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1.
Exp Neurol ; 347: 113907, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34715133

RESUMO

Propensity to relapse, even after long-term abstinence, is a crucial feature of methamphetamine (METH) abuse. We and other laboratories have reported that acute treatment of oxytocin (OXT), a hormone and neuropeptide, could inhibit reinstatement of METH seeking in animal studies. However, the effects of repeated OXT treatment on METH reinstatement as well as underlying mechanisms are still unclear. In the present study, the effects of repeated OXT treatment during abstinence on context- or restraint stress-induced reinstatement were investigated using the mice conditioned place preference (CPP) paradigm. After three intermittent injections of METH (2 mg/kg, i.p.) to induce CPP, mice received a daily bilateral intra-hippocampus injection of OXT (0.625, 1.25 or 2.5 µg) for 8 consecutive days before the context- or restraint stress-induced reinstatement test. Meanwhile, adult hippocampal neurogenesis (AHN) level was detected using immunostaining. To further clarify the role of AHN underlying OXT's effects on METH-CPP reinstatement, temozolomide (TMZ, 25 mg/kg, i.p.) was employed to deplete AHN prior to OXT treatment. The data showed that repeated OXT treatment (1.25 and 2.5 µg, intra-hippocampus) significantly inhibited both context- and restraint stress-induced METH-CPP reinstatement and concomitantly promoted AHN in a dose-dependent manner. Notably, TMZ pre-treatment markedly abolished all the above-mentioned effects of OXT, suggesting that AHN was closely involved in OXT's inhibition on reinstatement induced by both triggers. Taken together, the present study indicated that repeated OXT treatment during abstinence could inhibit both context- and restraint stress-induced METH-CPP reinstatement possibly by promoting AHN in mice, which provided a better understanding for OXT's beneficial effects on METH addiction.


Assuntos
Condicionamento Operante/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Metanfetamina/administração & dosagem , Neurogênese/efeitos dos fármacos , Ocitocina/administração & dosagem , Restrição Física/psicologia , Animais , Condicionamento Operante/fisiologia , Inibidores da Captação de Dopamina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Hipocampo/citologia , Hipocampo/fisiologia , Bombas de Infusão Implantáveis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/fisiologia , Restrição Física/efeitos adversos
2.
Nat Neurosci ; 24(11): 1601-1613, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34663957

RESUMO

The persistence of negative affect in pain leads to co-morbid symptoms such as anhedonia and depression-major health issues in the United States. The neuronal circuitry and contribution of specific cellular populations underlying these behavioral adaptations remains unknown. A common characteristic of negative affect is a decrease in motivation to initiate and complete goal-directed behavior, known as anhedonia. We report that in rodents, inflammatory pain decreased the activity of ventral tegmental area (VTA) dopamine (DA) neurons, which are critical mediators of motivational states. Pain increased rostromedial tegmental nucleus inhibitory tone onto VTA DA neurons, making them less excitable. Furthermore, the decreased activity of DA neurons was associated with reduced motivation for natural rewards, consistent with anhedonia-like behavior. Selective activation of VTA DA neurons was sufficient to restore baseline motivation and hedonic responses to natural rewards. These findings reveal pain-induced adaptations within VTA DA neurons that underlie anhedonia-like behavior.


Assuntos
Adaptação Fisiológica/fisiologia , Anedonia/fisiologia , Neurônios Dopaminérgicos/metabolismo , Dor/metabolismo , Área Tegmentar Ventral/metabolismo , Animais , Condicionamento Operante/fisiologia , Neurônios Dopaminérgicos/química , Feminino , Masculino , Optogenética/métodos , Dor/genética , Ratos , Ratos Long-Evans , Ratos Transgênicos , Área Tegmentar Ventral/química
3.
Sci Rep ; 11(1): 17826, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34497303

RESUMO

Sensation seeking is a multidimensional phenotype that predicts the development of drug addiction in humans and addiction-like drug seeking in rodents. Several lines of evidence suggest that chronic stress increases sensation seeking and addiction-like drug seeking through common genetic mechanisms. Discovery and characterization of these mechanisms would reveal how chronic stress interacts with the genome to influence sensation seeking and how drugs of abuse hijack these fundamental reward mechanisms to drive addiction. To this end, we tested the hypothesis that chronic isolation housing stress (relative to environmental enrichment) influences operant sensation seeking as a function of strain, sex, or their interaction. To determine if the BXD recombinant inbred panel could be used to identify genetic and epigenetic mechanisms underlying any identified gene-by-environment interactions, we used mice from the two BXD founder strains. Following 10 weeks of differential housing, we assessed operant sensation seeking using several reinforcement schedules. The primary finding from this study was that DBA/2J but not C57BL/6J mice were significantly vulnerable to an isolation-induced increase (relative to environmental enrichment) in sensation seeking during extinction when the sensory reward was no longer available; this effect was significantly more robust in females. These data reveal a previously unknown isolation-induced effect on extinction of operant sensation seeking that is sex-dependent, addiction-relevant, and that can be dissected using the BXD recombinant inbred panel.


Assuntos
Condicionamento Operante/fisiologia , Abrigo para Animais , Recompensa , Sensação/fisiologia , Animais , Extinção Psicológica/fisiologia , Feminino , Masculino , Camundongos , Fatores Sexuais , Especificidade da Espécie , Estresse Psicológico/fisiopatologia
4.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502393

RESUMO

Beta-phenylethylamine (ß-PEA) is a well-known and widespread endogenous neuroactive trace amine found throughout the central nervous system in humans. In this study, we demonstrated the effects of ß-PEA on psychomotor, rewarding, and reinforcing behaviors and affective state using the open-field test, conditioned place preference (CPP), self-administration, and ultrasonic vocalizations (USVs) paradigms. We also investigated the role of the dopamine (DA) D1 receptor in the behavioral effects of ß-PEA in rodents. Using enzyme-linked immunosorbent assay (ELISA) and Western immunoblotting, we also determined the DA concentration and the DA-related protein levels in the dorsal striatum of mice administered with acute ß-PEA. The results showed that acute ß-PEA increased stereotypic behaviors such as circling and head-twitching responses in mice. In the CPP experiment, ß-PEA increased place preference in mice. In the self-administration test, ß-PEA significantly enhanced self-administration during a 2 h session under fixed ratio (FR) schedules (FR1 and FR3) and produced a higher breakpoint during a 6 h session under progressive ratio schedules of reinforcement in rats. In addition, acute ß-PEA increased 50-kHz USV calls in rats. Furthermore, acute ß-PEA administration increased DA concentration and p-DAT and TH expression in the dorsal striatum of mice. Finally, pretreatment with SCH23390, a DA D1 receptor antagonist, attenuated ß-PEA-induced circling behavior and ß-PEA-taking behavior in rodents. Taken together, these findings suggest that ß-PEA has rewarding and reinforcing effects and psychoactive properties, which induce psychomotor behaviors and a positive affective state by activating the DA D1 receptor in the dorsal striatum.


Assuntos
Fenetilaminas/farmacologia , Receptores de Dopamina D1/metabolismo , Afeto/efeitos dos fármacos , Afeto/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Condicionamento Psicológico/efeitos dos fármacos , Dopamina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenetilaminas/metabolismo , Desempenho Psicomotor/efeitos dos fármacos , Receptores de Dopamina D1/efeitos dos fármacos , Reforço Psicológico , Recompensa , Autoadministração
5.
J Neurosci ; 41(41): 8589-8602, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34429377

RESUMO

The effective development of novel therapies in mouse models of neurologic disorders relies on behavioral assessments that provide accurate read-outs of neuronal dysfunction and/or degeneration. We designed an automated behavioral testing system (PiPaw), which integrates an operant lever-pulling task directly into the mouse home cage. This task is accessible to group-housed mice 24 h per day, enabling high-throughput longitudinal analysis of forelimb motor learning. Moreover, this design eliminates the need for exposure to novel environments and minimizes experimenter interaction, significantly reducing two of the largest stressors associated with animal behavior. Male mice improved their performance of this task over 1 week of testing by reducing intertrial variability of reward-related kinematic parameters (pull amplitude or peak velocity). In addition, mice displayed short-term improvements in reward rate, and a concomitant decrease in movement variability, over the course of brief bouts of task engagement. We used this system to assess motor learning in mouse models of the inherited neurodegenerative disorder, Huntington disease (HD). Despite having no baseline differences in task performance, male Q175-FDN HD mice were unable to modulate the variability of their movements to increase reward on either short or long timescales. Task training was associated with a decrease in the amplitude of spontaneous excitatory activity recorded from striatal medium spiny neurons in the hemisphere contralateral to the trained forelimb in WT mice; however, no such changes were observed in Q175-FDN mice. This behavioral screening platform should prove useful for preclinical drug trials toward improved treatments in HD and other neurologic disorders.SIGNIFICANCE STATEMENT In order to develop effective therapies for neurologic disorders, such as Huntington disease (HD), it is important to be able to accurately and reliably assess the behavior of mouse models of these conditions. Moreover, these behavioral assessments should provide an accurate readout of underlying neuronal dysfunction and/or degeneration. In this paper, we used an automated behavioral testing system to assess motor learning in mice within their home cage. Using this system, we were able to study motor abnormalities in HD mice with an unprecedented level of detail, and identified a specific behavioral deficit associated with an underlying impairment in striatal neuronal plasticity. These results validate the usefulness of this system for assessing behavior in mouse models of HD and other neurologic disorders.


Assuntos
Fenômenos Biomecânicos/fisiologia , Condicionamento Operante/fisiologia , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Atividade Motora/fisiologia , Recompensa , Animais , Ingestão de Líquidos/fisiologia , Membro Anterior/fisiopatologia , Técnicas de Introdução de Genes , Masculino , Camundongos , Camundongos Transgênicos
6.
Sci Rep ; 11(1): 14819, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285293

RESUMO

Blindsight is the residual visuo-motor ability without subjective awareness observed after lesions of the primary visual cortex (V1). Various visual functions are retained, however, instrumental visual associative learning remains to be investigated. Here we examined the secondary reinforcing properties of visual cues presented to the hemianopic field of macaque monkeys with unilateral V1 lesions. Our aim was to test the potential role of visual pathways bypassing V1 in reinforcing visual instrumental learning. When learning the location of a hidden area in an oculomotor search task, conditioned visual cues presented to the lesion-affected hemifield operated as an effective secondary reinforcer. We noted that not only the hidden area location, but also the vector of the saccade entering the target area was reinforced. Importantly, when the visual reinforcement signal was presented in the lesion-affected field, the monkeys continued searching, as opposed to stopping when the cue was presented in the intact field. This suggests the monkeys were less confident that the target location had been discovered when the reinforcement cue was presented in the affected field. These results indicate that the visual signals mediated by the residual visual pathways after V1 lesions can access fundamental reinforcement mechanisms but with impaired visual awareness.


Assuntos
Córtex Visual/fisiologia , Vias Visuais/fisiologia , Percepção Visual/fisiologia , Animais , Condicionamento Operante/fisiologia , Haplorrinos , Masculino
7.
J Neurosci ; 41(33): 7086-7102, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34261700

RESUMO

The G-protein-gated inwardly rectifying potassium (Kir3/GIRK) channel is the effector of many G-protein-coupled receptors (GPCRs). Its dysfunction has been linked to the pathophysiology of Down syndrome, Alzheimer's and Parkinson's diseases, psychiatric disorders, epilepsy, drug addiction, or alcoholism. In the hippocampus, GIRK channels decrease excitability of the cells and contribute to resting membrane potential and inhibitory neurotransmission. Here, to elucidate the role of GIRK channels activity in the maintenance of hippocampal-dependent cognitive functions, their involvement in controlling neuronal excitability at different levels of complexity was examined in C57BL/6 male mice. For that purpose, GIRK activity in the dorsal hippocampus CA3-CA1 synapse was pharmacologically modulated by two drugs: ML297, a GIRK channel opener, and Tertiapin-Q (TQ), a GIRK channel blocker. Ex vivo, using dorsal hippocampal slices, we studied the effect of pharmacological GIRK modulation on synaptic plasticity processes induced in CA1 by Schaffer collateral stimulation. In vivo, we performed acute intracerebroventricular (i.c.v.) injections of the two GIRK modulators to study their contribution to electrophysiological properties and synaptic plasticity of dorsal hippocampal CA3-CA1 synapse, and to learning and memory capabilities during hippocampal-dependent tasks. We found that pharmacological disruption of GIRK channel activity by i.c.v. injections, causing either function gain or function loss, induced learning and memory deficits by a mechanism involving neural excitability impairments and alterations in the induction and maintenance of long-term synaptic plasticity processes. These results support the contention that an accurate control of GIRK activity must take place in the hippocampus to sustain cognitive functions.SIGNIFICANCE STATEMENT Cognitive processes of learning and memory that rely on hippocampal synaptic plasticity processes are critically ruled by a finely tuned neural excitability. G-protein-gated inwardly rectifying K+ (GIRK) channels play a key role in maintaining resting membrane potential, cell excitability and inhibitory neurotransmission. Here, we demonstrate that modulation of GIRK channels activity, causing either function gain or function loss, transforms high-frequency stimulation (HFS)-induced long-term potentiation (LTP) into long-term depression (LTD), inducing deficits in hippocampal-dependent learning and memory. Together, our data show a crucial GIRK-activity-mediated mechanism that governs synaptic plasticity direction and modulates subsequent hippocampal-dependent cognitive functions.


Assuntos
Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/fisiologia , Hipocampo/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Condicionamento Operante/fisiologia , Emoções/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Aprendizagem/fisiologia , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/fisiologia , Desempenho Psicomotor/fisiologia
8.
Mol Pain ; 17: 17448069211013633, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33906493

RESUMO

Mouse behavioral assays have proven useful for the study of thermosensation, helping to identify receptors and circuits responsible for the transduction of thermal stimuli and information relay to the brain. However, these methods typically rely on observation of behavioral responses to various temperature stimuli to infer sensory ability and are often unable to disambiguate innocuous thermosensation from thermal nociception or to study thermosensory circuitry which do not produce easily detectable innate behavioral responses. Here we demonstrate a new testing apparatus capable of delivering small, rapid temperature change stimuli to the mouse's skin, permitting the use of operant conditioning to train mice to recognize and report temperature change. Using this assay, mice that were trained to detect a large temperature change were found to generalize this learning to distinguish much smaller temperature changes across the entire range of innocuous temperatures tested. Mice with ablated TRPV1 and TRPM8 neuronal populations had reduced ability to discriminate temperature differences in the warm (>35°C) and cool (<30°C) ranges, respectively. Furthermore, mice that were trained to recognize temperature changes in only the cool, TRPM8-mediated temperature range did not generalize this learning in the warm, TRPV1-mediated range (and vice versa), suggesting that thermosensory information from the TRPM8- and TRPV1-neuronal populations are perceptually distinct.


Assuntos
Condicionamento Operante/fisiologia , Discriminação Psicológica/fisiologia , Nociceptividade/fisiologia , Sensação Térmica/fisiologia , Animais , Feminino , Masculino , Camundongos , Pele , Temperatura
9.
Nat Neurosci ; 24(6): 831-842, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33820999

RESUMO

Social interactions and relationships are often rewarding, but the neural mechanisms through which social interaction drives positive experience remain poorly understood. In this study, we developed an automated operant conditioning system to measure social reward in mice and found that adult mice of both sexes display robust reinforcement of social interaction. Through cell-type-specific manipulations, we identified a crucial role for GABAergic neurons in the medial amygdala (MeA) in promoting the positive reinforcement of social interaction. Moreover, MeA GABAergic neurons mediate social reinforcement behavior through their projections to the medial preoptic area (MPOA) and promote dopamine release in the nucleus accumbens. Finally, activation of this MeA-to-MPOA circuit can robustly overcome avoidance behavior. Together, these findings establish the MeA as a key node for regulating social reward in both sexes, providing new insights into the regulation of social reward beyond the classic mesolimbic reward system.


Assuntos
Tonsila do Cerebelo/fisiologia , Condicionamento Operante/fisiologia , Hipotálamo/fisiologia , Rede Nervosa/fisiologia , Recompensa , Comportamento Social , Tonsila do Cerebelo/química , Animais , Feminino , Hipotálamo/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Rede Nervosa/química , Optogenética/métodos , Reforço Psicológico
10.
Psychopharmacology (Berl) ; 238(8): 2235-2247, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33890131

RESUMO

RATIONALE: Tobacco products are very addictive, partly because they contain nicotine which is reinforcing, but also because they include appealing aromas and tastes. Flavor additives are such sensory stimuli which enhance attractiveness, as well as use and abuse of tobacco and vaping products. Yet, the interaction between these flavor additives and nicotine remains poorly understood. OBJECTIVES: We want to understand how flavors may reduce nicotine' aversive taste and how it may enhance its voluntary oral self-administration in mice. METHODS: We first studied the effect of flavor additives on nicotine solution palatability in a free bottle choice paradigm. Second, we investigated the effect of vanilla flavoring on the different stages of nicotine (40 µg/ml) oral self-administration in mice. RESULTS: We show that adding flavors increase nicotine palatability and facilitate acquisition and maintenance of oral self-administration when compared to nicotine-alone group. Mice adapt their operant behavior depending on changes in nicotine concentration. All mice reinstate nicotine seeking upon presentation of associated cues. Nevertheless, vanilla-flavored nicotine was not more reinforcing than vanilla-flavored water which was reinforcing enough to drive similar operant response rates. CONCLUSIONS: Flavor additives increase nicotine oral consumption and help maintaining operant behavior in mice. Moreover, flavors can be very attractive and can have high reinforcing value by themselves. Thus, it is crucial that the investigation on how taste signals play an important role in modulating oral nicotine intake in rodent models remains explored.


Assuntos
Condicionamento Operante/efeitos dos fármacos , Aromatizantes/administração & dosagem , Nicotina/administração & dosagem , Reforço Psicológico , Produtos do Tabaco , Administração Oral , Animais , Condicionamento Operante/fisiologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Autoadministração/métodos , Autoadministração/psicologia , Paladar/efeitos dos fármacos , Paladar/fisiologia , Vaping/psicologia
11.
Psychopharmacology (Berl) ; 238(8): 2213-2224, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33907871

RESUMO

RATIONALE: Women meet criteria for substance use disorder after fewer years of drug use than men; this accelerated time course, or telescoping effect, has been observed for multiple drugs, including cocaine. Preclinical findings similarly indicate an enhanced vulnerability in females to developing an addiction-like phenotype; however, it is not yet known if this phenotype develops faster in females versus males. OBJECTIVES: The goal of this study was to determine using a rat model whether two key features of addiction in humans, an enhanced motivation for cocaine and compulsive use, emerge sooner during withdrawal from extended access cocaine self-administration in females versus males. METHODS: Motivation for cocaine, as assessed under a progressive-ratio reinforcement schedule, was determined prior to and following extended access cocaine self-administration (24 h/day, 96 infusions/day, 10 days) and after 7, 14, or 60 days of withdrawal. Compulsive use, or use despite punishment, was evaluated once progressive-ratio responding stabilized by adding histamine, an aversive stimulus, to the cocaine solutions. RESULTS: Motivation for cocaine increased from baseline sooner during withdrawal in females than males (at 7 versus 14 days); motivation was also highest in the 60-day group. Histamine decreased progressive-ratio responding for cocaine in both sexes, although effects were greatest in males in the 7-day withdrawal group; males reached the female-level of resistance to histamine punishment by 14 days of withdrawal. CONCLUSIONS: Female rats developed addition-like features sooner during withdrawal than male rats indicating that the telescoping effect observed in humans is biologically based. Additionally, like drug-seeking/craving, motivation for cocaine and measures of compulsive use incubate over withdrawal.


Assuntos
Comportamento Aditivo/psicologia , Transtornos Relacionados ao Uso de Cocaína/psicologia , Cocaína/administração & dosagem , Fenótipo , Caracteres Sexuais , Síndrome de Abstinência a Substâncias/psicologia , Animais , Comportamento Aditivo/genética , Cocaína/efeitos adversos , Transtornos Relacionados ao Uso de Cocaína/genética , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Inibidores da Captação de Dopamina/administração & dosagem , Inibidores da Captação de Dopamina/efeitos adversos , Feminino , Masculino , Motivação/efeitos dos fármacos , Motivação/fisiologia , Ratos , Ratos Sprague-Dawley , Autoadministração , Síndrome de Abstinência a Substâncias/genética
12.
Psychopharmacology (Berl) ; 238(8): 2261-2273, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33895852

RESUMO

RATIONALE: Escalation of drug intake and craving are two DSM-5 hallmark symptoms of opioid use disorder (OUD). OBJECTIVES: This study determined if escalation of intake as modeled by long access (LgA) self-administration (SA) and craving measured by reinstatement are related. METHODS: Adult male and female Sprague-Dawley rats were trained to self-administer fentanyl across 7 daily 1-h short access (ShA) sessions, followed by 21 SA sessions of either 1- or 6-h duration (ShA or LgA). Following 14 1-h extinction sessions, Experiment 1 assessed reinstatement induced by either fentanyl (10 or 30 µg/kg) or yohimbine (1 or 2 mg/kg), and Experiment 2 assessed reinstatement induced by a drug-associated cue light. RESULTS: Females acquired fentanyl SA faster than males. When shifted to LgA sessions, LgA rats escalated fentanyl intake, but ShA rats did not; no reliable sex difference in the rate of escalation was observed. In extinction, compared to ShA rats, LgA rats initially responded less and showed less decay of responding across sessions. A priming injection of fentanyl induced reinstatement, with LgA rats reinstating more than ShA rats at the 30 µg/kg dose. Yohimbine (1 mg/kg) also induced reinstatement, but there was no effect of access group or sex. With cue-induced reinstatement, LgA females reinstated less than LgA males and ShA females. CONCLUSION: Among the different reinstatement tests assessed, escalation of fentanyl SA increased only drug-primed reinstatement, suggesting a limited relationship between escalation of drug intake and craving (reinstatement) for OUD.


Assuntos
Analgésicos Opioides/administração & dosagem , Condicionamento Operante/efeitos dos fármacos , Fissura/efeitos dos fármacos , Fentanila/administração & dosagem , Caracteres Sexuais , Animais , Cocaína/administração & dosagem , Condicionamento Operante/fisiologia , Fissura/fisiologia , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Autoadministração/psicologia
13.
Psychopharmacology (Berl) ; 238(7): 1923-1936, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33839903

RESUMO

RATIONALE: Cocaine addiction is a chronic relapsing disorder that lacks of an effective treatment. Isoflavones are a family of compounds present in different plants and vegetables like soybeans that share a common chemical structure. Previous studies have described that synthetic derivatives from the natural isoflavone daidzin can modulate cocaine addiction, by a mechanism suggested to involve aldehyde-dehydrogenase (ALDH) activities. OBJECTIVES: Based on these previous studies, we investigated the effects of three natural isoflavones, daidzin, daidzein, and genistein, on the modulation of the cocaine reinforcing effects and on cue-induced reinstatement in an operant mouse model of cocaine self-administration. RESULTS: Chronic treatment with daidzein or genistein decreased operant responding to obtain cocaine intravenous infusions. On the other hand, daidzein and daidzin, but not genistein, were effective in decreasing cue-induced cocaine reinstatement. Complementary studies revealed that daidzein effects on cocaine reinforcement were mediated through a mechanism that involved dopamine type-2/3 receptors (DA-D2/3) activities. CONCLUSIONS: Our results suggest that these natural compounds alone or in combination can be a potential therapeutic approach for cocaine addiction. Further clinical studies are required in order to ascertain their potential therapeutic use.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Cocaína/administração & dosagem , Sinais (Psicologia) , Isoflavonas/administração & dosagem , Fitoestrógenos/administração & dosagem , Reforço Psicológico , Animais , Transtornos Relacionados ao Uso de Cocaína/psicologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Inibidores da Captação de Dopamina/administração & dosagem , Relação Dose-Resposta a Droga , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Autoadministração
14.
Learn Mem ; 28(4): 104-108, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33723029

RESUMO

The dopamine system has been implicated in decision-making particularly when associated with effortful behavior. We examined acute optogenetic stimulation of dopamine cells in the ventral tegmental area (VTA) as mice engaged in an effort-based decision-making task. Tyrosine hydroxylase-Cre mice were injected with Cre-dependent ChR2 or eYFP control virus in the VTA. While eYFP control mice showed effortful discounting, stimulation of dopamine cells in ChR2 mice disrupted effort-based decision-making by reducing choice toward the lever associated with a preferred outcome and greater effort. Surprisingly, disruptions in effortful discounting were observed in subsequent test sessions conducted in the absence of optogenetic stimulation, however during these sessions ChR2 mice displayed enhanced high choice responding across trial blocks. These findings suggest increases in VTA dopamine cell activity can disrupt effort-based decision-making in distinct ways dependent on the timing of optogenetic stimulation.


Assuntos
Comportamento Animal/fisiologia , Tomada de Decisões/fisiologia , Neurônios Dopaminérgicos/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Condicionamento Operante/fisiologia , Camundongos , Optogenética , Desempenho Psicomotor/fisiologia , Tirosina 3-Mono-Oxigenase , Área Tegmentar Ventral/citologia
15.
Psychopharmacology (Berl) ; 238(7): 1885-1897, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33765177

RESUMO

RATIONALE AND OBJECTIVE: Pain-related factors increase the risk for opioid addiction, and pain may function as a negative reinforcer to increase opioid taking and seeking. However, experimental pain-related manipulations generally do not increase opioid self-administration in rodents. This discrepancy may reflect insufficient learning of pain-relief contingencies or confounding effects of pain-related behavioral impairments. Here, we determined if pairing noxious stimuli with opioid self-administration would promote pain-related reinstatement of opioid seeking or increase opioid choice over food. METHODS: In Experiment 1, rats self-administered fentanyl in the presence or absence of repeated intraplantar capsaicin injections in distinct contexts to model context-specific exposure to cutaneous nociception. After capsaicin-free extinction in both contexts, we tested if capsaicin would reinstate fentanyl seeking. In Experiment 2, rats self-administered heroin after intraperitoneal (i.p.) lactic acid injections to model acute visceral inflammatory pain. After lactic acid-free extinction, we tested if lactic acid would reinstate heroin seeking. In Experiment 3, we tested if repeated i.p. lactic acid or intraplantar Complete Freund's Adjuvant (CFA; to model sustained inflammatory pain) would increase fentanyl choice over food. RESULTS: In Experiments 1-2, neither capsaicin nor lactic acid reinstated opioid seeking after extinction, and lactic acid did not increase heroin-induced reinstatement. In Experiment 3, lactic acid and CFA decreased reinforcement rate without affecting fentanyl choice. CONCLUSIONS: Results extend the range of conditions across which pain-related manipulations fail to increase opioid seeking in rats and suggest that enhanced opioid-addiction risk in humans with chronic pain involves factors other than enhanced opioid reinforcement and relapse.


Assuntos
Analgésicos Opioides/administração & dosagem , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Procura de Droga/efeitos dos fármacos , Medição da Dor/psicologia , Dor/psicologia , Reforço Psicológico , Animais , Comportamento de Escolha/fisiologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Comportamento de Procura de Droga/fisiologia , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Feminino , Fentanila/farmacologia , Masculino , Transtornos Relacionados ao Uso de Opioides/psicologia , Dor/tratamento farmacológico , Medição da Dor/métodos , Ratos , Autoadministração/métodos
16.
Neurobiol Aging ; 100: 106-117, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33524848

RESUMO

The reduction of tau or hyperphosphorylated tau (p-tau) has been proposed as a therapeutic strategy for Alzheimer's disease (AD) and frontotemporal dementia (FTD). Cognitive decline and sleep-wake dysregulation seen in AD and FTD patients are mimicked in transgenic and null-mutation mouse models of tauopathy. Alterations in the reward system are additional symptoms of AD and FTD. However, the role of tau in reward processes is not well understood. The present study aimed to examine reward and reward-motivated cognitive processes in male and female tau knockout (tau-/-) and wild-type mice using progressive ratio and reversal learning tasks. Tau-/- mice were heavier, ate more in the home cage, and reached criterion in operant lever training faster than wild-type mice. Tau-/- mice had a higher breakpoint in progressive ratio but were unimpaired in reversal learning or reward sensitivity. These data indicate that tau loss of function alters reward processing. This may help to explain aberrant reward-related behaviors in tauopathy patients and highlights a potentially important area for consideration in the development of anti-tau therapies.


Assuntos
Cognição/fisiologia , Mutação com Perda de Função , Motivação/genética , Recompensa , Proteínas tau/genética , Proteínas tau/metabolismo , Doença de Alzheimer/psicologia , Animais , Condicionamento Operante/fisiologia , Modelos Animais de Doenças , Feminino , Demência Frontotemporal/psicologia , Aprendizagem/fisiologia , Masculino , Camundongos Knockout , Tauopatias/psicologia
17.
Sci Rep ; 11(1): 2970, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536607

RESUMO

Altered functioning of GABAergic interneurons expressing parvalbumin (PV) in the basal ganglia-thalamo-cortical circuit are likely to be involved in several human psychiatric disorders characterized by deficits in attention and sensory gating with dysfunctional decision-making behavior. However, the contribution of these interneurons in the ability to acquire demanding learning tasks remains unclear. Here, we combine an operant conditioning task with local field potentials simultaneously recorded in several nuclei involved in reward circuits of wild-type (WT) and PV-deficient (PVKO) mice, which are characterized by changes in firing activity of PV-expressing interneurons. In comparison with WT mice, PVKO animals presented significant deficits in the acquisition of the selected learning task. Recordings from prefrontal cortex, nucleus accumbens (NAc) and hippocampus showed significant decreases of the spectral power in beta and gamma bands in PVKO compared with WT mice particularly during the performance of the operant conditioning task. From the first to the last session, at all frequency bands the spectral power in NAc tended to increase in WT and to decrease in PVKO. Results indicate that PV deficiency impairs signaling necessary for instrumental learning and the recognition of natural rewards.


Assuntos
Condicionamento Operante/fisiologia , Neurônios GABAérgicos/metabolismo , Interneurônios/metabolismo , Parvalbuminas/deficiência , Animais , Masculino , Camundongos , Camundongos Knockout , Modelos Animais , Parvalbuminas/genética , Recompensa , Filtro Sensorial/fisiologia
18.
Nat Neurosci ; 24(3): 326-330, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33603228

RESUMO

By investigating the topology of neuronal co-activity, we found that mnemonic information spans multiple operational axes in the mouse hippocampus network. High-activity principal cells form the core of each memory along a first axis, segregating spatial contexts and novelty. Low-activity cells join co-activity motifs across behavioral events and enable their crosstalk along two other axes. This reveals an organizational principle for continuous integration and interaction of hippocampal memories.


Assuntos
Condicionamento Operante/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Sacarose/administração & dosagem , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Condicionamento Operante/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Rede Nervosa/efeitos dos fármacos , Neurônios/efeitos dos fármacos
19.
Neuropharmacology ; 186: 108454, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33444639

RESUMO

Positive modulation of cAMP signalling by phosphodiesterase (PDE) inhibitors has recently been explored as a potential target for the reversal of cognitive and behavioural deficits implicating the corticoaccumbal circuit. Previous studies show that PDE type 1 isoform B (PDE1B) inhibition may improve memory function in rodent models; however, the contribution of PDE1B inhibition to impulsivity, attentional and motivational functions as well as its neurophysiological effects have not been investigated. To address this, we recorded single unit activity in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) in Lister Hooded rats treated with the PDE1B inhibitor Lu AF64386 and tested in the 5-choice serial reaction time task (5-CSRTT). We also asked whether PDE1B inhibition modulates neurophysiological deficits produced by subchronic phencyclidine (PCP) treatment, a rat pharmacological model of schizophrenia. Lu AF64386 significantly affected behavioural parameters consistent with a reduction in goal-directed behaviour, however without affecting accuracy. Additionally, it reduced mPFC neuronal activity. Pre-treatment with PCP did not affect behavioural parameters, however it significantly disrupted overall neuronal firing while increasing phasic responses to reward-predicting cues and disrupting mPFC-NAc cross-talk. The latter two effects were reversed by Lu AF64386. These findings suggest PDE1B inhibition may be beneficial in disorders implicating a dysfunction of the mPFC-NAc network.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/antagonistas & inibidores , Objetivos , Fenciclidina/toxicidade , Inibidores de Fosfodiesterase/uso terapêutico , Córtex Pré-Frontal/enzimologia , Esquizofrenia/enzimologia , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Modelos Animais de Doenças , Feminino , Alucinógenos/toxicidade , Inibidores de Fosfodiesterase/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Ratos , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico
20.
Sci Rep ; 11(1): 1663, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462278

RESUMO

The operant conditioning has been less studied than the classical conditioning as a mechanism of placebo-like effect, and two distinct learning mechanisms have never been compared to each other in terms of their neural activities. Twenty-one participants completed cue-learning based pain rating tasks while their brain responses were measured using functional magnetic resonance imaging. After choosing (instrumental) or viewing (classical) one of three predictive cues (low- and high-pain cues with different level of certainty), they received painful stimuli according to the selected cues. Participants completed the same task during the test session, except that they received only a high pain stimulus regardless of the selected cues to identify the effects of two learning paradigms. While receiving a high pain stimulation, low-pain cue significantly reduced pain ratings compared to high-pain cue, and the overall ratings were significantly lower under operant than under classical conditioning. Operant behavior activated the temporoparietal junction significantly more than the passive behavior did, and neural activity in the primary somatosensory cortex was significantly reduced during pain in instrumental as compared with classical conditioning trials. The results suggest that pain modulation can be induced by classical and operant conditioning, and mechanisms of attention and context change are involved in instrumental learning.


Assuntos
Encéfalo/fisiologia , Condicionamento Clássico/fisiologia , Condicionamento Operante/fisiologia , Relações Metafísicas Mente-Corpo/fisiologia , Manejo da Dor/métodos , Dor/fisiopatologia , Adulto , Atenção/fisiologia , Sinais (Psicologia) , Medo/fisiologia , Medo/psicologia , Feminino , Humanos , Aprendizagem/fisiologia , Imageamento por Ressonância Magnética/métodos , Masculino , Dor/psicologia , Medição da Dor/métodos , Projetos Piloto , Adulto Jovem
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