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1.
Neurosci Lett ; 745: 135551, 2021 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-33346074

RESUMO

BACKGROUND: Previous studies suggest that muscarinic cholinergic receptors might act upon the dopamine release in the mesolimbic system and alter drug-reinforcing values related to drug craving. AIMS: We examined the effects of systemic biperiden administration, a muscarinic cholinergic (M1/M4) receptor antagonist, on ethanol (dose of 2 g/Kg) conditioned place preference (CPP), neuronal activation, dopamine and its metabolites levels in the nucleus accumbens. METHODS: Thirty minutes before the ethanol-induced CPP test, mice received saline or biperiden at doses of 1.0, 5.0, or 10.0 mg/kg. The time spent in each compartment was recorded for 15 min. After the CPP protocol, animals were euthanized, and we investigated the activation of the nucleus accumbens by immunohistochemistry for Fos. We also quantified dopamine, homovanillic acid (HVA), and dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens by high-performance liquid chromatography (HPLC). Additionally, the rotarod was employed to evaluate the effects of biperiden on motor coordination. RESULTS: Biperiden at different doses (1.0, 5.0, and 10.0 mg/kg) blocked the expression of ethanol-induced CPP. These biperiden doses increased the number of Fos-positive cells and the dopamine turnover in the nucleus accumbens. None of the doses affected the motor coordination evaluated by the rotarod. CONCLUSIONS: Our results show that biperiden can modulate the effect of alcohol reward, and its mechanism of action may involve a change in dopamine and cholinergic mesolimbic neurotransmission.


Assuntos
Biperideno/administração & dosagem , Condicionamento Clássico/efeitos dos fármacos , Etanol/administração & dosagem , Antagonistas Muscarínicos/administração & dosagem , Receptor Muscarínico M1/antagonistas & inibidores , Receptor Muscarínico M4/antagonistas & inibidores , Animais , Condicionamento Clássico/fisiologia , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Ácido Homovanílico/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M4/metabolismo
2.
PLoS One ; 15(9): e0239270, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32936829

RESUMO

In a between-subject comparison of two memantine administration schedules we observed that treatment with the NMDA receptor antagonist memantine before testing sessions reduced ingestion of a 10% sucrose solution in rats, due to reduced licking burst size, thus suggesting a blunted hedonic response. Conversely, daily post-session administration reduced burst number, indicating a reduced level of behavioural activation, likely due to the development of conditioned taste aversion (CTA). In this study, the effect of pre-session and post-session memantine administration was investigated within-subjects. Memantine was administered in daily intraperitoneal injections for 13 days, on alternate days, either 1-h before-"before testing" sessions-or immediately after a 30-min session-"after testing" sessions. The effects on the microstructure of licking for a 10% sucrose solution were examined in the course of treatment and for 21 days after treatment discontinuation. The results show reduced burst size in the "before testing" sessions, without effects on the intra-burst lick rate, an index of motoric effects. Moreover, burst number was reduced since the third session of both administration conditions until the end of treatment. Interestingly, the effect of memantine of reducing the activation of ingestive behaviour was less pronounced in this study with respect to that observed with the previous study post-session administration schedule, in spite of the longer treatment. This apparent paradox might be explained if one considers these effects as instances of a memory-related effect, such as the development of CTA. In the framework of this hypothesis, the "before testing" sessions, not being followed by memantine administration, can be considered as extinction sessions performed every other day. Moreover, the animals treated with memantine at the highest dose failed to recover to pre-treatment ingestion levels 21 days after treatment discontinuation, while the animals treated after testing sessions in the previously published study showed a complete recovery well before the 15th day test. Within the same interpretative framework, this might depend by the reduced number and frequency of the extinction trials-i.e. the number of the sessions run after treatment discontinuation-in the present study. These results provide further support to the conclusion that memantine administration before sessions reduce burst size, an effect which is likely due to blockade of NMDA receptors occurring during behavioural testing. The observation that this effect can be obtained even in absence of a reduced intra-burst lick rate, which rules out the involvement of motor impairment, provides an important piece of evidence in support to the interpretation of this effect as a blunted hedonic response. Moreover, these results provide further evidence that burst number reduction is due to a memory-related effect induced by memantine administration after sessions.


Assuntos
Comportamento Alimentar/efeitos dos fármacos , Memantina/farmacologia , Memória/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Condicionamento Clássico/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Ingestão de Alimentos , Humanos , Memantina/efeitos adversos , Memória/fisiologia , Ratos , Receptores de N-Metil-D-Aspartato/genética
3.
Nat Commun ; 11(1): 3764, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724058

RESUMO

Context can influence reactions to environmental cues and this elemental process has implications for substance use disorder. Using an animal model, we show that an alcohol-associated context elevates entry into a fluid port triggered by a conditioned stimulus (CS) that predicted alcohol (CS-triggered alcohol-seeking). This effect persists across multiple sessions and, after it diminishes in extinction, the alcohol context retains the capacity to augment reinstatement. Systemically administered eticlopride and chemogenetic inhibition of ventral tegmental area (VTA) dopamine neurons reduce CS-triggered alcohol-seeking. Chemogenetically silencing VTA dopamine terminals in the nucleus accumbens (NAc) core reduces CS-triggered alcohol-seeking, irrespective of context, whereas silencing VTA dopamine terminals in the NAc shell selectively reduces the elevation of CS-triggered alcohol-seeking in an alcohol context. This dissociation reveals new roles for divergent mesolimbic dopamine circuits in the control of responding to a discrete cue for alcohol and in the amplification of this behaviour in an alcohol context.


Assuntos
Transtornos Relacionados ao Uso de Álcool/psicologia , Dopamina/metabolismo , Etanol/administração & dosagem , Extinção Psicológica/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Sinais (Psicologia) , Modelos Animais de Doenças , Antagonistas de Dopamina/administração & dosagem , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Comportamento de Procura de Droga/efeitos dos fármacos , Comportamento de Procura de Droga/fisiologia , Extinção Psicológica/efeitos dos fármacos , Feminino , Humanos , Masculino , Ratos , Salicilamidas/administração & dosagem , Técnicas Estereotáxicas , Área Tegmentar Ventral/citologia
4.
Life Sci ; 256: 118014, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32593712

RESUMO

The age and strength of fear memory are two potential parameters that can be influenced by the impairing effects of pharmacological agents on reconsolidation of fear memory. In reconsolidation, stored information is rendered labile again after being reactivated. Pharmacological manipulations at this stage result in an inability to retrieve the fear memories, suggesting that they are erased or persistently inhibited. This fear memory impairment phenomenon can be valuable to treat post-traumatic stress disorders (PTSD). Previously ß-adrenergic antagonist propranolol has been repeatedly reported to impair fear memory in the treatment of PTSD. Atropine has also shown to disrupt memory formation. The present study was therefore designed to compare the effects of atropine and propranolol on reconsolidation of older fear memory in rat model of PTSD using Pavlovian fear conditioning apparatus. For this purpose 18 rats were taken and divided into control, atropine and propranolol groups and subjected to Pavlovian fear conditioning trials in order to develop animal model of PTSD. To evaluate the reconsolidation impairment of fear memory by atropine and propranolol, short term and long term memory was tested after reactivation of fear memory in rats. The present findings demonstrate that atropine significantly decreases fear expression. These results suggest that atropine significantly reduces the strength of fear memories and may be effective in the treatment of psychiatric disorders especially in PTSD.


Assuntos
Atropina/farmacologia , Medo/efeitos dos fármacos , Propranolol/farmacologia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Antagonistas Adrenérgicos beta/farmacologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Memória/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Ratos , Ratos Wistar , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/metabolismo , Transtornos de Estresse Pós-Traumáticos/fisiopatologia
5.
Psychopharmacology (Berl) ; 237(7): 2161-2172, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32363439

RESUMO

The ability to discriminate between danger and safety is crucial for survival across species. Whereas danger signals predict the onset of a potentially threatening event, safety signals indicate the non-occurrence of an aversive event, thereby reducing fear and stress responses. While the neural basis of conditioned safety remains to be elucidated, fear extinction studies provide evidence that the infralimbic cortex (IL) modulates fear inhibition. In the current study, the IL was temporarily inactivated with local muscimol injections in male and female rats. The effect of IL inactivation on the acquisition and expression of conditioned safety was investigated utilizing the startle response. Temporary inactivation of the IL prior to conditioning did not affect the acquisition of conditioned safety, whereas IL inactivation during the expression test completely blocked the expression of conditioned safety in male and female rats. Inactivation of the neighboring prelimbic (PL) cortex during the expression test did not affect the expression of safety memory. Our findings suggest that the IL is a critical brain region for the expression of safety memory. Because patients suffering from anxiety disorders are often unable to make use of safety cues to inhibit fear, the present findings are of clinical relevance and could potentially contribute to therapy optimization of anxiety-related psychiatric disorders.


Assuntos
Condicionamento Clássico/fisiologia , Medo/fisiologia , Inibição Psicológica , Memória/fisiologia , Córtex Pré-Frontal/metabolismo , Reflexo de Sobressalto/fisiologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Medo/psicologia , Feminino , Agonistas de Receptores de GABA-A/farmacologia , Masculino , Memória/efeitos dos fármacos , Muscimol/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacos
6.
PLoS One ; 15(3): e0229692, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32191722

RESUMO

It has been demonstrated that secretion of several hormones can be classically conditioned, however, the underlying brain responses of such conditioning have never been investigated before. In this study we aimed to investigate how oxytocin administration and classically conditioned oxytocin influence brain responses. In total, 88 females were allocated to one of three groups: oxytocin administration, conditioned oxytocin, or placebo, and underwent an experiment consisting of three acquisition and three evocation days. Participants in the conditioned group received 24 IU of oxytocin together with a conditioned stimulus (CS) during three acquisition days and placebo with the CS on three evocation days. The oxytocin administration group received 24 IU of oxytocin and the placebo group received placebo during all days. On the last evocation day, fMRI scanning was performed for all participants during three tasks previously shown to be affected by oxytocin: presentation of emotional faces, crying baby sounds and heat pain. Region of interest analysis revealed that there was significantly lower activation in the right amygdala and in two clusters in the left superior temporal gyrus in the oxytocin administration group compared to the placebo group in response to observing fearful faces. The activation in the conditioned oxytocin group was in between the other two groups for these clusters but did not significantly differ from either group. No group differences were found in the other tasks. Preliminary evidence was found for brain activation of a conditioned oxytocin response; however, despite this trend in the expected direction, the conditioned group did not significantly differ from other groups. Future research should, therefore, investigate the optimal timing of conditioned endocrine responses and study whether the findings generalize to other hormones as well.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Ocitocina/administração & dosagem , Ocitocina/fisiologia , Estimulação Acústica , Choro , Expressão Facial , Feminino , Neuroimagem Funcional , Humanos , Imagem por Ressonância Magnética , Sprays Nasais , Percepção da Dor/efeitos dos fármacos , Percepção da Dor/fisiologia , Estimulação Luminosa , Saliva/metabolismo , Método Simples-Cego , Adulto Jovem
7.
Nature ; 579(7800): 555-560, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32214250

RESUMO

Dopamine D2 receptors (D2Rs) are densely expressed in the striatum and have been linked to neuropsychiatric disorders such as schizophrenia1,2. High-affinity binding of dopamine suggests that D2Rs detect transient reductions in dopamine concentration (the dopamine dip) during punishment learning3-5. However, the nature and cellular basis of D2R-dependent behaviour are unclear. Here we show that tone reward conditioning induces marked stimulus generalization in a manner that depends on dopamine D1 receptors (D1Rs) in the nucleus accumbens (NAc) of mice, and that discrimination learning refines the conditioning using a dopamine dip. In NAc slices, a narrow dopamine dip (as short as 0.4 s) was detected by D2Rs to disinhibit adenosine A2A receptor (A2AR)-mediated enlargement of dendritic spines in D2R-expressing spiny projection neurons (D2-SPNs). Plasticity-related signalling by Ca2+/calmodulin-dependent protein kinase II and A2ARs in the NAc was required for discrimination learning. By contrast, extinction learning did not involve dopamine dips or D2-SPNs. Treatment with methamphetamine, which dysregulates dopamine signalling, impaired discrimination learning and spine enlargement, and these impairments were reversed by a D2R antagonist. Our data show that D2Rs refine the generalized reward learning mediated by D1Rs.


Assuntos
Espinhas Dendríticas/fisiologia , Aprendizagem por Discriminação/fisiologia , Receptores de Dopamina D2/metabolismo , Animais , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Condicionamento Clássico/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Dopamina/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Extinção Psicológica/efeitos dos fármacos , Masculino , Metanfetamina/antagonistas & inibidores , Metanfetamina/farmacologia , Camundongos , Plasticidade Neuronal , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Optogenética , Receptor A2A de Adenosina/metabolismo , Receptores de Dopamina D1/metabolismo , Recompensa , Transdução de Sinais/efeitos dos fármacos , Sinapses/metabolismo
8.
Behav Pharmacol ; 31(2&3): 196-206, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32040018

RESUMO

Relapsing to drugs of abuse is a challenging problem in treatment of addiction and stress is believed to be a major risk factor in relapse to drugs. The hippocampus region and dopamine signaling play a critical role in reward-related behaviors. The purpose of this study is to identify the involvement of D1- and D2-like receptors in the CA1 region of hippocampus in the reinstatement induced by a combination of food deprivation stress and a sub-threshold dose of morphine in extinguished morphine-conditioning place preference in rats. Adult male rats treated with one specific doses of SCH-23390 or sulpiride (0.5, 2 and 4 µg/0.5 µl vehicle/side) as D1- and D2-like receptors antagonists into the CA1 in separate groups, following the conditioning and extinction phase of morphine-conditioning place preference, before initiating the food deprivation stress on the last day of extinction. Then, the food deprived animals examined for reinstatement by injection of the sub-threshold dose of morphine (0.5 mg/kg, s.c.) on reinstatement day. Conditioning place preference scores and locomotor activities were recorded during test. Our results showed that combination of food deprivation stress and a sub-threshold dose of morphine induced the reinstatement of morphine-conditioning place preference. The induced reinstatement was decreased by two higher doses of SCH-23390 (2 and 4 µg/0.5 µl vehicle/side). However, the sulpiride (0.5, 2 and 4 µg/0.5 µl vehicle/side) could not reduce the reinstatement. Results showed that the role of D1-like receptor in the CA1 region was more prominent than D2-like receptor in reinstatement induced by food deprivation stress and re-exposure to morphine. Therefore the D1-like receptor in the CA1 might be a potential therapeutic target for treatment of opiate addiction.


Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Animais , Benzazepinas/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Privação de Alimentos , Hipocampo/efeitos dos fármacos , Masculino , Morfina/farmacologia , Entorpecentes/farmacologia , Ratos , Ratos Wistar , Receptores de Dopamina D2/metabolismo , Sulpirida/farmacologia
9.
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
10.
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
11.
Psychopharmacology (Berl) ; 237(4): 1043-1053, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31912191

RESUMO

RATIONALE AND OBJECTIVE: Alcohol is a recreational substance that is generally socially acceptable and legal in most areas worldwide. An alcohol overdose will produce an inhibitory effect on the brain and impair cognition and memory. In this study, we examined the effect of alcohol on the acquisition, consolidation, and reconsolidation of drug reward memory induced by morphine and cocaine in rats. METHODS: Rats were trained to acquire morphine sulfate (10 mg/kg, s.c.) and cocaine (10 mg/kg, i.p.) conditioned place preference (CPP) via an unbiased CPP paradigm. Vehicle or alcohol (0.25, 0.75, 1.5 g/kg, i.p.) was administered at various time-points, including 30 min before each CPP conditioning session (acquisition), immediately after each CPP conditioning session (consolidation), immediately after the reactivation of CPP (reconsolidation with re-exposure), or without reactivation to the drug-paired context (reconsolidation without re-exposure). Conditioning scores were recorded before or after each conditioning session or memory reactivation. RESULTS: Alcohol at a dose of 1.5 g/kg but not 0.25 g/kg or 0.75 g/kg significantly inhibited the acquisition and reconsolidation of morphine- and cocaine-associated memory. In contrast, alcohol had no effect on the consolidation of morphine- or cocaine-induced CPP. CONCLUSIONS: The results suggested that pre-exposure alcohol dose-dependently attenuated morphine- or cocaine-induced place preference and prevented drug reinstatement in rats by disrupting memory reconsolidation, which may be explained by the inhibitory effect of alcohol on dopaminergic and glutamatergic neurotransmission.


Assuntos
Cocaína/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Etanol/farmacologia , Memória/efeitos dos fármacos , Morfina/farmacologia , Recompensa , Animais , Condicionamento Clássico/fisiologia , Relação Dose-Resposta a Droga , Injeções Intraperitoneais , Masculino , Memória/fisiologia , Ratos , Ratos Sprague-Dawley
12.
Psychopharmacology (Berl) ; 237(5): 1291-1303, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31984445

RESUMO

RATIONALE AND OBJECTIVE: The aim of this study was to investigate the possible facilitating effect of the partial NMDA receptor agonist D-cycloserine (DCS) on memory consolidation of conditioned sexual responses and to examine the capability of DCS to reduce context-specificity of learning. METHODS: In a randomized placebo-controlled double-blind trial, 50 healthy females were exposed to a differential conditioning procedure. Two pictures of a male abdomen were used as conditional stimuli (CSs), of which one (the CS+) was followed by the unconditional stimulus (US), a genital vibrotactile stimulus. After the conditioning session on day 1, participants received either 125 mg of DCS or a placebo. The effects of DCS on affect, sexual arousal and US expectancy in response to the CS+ and CS- were examined 24 h after the conditioning procedure. RESULTS: A main effect of DCS was found on affect at the first test trials (p = 0.04, ηp2 = 0.09), and a similar non-significant but trend level effect was found for sexual arousal (p = 0.06, ηp2 = 0.07), which appeared to persist over a longer time (p = 0.07, ηp2 = 0.08). Unexpectedly, ratings of positive affect and sexual arousal in response to both the CS+ and the CS- were higher in the DCS condition compared to the control condition, possibly indicating that DCS administration reduced stimulus specificity. Since the results did not show clear evidence for context learning, we were not able to test effects on context-specificity of learning. CONCLUSION: Although largely inconclusive, the results provide tentative support for a facilitating effect of DCS on affect and sexual arousal in response to stimuli that were presented in a sexual conditioning procedure, however, no conclusions can be drawn about effects of DCS on sexual reward learning, since the design and results do not lend themselves to unambiguous interpretation.


Assuntos
Condicionamento Clássico/efeitos dos fármacos , Ciclosserina/farmacologia , Consolidação da Memória/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/agonistas , Comportamento Sexual/efeitos dos fármacos , Comportamento Sexual/psicologia , Adulto , Clitóris/efeitos dos fármacos , Clitóris/fisiologia , Condicionamento Clássico/fisiologia , Método Duplo-Cego , Emoções/efeitos dos fármacos , Emoções/fisiologia , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Feminino , Humanos , Masculino , Consolidação da Memória/fisiologia , Estimulação Luminosa/métodos , Recompensa , Comportamento Sexual/fisiologia , Vibração , Adulto Jovem
13.
Psychopharmacology (Berl) ; 237(5): 1249-1266, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31980843

RESUMO

BACKGROUND: Pavlovian stimuli can influence instrumental behaviors via phenomena such as Pavlovian-to-instrumental transfer (PIT). PIT arises via dissociable processes as sensory-specific PIT (SS-PIT) and general PIT. The basolateral amygdala (BLA) mediates SS-PIT, but not general PIT. However, the specific BLA neuronal populations involved are unknown. AIMS: To determine the contribution of glutamatergic BLA neurons to the expression of SS-PIT and to the recall of sensory-specific properties of stimulus-outcome associations. METHODS: BLA neurons were transduced with virus containing either GFP or hM4Di, driven by the CamKII promoter. Rats were then tested for SS and general PIT and subsequently for expression of Pavlovian outcome devaluation effects and conditioned taste aversion following injections of vehicle or clozapine-N-oxide (CNO, the hM4Di agonist). RESULTS: CNO selectively blocked SS-PIT in the hM4Di-expressing group, but not controls, without altering expression of Pavlovian outcome devaluation or sensory-specific taste aversion in either group. Unexpectedly, CNO disrupted general PIT in both groups. CONCLUSIONS: CamKII BLA neurons mediate the expression of SS-PIT by enabling Pavlovian stimuli to trigger recall of the correct action-outcome associations rather than by mediating recall of the sensory-specific properties of the stimulus-outcome association. Separately, our data demonstrate that CNO alone is sufficient to disrupt affective, but not sensory-specific processes, an effect that was not due to generalized motor disruption. This non-specific effect on general PIT may be related to CNO-induced shifts in internal state. Together, these data identify BLA CamKII neurons as critical for the expression of SS-PIT and reveal important considerations for using CNO to study general affective motivation.


Assuntos
Complexo Nuclear Basolateral da Amígdala/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Clozapina/análogos & derivados , Condicionamento Clássico/fisiologia , Neurônios/metabolismo , Piperazinas/metabolismo , Animais , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Clozapina/administração & dosagem , Condicionamento Clássico/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Comportamento Alimentar/psicologia , Feminino , Masculino , Motivação/efeitos dos fármacos , Motivação/fisiologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
14.
Behav Neurosci ; 134(2): 144-152, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31916795

RESUMO

Several studies suggest that the perirhinal cortex (PER) may function to unitize stimulus components across time or modalities. While the PER has been shown to be critical for fear acquisition to discontinuous stimuli, the role of the PER in fear extinction memory has not been evaluated. The current study assessed the involvement of the PER during fear extinction training to a continuous or discontinuous conditioned stimulus (CS). Rats were randomly assigned to 1 of 4 groups based on 2 factors: the CS type (a continuous or discontinuous light) and a pretesting PER manipulation (muscimol inactivation or saline). Results showed that PER inactivation impaired fear memory to both CS types; however, PER inactivation had only impaired extinction memory to the discontinuous light. These results suggest the role of the PER in stimulus unitization extends to supporting the acquisition of fear extinction memory. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


Assuntos
Condicionamento Clássico , Extinção Psicológica/fisiologia , Medo/fisiologia , Rememoração Mental/fisiologia , Córtex Perirrinal/fisiologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Agonistas de Receptores de GABA-A/administração & dosagem , Masculino , Rememoração Mental/efeitos dos fármacos , Muscimol/administração & dosagem , Córtex Perirrinal/efeitos dos fármacos , Estimulação Luminosa , Ratos Sprague-Dawley , Percepção Visual/efeitos dos fármacos
15.
J Neurosci ; 40(4): 907-916, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31801809

RESUMO

Stress impairs extinction learning, and these deficits depend, in part, on stress-induced norepinephrine (NE) release in the basolateral amygdala (BLA). For example, systemic or intra-BLA administration of propranolol reduces the immediate extinction deficit (IED), an impairment in extinction learning that occurs when extinction trials are administered soon after fear conditioning. Here, we explored whether locus coeruleus (LC)-NE regulates stress-induced changes in spike firing in the BLA and consequent extinction learning impairments. Rats were implanted with recording arrays in the BLA and, after recovery from surgery, underwent a standard auditory fear conditioning procedure. Fear conditioning produced an immediate and dramatic increase in the spontaneous firing of BLA neurons that persisted (and in some units, increased further) up to an hour after conditioning. This stress-induced increase in BLA firing was prevented by systemic administration of propranolol. Conditioning with a weaker footshock caused smaller increases in BLA firing rate, but this could be augmented by chemogenetic activation of the LC. Conditioned freezing in response to a tone paired with a weak footshock was immune to the IED, but chemogenetic activation of the LC before the weak conditioning protocol increased conditioned freezing behavior and induced an IED; this effect was blocked with intra-BLA infusions of propranolol. These data suggest that stress-induced activation of the LC increases BLA spike firing and causes impairments in extinction learning. Stress-induced increases in BLA activity mediated by LC-NE may be a viable therapeutic target for individuals with stress- and trauma-related disorders.SIGNIFICANCE STATEMENT Patients with post-traumatic stress disorder (PTSD) show heightened amygdala activity; elevated levels of stress hormones, including norepinephrine; and are resistant to the extinction of fear memories. Here, we show that stress increases basolateral amygdala (BLA) spike firing. This could be attenuated by systemic propranolol and mimicked by chemogenetic activation of the locus coeruleus (LC), the source of forebrain norepinephrine (NE). Finally, we show that LC-NE activation is sufficient to produce extinction deficits, and this is blocked by intra-BLA propranolol. Stress-induced increases in BLA activity mediated by LC-NE may be a viable therapeutic target for individuals with PTSD and related disorders.


Assuntos
Potenciais de Ação/fisiologia , Complexo Nuclear Basolateral da Amígdala/fisiologia , Condicionamento Clássico/fisiologia , Extinção Psicológica/fisiologia , Aprendizagem/fisiologia , Locus Cerúleo/fisiologia , Neurônios/fisiologia , Potenciais de Ação/efeitos dos fármacos , Antagonistas Adrenérgicos beta/farmacologia , Animais , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Locus Cerúleo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Propranolol/farmacologia , Ratos
16.
Psychopharmacology (Berl) ; 237(2): 557-570, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31740992

RESUMO

RATIONAL: Morphine is one of the most well-known and potent analgesic agents; however, it can also induce various side effects. Thus, finding drugs and mechanisms which can potentiate the analgesic effects of low doses of morphine will be a good strategy for pain management. OBJECTIVE: The involvement of µ-opioid receptors and ventral tegmental area (VTA) glutamatergic system in harmaline and morphine combination on the nociceptive response were investigated. Also, we examined reward efficacy and tolerance expression following the drugs. METHODS: Animals were bilaterally cannulated in the VTA by stereotaxic instrument. A tail-flick (TF) apparatus and conditioned place preference (CPP) paradigm were used to measure nociceptive response and rewarding effects in male NMRI mice respectively. RESULTS: Morphine (2 mg/kg, i.p.) had no effect in TF test. Also, harmaline (1.25 and 5 mg/kg, i.p.) could not change pain threshold. Combination of a non-effective dose of harmaline (5 mg/kg) and morphine (2 mg/kg) produced antinociception and also prevented morphine tolerance but had no effect on the acquisition of CPP. Systemic administration of naloxone (0.5 and 1 mg/kg) and intra-VTA microinjection of NMDA (0.06 and 0.1 µg/mouse) before harmaline (5 mg/kg) plus morphine (2 mg/kg) prevented antinociception induced by the drugs. D-AP5 (0.5 and 1 µg/mouse, intra-VTA) potentiated the effect of low-dose harmaline (1.25 mg/kg) and morphine (2 mg/kg) and induced antinociception. Microinjection of the same doses of NMDA or D-AP5 into the VTA alone had no effect on pain threshold. CONCLUSION: The findings showed that harmaline potentiated the analgesic effect of morphine and reduced morphine tolerance. Glutamatergic and µ-opioidergic system interactions in the VTA seem to have a modulatory role in harmaline plus morphine-induced analgesia.


Assuntos
Harmalina/administração & dosagem , Morfina/administração & dosagem , Medição da Dor/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/agonistas , Receptores Opioides mu/agonistas , Área Tegmentar Ventral/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Animais , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Relação Dose-Resposta a Droga , Injeções Intraventriculares , Masculino , Camundongos , Medição da Dor/métodos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/fisiologia , Área Tegmentar Ventral/fisiologia
17.
Psychopharmacology (Berl) ; 237(3): 707-721, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31786650

RESUMO

RATIONALE: During the last few decades, alcohol use disorders (AUD) have reached an epidemic prevalence, yet social influences on alcoholism have not been fully addressed. Several factors can modulate alcohol intake. On one hand, stress can reinforce ethanol-induced behaviors and be an important component in AUD and alcoholism. On the other hand, environmental enrichment (EE) has a neuroprotective role and prevents the development of excessive ethanol intake in rodents. However, studies showing the role of EE in chronic psychosocial stress-impaired ethanol-conditioned rewards are nonexistent. AIM: The purpose of the current study is to explore the potential protective role of EE on extinction and reinstatement of ethanol-conditioned place preference (EtOH-CPP) following chronic psychosocial stress. METHODS: In the first experiment and after the EtOH-CPP test, the mice were subjected to 15 days of chronic stress, then housed in a standard (SE) or enriched environment (EE) while EtOH-CPP extinction was achieved by repeated exposure to the CPP chambers without ethanol injection. In the second experiment and after the EtOH-CPP test, extinction was achieved as described above. Mice were then exposed to chronic stress for 2 weeks before being housed in a SE or EE. EtOH-CPP reinstatement was induced by a single exposure to the conditioning chambers. RESULTS: As expected, stress exposure increased anxiety-like behavior and reduced weight gain. More importantly, we found that EE significantly shortened chronic stress-delayed extinction and decreased the reinstatement of EtOH-CPP. CONCLUSION: These results support the hypothesis that EE reduces the impact of alcohol-associated environmental stimuli, and hence it may be a general intervention for reducing cue-elicited craving and relapse in humans.


Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Condicionamento Psicológico/efeitos dos fármacos , Meio Ambiente , Etanol/administração & dosagem , Extinção Psicológica/efeitos dos fármacos , Estresse Psicológico/psicologia , Consumo de Bebidas Alcoólicas/terapia , Animais , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Condicionamento Psicológico/fisiologia , Extinção Psicológica/fisiologia , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reforço Psicológico , Recompensa , Estresse Psicológico/terapia
18.
Dev Psychobiol ; 62(3): 380-385, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31621064

RESUMO

The ontogeny and NMDA-receptor (NMDAR) mechanisms of context conditioning were examined during standard contextual fear conditioning (sCFC) - involving context and context-shock learning in the same trial - as a comparison with our previous reports on the Context Preexposure Facilitation Effect (CPFE), which separates these two types of learning by 24 hr. In Experiment 1, systemic administration of the NMDAR antagonist, MK-801, prior to conditioning disrupted retention but not post-shock freezing during sCFC in PD31 rats. Experiment 2 replicated and extended this effect to PD17 versus PD31 rats. Consistent with Experiment 1, pre-training MK-801 spared post-shock freezing but impaired retention freezing in PD31 rats. In contrast, pre-training MK-801 disrupted post-shock freezing in PD17 rats, which showed no retention freezing regardless of drug. These results reveal developmental differences in the role of NMDAR activity in the acquisition versus retention of a context-shock association during sCFC in pre-weanling and adolescent rats.


Assuntos
Comportamento Animal/fisiologia , Condicionamento Clássico/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Medo/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Retenção Psicológica/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Medo/efeitos dos fármacos , Feminino , Reação de Congelamento Cataléptica/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Masculino , Ratos , Ratos Long-Evans , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Retenção Psicológica/efeitos dos fármacos
19.
Psychopharmacology (Berl) ; 237(2): 385-394, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31667531

RESUMO

RATIONALE: Cocaine is a psychostimulant drug that facilitates monoaminergic neurotransmission. The endocannabinoid system, comprising the cannabinoid receptors (CB1R and CB2R), the endocannabinoids, and their metabolizing-enzymes, modulates the mesolimbic dopaminergic pathway and represents a potential target for the treatment of addiction. OBJECTIVES: Here, we tested the hypothesis that the cannabinoid receptors are implicated in cocaine-induced motor sensitization, conditioned place preference (CPP), and hippocampal activation. METHODS: Male Swiss mice received injections of AM251 (CB1R antagonist; 0.3-10 mg/kg) or JWH133 (CB2R agonist; 1-10 mg/kg) before acquisition or expression of cocaine (20 mg/kg)-induced sensitization and CPP. After the CPP test, cFos-staining was employed as a marker of neuronal activation in the hippocampus. RESULTS: AM251 inhibited the acquisition (0.3, 1, and 3 mg/kg) and expression (1 and 3 mg/kg) of sensitization, as well as the acquisition (10 mg/kg) of CPP. JWH133 inhibited the acquisition (0.3 and 1 mg/kg) and expression (1 and 3 mg/kg) of both sensitization and CPP. JWH133 effects were reversed by AM630 (CB2R antagonist; 5 mg/kg). AM251 and JWH133 also prevented neuronal activation (c-Fos expression) in the hippocampus of CPP-exposed animals. CONCLUSIONS: CB1R and CB2R have opposite roles in modulating cocaine-induced sensitization and CPP, possibly by preventing neuronal activation in the hippocampus.


Assuntos
Cocaína/farmacologia , Condicionamento Clássico/fisiologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/fisiologia , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/fisiologia , Animais , Canabinoides/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Camundongos , Piperidinas/farmacologia , Pirazóis/farmacologia
20.
Psychopharmacology (Berl) ; 237(1): 93-102, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31422429

RESUMO

INTRODUCTION: Placebo effects in human clinical trials for depression treatment are robust and often comparable to drug effects. Placebo effects are traditionally difficult to study in rodents due to the slow-onset action of classical antidepressant drugs. We hypothesized that the rapid antidepressant actions of ketamine would allow modeling antidepressant placebo effects in rodents. METHODS: Male and female CD-1 mice received either ketamine or saline injections with concomitant exposure to specific environmental conditioning stimuli, for a total of three drug/conditioning sessions each 2 weeks apart. Two weeks later, during an evocation phase, mice were exposed to the drug-paired conditioning stimuli or no conditioned stimuli followed by testing for motor stimulatory actions and antidepressant-like effects using the forced swim test. Negative (no ketamine administration at any time) and positive (acute ketamine administration prior to evocation testing) control groups were included as comparators. RESULTS: Both male and female mice exhibited increased locomotor activity following ketamine administration during the conditioning phase, which was not observed following exposure to the conditioning stimuli. Exposure to the conditioning stimuli previously paired with ketamine, similar to an acute ketamine administration, reduced immobility time in the forced swim test both 1 and 24 h after administration in male, but not female, mice. CONCLUSIONS: These results represent the first evidence of antidepressant-like placebo-conditioned effects in an animal model. The developed approach can be used as a model to explore the neurobiological mechanisms of placebo effects, their possible sexually dimorphic effects, and relevance to mechanisms underlying antidepressant action.


Assuntos
Antidepressivos/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Transtorno Depressivo/tratamento farmacológico , Ketamina/farmacologia , Animais , Antidepressivos/uso terapêutico , Modelos Animais de Doenças , Feminino , Ketamina/uso terapêutico , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Efeito Placebo , Natação
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