13.
Pharmacol Biochem Behav ; 181: 60-68, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31004629

RESUMO

Adolescents are more sensitive than adults to the neural and behavioral effects of psychostimulants, and exhibit greater vulnerability to drug abuse, dependence or relapse into these conditions. We have reported that cocaine pretreatment during adolescence promotes the expression of behavioral sensitization to a greater extent than when the pretreatment occurs at adulthood. Behavioral sensitization has been associated to the transition from drug use to addiction and is postulated to indicate heightened sensitivity to the appetitive motivational effects of drugs. The relationship between behavioral sensitization and conventional measures of drug reward, such as conditioned place preference (CPP), has yet to be thoroughly investigated, and little is known about age-related differences in this phenomenon. The present study tested cocaine-induced CPP in adolescent and adult mice exposed to cocaine (or vehicle) pretreatment, either in an intermittent or "binge" (i.e., heavy cocaine use on a single occasion, which increases the likelihood of experiencing cocaine-related problems) fashion. Cocaine administration induced behavioral sensitization to a greater extent in adolescent than in adult mice. Cocaine-induced CPP was fairly similar in vehicle pretreated adolescent and adult mice, yet greater in adolescent vs. adults after cocaine-induced sensitization. The results confirmed the higher sensitivity of adolescent mice to cocaine-induced behavioral sensitization and suggest its association with greater sensitivity to cocaine's rewarding effects.


Assuntos
Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/administração & dosagem , Cocaína/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Recompensa , Solução Salina/administração & dosagem , Solução Salina/farmacologia
14.
Psychopharmacology (Berl) ; 236(7): 2069-2082, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30879119

RESUMO

RATIONALE: Pregabalin is a psychoactive drug indicated in the treatment of epilepsy, neuropathic pain, and generalized anxiety disorders. Pregabalin acts on different neurotransmission systems by inactivating the alpha2-delta subunit of voltage-gated calcium channels. In light of this pharmacological property, the hypothesis has been raised that pregabalin may regulate the mesolimbic dopamine pathway and thereby display a potential for misuse or abuse as recently observed in humans. Although some preclinical data support this possibility, the rewarding properties of gabapentinoid are still a matter for debate. OBJECTIVE: The aim of this work was to evaluate the rewarding properties of pregabalin and to determine its putative mechanism of action in healthy mice. RESULTS: Pregabalin alone (60 mg/kg; s.c.) produced a rewarding effect in the conditioned place preference (CPP) test albeit to a lower extent than cocaine (30 mg/kg; s.c.). Interestingly, when assessing locomotor activity in the CPP, the PGB60 group, similarly to the cocaine group, showed an increased locomotor activity. In vivo single unit extracellular recording showed that pregabalin had mixed effects on dopamine (DA) neuronal activity in the ventral tegmental area since it decreased the activity of 50% of neurons and increased 28.5% of them. In contrast, cocaine decreased 75% of VTA DA neuronal activity whereas none of the neurons were activated. Intracerebal microdialysis was then conducted in awake freely mice to determine to what extent such electrophysiological parameters influence the extracellular DA concentrations ([DA]ext) in the nucleus accumbens. Although pregabalin failed to modify this parameter, cocaine produced a robust increase (800%) in [DA]ext. CONCLUSIONS: Collectively, these electrophysiological and neurochemical experiments suggest that the rewarding properties of pregabalin result from a different mode of action than that observed with cocaine. Further experiments are warranted to determine whether such undesirable effects can be potentiated under pathological conditions such as neuropathic pain, mood disorders, or addiction and to identify the key neurotransmitter system involved.


Assuntos
Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Núcleo Accumbens/metabolismo , Pregabalina/farmacologia , Recompensa , Área Tegmentar Ventral/metabolismo , Analgésicos/farmacologia , Animais , Cocaína/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microdiálise/métodos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacos
15.
Behav Neurosci ; 133(4): 361-377, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30869950

RESUMO

Reward uncertainty is a common characteristic of gambling and may powerfully enhance attraction to gambling-related cues, thus promoting maladaptive gambling behaviors in susceptible individuals. The co-occurrence of gambling disorder with tobacco use disorder (60.4%) suggests a common mechanism for their pathology, and comorbid anxiety (41.3%) might further promote the maintenance of these behaviors. However, it is unknown how nicotine or anxiety might contribute to cue and reward attraction, or promote disordered gambling behavior. In the present study, we investigated the effects of nicotine (0.4 mg/kg, SC) on the desire for uncertain rewards and their cues in male and female Sprague-Dawley rats. During an autoshaping task, rats learned to associate a lever + tone cue with the delivery of sucrose pellet rewards under either certain or uncertain (probability and magnitude) reward conditions. Subsequently, we tested the ability of gambling-like cues to serve as a conditioned reinforcer, and to promote motivation for sucrose rewards during a progressive ratio task. Finally, anxiety behavior was measured to examine its interaction with nicotine and uncertainty. Here, we found that nicotine enhanced attraction to the magazine under certain but not uncertain reward conditions, and increased cue-triggered behaviors. Conversely, in the progressive ratio task, exposure to uncertain conditions and nicotine enhanced motivation for reward, compared with certain conditions. These results suggest that nicotine may interact with both certain and uncertain reward conditions to increase cue-triggered behavior and enhance motivation for rewards, providing possible insight into the comorbid relationship between pathological gambling and tobacco use. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Condicionamento Clássico/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Nicotina/farmacologia , Animais , Ansiedade/metabolismo , Transtornos de Ansiedade , Condicionamento Operante/fisiologia , Sinais (Psicologia) , Feminino , Jogo de Azar/metabolismo , Masculino , Motivação , Nicotina/metabolismo , Probabilidade , Ratos , Ratos Sprague-Dawley , Recompensa , Incerteza
16.
Neurosci Lett ; 703: 145-148, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-30890472

RESUMO

While the psychoactive stimulant nicotine has been the subject of extensive research, considerably less attention has focused on other compounds found in either tobacco smoke or that are nicotine metabolites. Recent papers have suggested that some of the compounds in question may either alter nicotine's effects or have reinforcing properties themselves, although they would only be experienced after consumption of tobacco. The potential for these compounds to function as reinforcers or to potentiate the reinforcing properties of nicotine merits investigation. To pursue this line of inquiry, we examined cotinine in a planarian model of environmental place preference. In the present study, planarians demonstrated that the compound cotinine, which is present in tobacco smoke, and is also the principal nicotine metabolite, establishes a conditioned place preference. These data represent the first ever demonstration that cotinine will establish a conditioned place preference in planarians and possibly contribute to the addictive properties of nicotine.


Assuntos
Condicionamento Clássico/efeitos dos fármacos , Cotinina/toxicidade , Planárias/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Planárias/fisiologia
17.
Neurobiol Learn Mem ; 161: 26-36, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30851433

RESUMO

The association of a sensory cue and an aversive footshock that are separated in time, as in trace fear conditioning, requires persistent activity in prelimbic cortex during the cue-shock interval. The activation of muscarinic acetylcholine receptors has been shown to facilitate persistent firing of cortical cells in response to brief stimulation, and muscarinic antagonists in the prefrontal cortex impair working memory. It is unknown, however, if the acquisition of associative trace fear conditioning is dependent on muscarinic signaling in the prefrontal cortex. Here, we delivered the muscarinic receptor antagonist scopolamine to the prelimbic cortex of rats prior to trace fear conditioning and tested their memories of the cue and training context the following day. The effect of scopolamine on working memory performance was also tested using a spatial delayed non-match to sample task. Male and female subjects were included to examine potential sex differences in the modulation of memory formation, as we have previously observed for pituitary adenylate cyclase-activating polypeptide signaling in the prefrontal cortex (Kirry et al., 2018). We found that pre-training administration of intra-prelimbic scopolamine impaired the formation of cued and contextual fear memories in males, but not females at a dose that impairs spatial working memory in both sexes. Fear memory formation in females was impaired by a higher dose of scopolamine and this impairment was gated by estrous cycle stage: scopolamine failed to impair memory in rats in the diestrus or proestrus stages of the estrous cycle. These findings add to the growing body of evidence that the prefrontal cortex is sexually dimorphic in learning and memory and additionally suggest that males and females differentially engage prefrontal neuromodulatory systems in support of learning.


Assuntos
Condicionamento Clássico/efeitos dos fármacos , Ciclo Estral/fisiologia , Medo/fisiologia , Memória de Curto Prazo/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Receptores Muscarínicos/fisiologia , Escopolamina/farmacologia , Caracteres Sexuais , Memória Espacial/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Sinais (Psicologia) , Feminino , Masculino , Antagonistas Muscarínicos/administração & dosagem , Córtex Pré-Frontal , Ratos , Ratos Long-Evans , Receptores Muscarínicos/efeitos dos fármacos , Escopolamina/administração & dosagem
18.
Mol Brain ; 12(1): 28, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30925893

RESUMO

It is generally believed that fear is rapidly triggered by a distinct cue while anxiety onset is less precise and not associated with a distinct cue. Although it has been claimed that both processes can be measured with certain independence of each other, it is unclear how exactly they differ. In this study, we measured anxiety in mice that received discriminative fear conditioning using behavioral, heart rate and calcium (Ca2+) responses in the ventral hippocampal CA1 (vCA1) neurons. We found that the occurrence of fear significantly interfered with anxiety measurements under various conditions. Diazepam reduced basal anxiety level but had no effect during the presentation of conditioned stimulus (CS). Injection of an inhibitory peptide of PKMzeta (ZIP) into the basolateral amygdala almost entirely abolished CS-triggered fear expression and reduced anxiety to basal level. Heart rate measures suggested a small reduction in anxiety during CS-. Calcium responses in the lateral hypothalamus-projecting vCA1 neurons showed a steady decay during CS suggesting a reduced anxiety. Thus, under our experimental conditions, CS presentations likely reduce anxiety level in the fear-conditioned mice.


Assuntos
Ansiedade/fisiopatologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/patologia , Cálcio/metabolismo , Condicionamento Clássico/efeitos dos fármacos , Diazepam/farmacologia , Diazepam/uso terapêutico , Medo/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/patologia , Hipotálamo/fisiopatologia , Lipopeptídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo
19.
Artigo em Inglês | MEDLINE | ID: mdl-30826460

RESUMO

Sensitization of motor activity is a behavioural test to evaluate the effects of psychostimulants. Conditioned place preference (CPP) is an associative learning procedure to examine the rewarding properties of drugs. We aimed to assess whether motor sensitization to drugs of abuse can make zebrafish more vulnerable to establishing drug-induced CPP. We first evaluated sensitization of locomotor activity of zebrafish to repeated administrations of nicotine and cocaine during 5 days and after 5 days of withdrawal. After withdrawal, when zebrafish were re-exposed to the same dose of nicotine or cocaine locomotor activity was increased by 103% and 166%, respectively. Different groups of zebrafish were sensitized to nicotine or cocaine and trained on a nicotine-CPP task the day after withdrawal. The nicotine dose selected for sensitization was not effective for developing CPP in naïve zebrafish whereas it elicited CPP in zebrafish that were previously sensitized to nicotine or cocaine. Levels of nicotinic acetylcholine receptor ß2, α6 and α7 subunit, Pitx3, and tyrosine hydroxylase 1 (TH1) mRNAs were increased in the brain of nicotine- and cocaine-sensitized zebrafish. Nicotine-CPP performed with drug-sensitized zebrafish provoked further enhancements in the expression of α6 and α7 subunit, Pitx3, and TH1 mRNAs suggesting that the expression of these molecules in the reward pathway is involved in both processes. Our findings indicate that repeated exposures to low doses of drugs of abuse can increase subject's sensitivity to the rewarding properties of the same or different drugs. This further suggests that casual drug intake increases the probability of becoming addict.


Assuntos
Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Cocaína/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Nicotina/farmacologia , Receptores Nicotínicos/biossíntese , Peixe-Zebra , Animais , Encéfalo/metabolismo , Proteínas de Homeodomínio/biossíntese , Locomoção/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/biossíntese , Proteínas de Peixe-Zebra/biossíntese
20.
Neuropsychopharmacology ; 44(7): 1189-1197, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30728447

RESUMO

While preclinical work has aimed to outline the neural mechanisms of drug addiction, it has overwhelmingly focused on male subjects. There has been a push in recent years to incorporate females into existing addiction models; however, males and females often have different behavioral strategies, making it important to not only include females, but to develop models that assess the factors that comprise female drug addiction. Traditional self-administration models often include light or tone cues that serve as discriminative stimuli and/or consequent stimuli, making it nearly impossible to disentangle the effects of cue learning, the cues themselves, and acute effects of psychostimulant drugs. To disentangle the interaction between drug-associated cues and the consummatory and appetitive responding driven by cocaine, we have developed a new behavioral procedure that combines Pavlovian-instrumental transfer with behavioral economic analysis. This task can be completed within a single session, allowing for studies looking at estrous cycle stage-dependent effects in intact cycling females, something that has been difficult in the past. In this study, we found no differences in self-administration across the estrous cycle in the absence of cues; however, when cues were introduced, the cues that acquired value during estrus-but not during diestrus or in males-increased motivation. Cues paired during estrus also increased c-fos expression to a greater extent in striatal regions, an effect that may underlie the observed increases in seeking induced by these cues, even weeks later. Together, these data suggest that fundamental differences in the motivational properties of psychostimulant drugs between males and females are complex and are driven primarily by the interaction between drug-associated stimuli and drug effects.


Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína/farmacologia , Sinais (Psicologia) , Inibidores da Captação de Dopamina/farmacologia , Ciclo Estral , Animais , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Modelos Animais de Doenças , Economia Comportamental , Ciclo Estral/efeitos dos fármacos , Ciclo Estral/fisiologia , Feminino , Masculino , Ratos Sprague-Dawley
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