RESUMO
BACKGROUND: The neurotransmitter dopamine plays an important role in the processing of emotional memories, and prior research suggests that dopaminergic manipulations immediately after fear learning can affect the retention and generalization of acquired fear. AIMS: The current study focuses specifically on the role of dopamine D2 receptors (D2Rs) regarding fear generalization in adult, male Wistar rats, and aims to replicate previous findings in mice. METHODS: In a series of five experiments, D2R (ant)agonists were injected systemically, immediately after differential cued fear conditioning (CS+ followed by shock, CS- without shock). All five experiments involved the administration of the D2R agonist quinpirole at different doses versus saline (n = 12, 16, or 44 rats/group). In addition, one of the studies administered the D2R antagonist raclopride (n = 12). One day later, freezing during the CS+ and CS- was assessed. RESULTS: We found no indications for an effect of quinpirole or raclopride on fear generalization during this drug-free test. Importantly, and contradicting earlier research in mice, the evidence for the absence of an effect of D2R agonist quinpirole (1 mg/kg) on fear generalization was substantial according to Bayesian analyses and was observed in a highly powered experiment (N = 87). We did find acute behavioral effects in line with the literature, for both quinpirole and raclopride in a locomotor activity test. CONCLUSION: In contrast with prior studies in mice, we have obtained evidence against a preventative effect of post-training D2R agonist quinpirole administration on subsequent fear generalization in rats.
Assuntos
Condicionamento Clássico , Agonistas de Dopamina , Medo , Generalização Psicológica , Quimpirol , Racloprida , Ratos Wistar , Receptores de Dopamina D2 , Animais , Medo/efeitos dos fármacos , Masculino , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Quimpirol/farmacologia , Agonistas de Dopamina/farmacologia , Ratos , Generalização Psicológica/efeitos dos fármacos , Racloprida/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologiaRESUMO
Labilization-reconsolidation, which relies on retrieval, has been considered an opportunity to attenuate the negative aspects of traumatic memories. A therapeutic strategy based on reconsolidation blockade is deemed more effective than current therapies relying on memory extinction. Nevertheless, extremely stressful memories frequently prove resistant to this process. Here, after inducing robust fear memory in mice through strong fear conditioning, we examined the possibility of rendering it susceptible to pharmacological modulation based on the degree of generalized fear (GF). To achieve this, we established an ordered gradient of GF, determined by the perceptual similarity between the associated context (CA) and non-associated contexts (CB, CC, CD, and CE) to the aversive event. We observed that as the exposure context became less similar to CA, the defensive pattern shifted from passive to active behaviors in both male and female mice. Subsequently, in conditioned animals, we administered propranolol after exposure to the different contexts (CA, CB, CC, CD or CE). In males, propranolol treatment resulted in reduced freezing time and enhanced risk assessment behaviors when administered following exposure to CA or CB, but not after CC, CD, or CE, compared to the control group. In females, a similar change in behavioral pattern was observed with propranolol administered after exposure to CC, but not after the other contexts. These results highlight the possibility of indirectly manipulating a robust contextual fear memory by controlling the level of generalization during recall. Additionally, it was demonstrated that the effect of propranolol on reconsolidation would not lead to a reduction in fear memory per se, but rather to its reorganization resulting in greater behavioral flexibility (from passive to active behaviors). Finally, from a clinical viewpoint, this would be of considerable relevance since following this strategy could make the treatment of psychiatric disorders associated with traumatic memory formation more effective and less stressful.
Assuntos
Condicionamento Clássico , Medo , Propranolol , Medo/efeitos dos fármacos , Medo/fisiologia , Animais , Masculino , Propranolol/farmacologia , Feminino , Camundongos , Condicionamento Clássico/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , Consolidação da Memória/fisiologia , Camundongos Endogâmicos C57BL , Memória/efeitos dos fármacos , Memória/fisiologia , Generalização Psicológica/efeitos dos fármacos , Generalização Psicológica/fisiologia , Extinção Psicológica/efeitos dos fármacosRESUMO
INTRODUCTION: Interoceptive stimuli elicited by drug administration acquire conditioned modulatory properties of the induction of conditioned appetitive behaviours by exteroceptive cues. This effect may be modeled using a drug discrimination task in which the drug stimulus is trained as a positive-feature (FP) occasion setter (OS) that disambiguates the relation between an exteroceptive light conditioned stimulus (CS) and a sucrose unconditioned stimulus (US). We previously reported that females are less sensitive to generalization of a FP morphine OS than males, so we investigated the role of endogenous ovarian hormones in this difference. METHODS: Male and female rats received intermixed injections of 3.2 mg/kg morphine or saline before each daily training session. Training consisted of 8 presentations of the CS, each followed by access to sucrose on morphine, but not saline sessions. Following acquisiton, rats were tested for generalization of the morphine stimulus to 0, 1.0, 3.2, and 5.4 mg/kg morphine. Female rats were monitored for estrous cyclicity using vaginal cytology throughout the study. RESULTS: Both sexes acquired stable drug discrimination. A gradient of generalization was measured across morphine doses and this behaviour did not differ by sex, nor did it differ across the estrous cycle in females. CONCLUSIONS: Morphine generalization is independent of fluctuations in levels of sex and endogenous gonadal hormones in females under these experimental conditions.
Assuntos
Ciclo Estral , Morfina , Animais , Feminino , Masculino , Ciclo Estral/fisiologia , Ciclo Estral/efeitos dos fármacos , Morfina/farmacologia , Ratos , Generalização Psicológica/efeitos dos fármacos , Generalização Psicológica/fisiologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Ratos Sprague-Dawley , Interocepção/fisiologia , Interocepção/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Aprendizagem por Discriminação/fisiologiaRESUMO
Stressful and emotionally arousing experiences create strong memories that seem to lose specificity over time. It is uncertain, however, how the stress system contributes to the phenomenon of time-dependent fear generalization. Here, we investigated whether post-training corticosterone (CORT-HBC) injections, given after different training intensities, affect contextual fear memory specificity at several time points. We trained male Wistar rats on the contextual fear conditioning (CFC) task using two footshock intensities (mild CFC, 3 footshocks of 0.3 mA, or moderate CFC, 3x 0.6 mA) and immediately after the training session we administered CORT-HBC systemically. We first tested the animals in a novel context and then in the training context at different intervals following training (2, 14, 28 or 42 days). By measuring freezing in the novel context and then contrasting freezing times shown in both contexts, we inferred contextual fear generalization for each rat, classifying them into Generalizers or Discriminators. Following mild CFC training, the glucocorticoid injection promoted an accurate contextual memory at the recent time point (2 days), and increase the contextual memory accuracy 28 days after training. In contrast, after the moderate CFC training, CORT-HBC facilitated contextual generalization at 14 days, compared to the control group that maintained contextual discrimination at this timepoint. For this training intensity, however, CORT-HBC did not have any effect on recent memory specificity. These findings indicate that treatment with CORT-HBC immediately after the encoding of mild or moderately arousing experiences may differentially modulate memory consolidation and time-dependent fear generalization.
Assuntos
Condicionamento Clássico/efeitos dos fármacos , Corticosterona/farmacologia , Medo/efeitos dos fármacos , Generalização Psicológica/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Wistar , Fatores de TempoRESUMO
BACKGROUND: A previously acquired fear response often spreads to perceptually or conceptually close stimuli or contexts. This process, known as fear generalization, facilitates the avoidance of danger, and dysregulations in this process play an important role in anxiety disorders. Oxytocin (OT) has been shown to modulate fear learning, yet effects on fear generalization remain unknown. METHODS: We employed a randomized, placebo-controlled, double-blind, between-subject design during which healthy male participants received either intranasal OT or placebo (PLC) following fear acquisition and before fear generalization with concomitant acquisition of skin conductance responses (SCRs). Twenty-four to 72 h before the fear learning and immediately after the fear generalization task, participants additionally complete a discrimination threshold task. RESULTS: Relative to PLC, OT significantly reduced perceived risk and SCRs towards the CS+ and GS1 (the generalization stimulus that is most similar to CS+) during fear generalization, whereas the discrimination threshold was not affected. CONCLUSIONS: Together, the results suggest that OT can attenuate fear generalization in the absence of effects on discrimination threshold. This study provides the first evidence for effects of OT on fear generalization in humans and suggests that OT may have therapeutic potential in anxiety disorders characterized by dysregulated fear generalization.
Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Discriminação Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Generalização Psicológica/efeitos dos fármacos , Ocitocina/farmacologia , Administração Intranasal , Adulto , Condicionamento Clássico/efeitos dos fármacos , Método Duplo-Cego , Reconhecimento Facial/efeitos dos fármacos , Medo/psicologia , Feminino , Humanos , Aprendizagem/efeitos dos fármacos , Masculino , Ocitocina/administração & dosagem , Adulto JovemRESUMO
BACKGROUND: While healthy individuals and patients with anxiety disorders easily generalize fear responses, extinction learning is more stimulus specific. Treatments aiming to generalize extinction learning are urgently needed, since they comprise the potential to overcome stimulus specificity and reduce relapses, particularly in the face of stressful events. METHODS: In the current 3-day functional magnetic resonance imaging fear conditioning paradigm, we aimed to create a generalized extinction memory trace in 60 healthy men and women by presenting multiple sizes of 1 conditioned stimulus during extinction training (CS+G; generalized), whereas the other conditioned stimulus was solely presented in its original size (CS+N; nongeneralized). Recall was tested on the third day after pharmacological administration of either the stress hormone cortisol or placebo. RESULTS: After successful fear acquisition, prolonged activation of the amygdala and insula and deactivation of the ventromedial prefrontal cortex for CS+G compared with CS+N during extinction learning indicated sustained fear to the generalization stimuli. In line with our hypotheses, reduced amygdala activation was observed after extinction generalization on the third day in the contrast CS+G minus CS+N, possibly reflecting an attenuated return of fear. Cortisol administration before recall, however, blocked this effect. CONCLUSIONS: Taken together, the findings show that extinction generalization was associated with decreased activation of the fear network during recall after prolonged activation of the fear network during extinction learning. However, the generalization of the extinction memory did not counteract the detrimental effects of stress hormones on recall. Thus, stimulus-based extinction generalization may not be sufficient to reduce relapses after stressful experiences.
Assuntos
Tonsila do Cerebelo/fisiologia , Condicionamento Clássico/fisiologia , Extinção Psicológica/fisiologia , Generalização Psicológica/fisiologia , Glucocorticoides/farmacologia , Hidrocortisona/farmacologia , Córtex Insular/fisiologia , Córtex Pré-Frontal/fisiologia , Adolescente , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Condicionamento Clássico/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/fisiologia , Feminino , Generalização Psicológica/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Humanos , Hidrocortisona/administração & dosagem , Córtex Insular/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Rememoração Mental/efeitos dos fármacos , Rememoração Mental/fisiologia , Rede Nervosa , Córtex Pré-Frontal/diagnóstico por imagem , Adulto JovemRESUMO
Memories remain dynamic after consolidation, and when reactivated, they can be rendered vulnerable to various pharmacological agents that disrupt the later expression of memory (i.e., amnesia). Such drug-induced post-reactivation amnesia has traditionally been studied in AAA experimental designs, where a memory is initially created for a stimulus A (be it a singular cue or a context) and later reactivated and tested through exposure to the exact same stimulus. Using a contextual fear conditioning procedure in rats and midazolam as amnestic agent, we recently demonstrated that drug-induced amnesia can also be obtained when memories are reactivated through exposure to a generalization stimulus (GS, context B) and later tested for that same generalization stimulus (ABB design). However, this amnestic intervention leaves fear expression intact when at test animals are instead presented with the original training stimulus (ABA design) or a novel generalization stimulus (ABC design). The underlying mechanisms of post-reactivation memory malleability and of MDZ-induced amnesia for a generalization context remain largely unknown. Here, we evaluated whether, like typical CS-mediated (or AAA) post-reactivation amnesia, GS-mediated (ABB) post-reactivation amnesia displays key features of a destabilization-based phenomenon. We first show that ABB post-reactivation amnesia is critically dependent on prediction error at the time of memory reactivation and provide evidence for its temporally graded nature. In line with the known role of GluN2B-NMDA receptor activation in memory destabilization, we further demonstrate that pre-reactivation administration of ifenprodil, a selective antagonist of GluN2B-NMDA receptors, prevents MDZ-induced ABB amnesia. In sum, our data reveal that ABB MDZ-induced post-reactivation amnesia exhibits the hallmark features of a destabilization-dependent phenomenon. Implication of our findings for a reconsolidation-based account of post-reactivation amnesia are discussed.
Assuntos
Rememoração Mental/efeitos dos fármacos , Midazolam/farmacologia , Retenção Psicológica/efeitos dos fármacos , Animais , Condicionamento Clássico/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/psicologia , Generalização Psicológica/efeitos dos fármacos , Masculino , Ratos , Ratos WistarRESUMO
The efficacy of pharmacological disruption of fear memory reconsolidation depends on several factors, including memory strength and age. We built on previous observations that systemic treatment with the nootropic nefiracetam potentiates cued fear memory destabilization to facilitate mifepristone-induced reconsolidation impairment. Here, we applied nefiratecam and mifepristone to strongly conditioned, 1-wk-old contextual fear memories in male rats. Unexpectedly, the combined treatment did not result in impairment of contextual fear expression. However, mifepristone did reduce freezing to a novel context. These observations suggest that strong and established contextual fear memories do undergo destabilization without the need for pharmacological facilitation, and that impairments in strong context fear memory reconsolidation can manifest as a reduction in generalization.
Assuntos
Medo/efeitos dos fármacos , Generalização Psicológica/efeitos dos fármacos , Memória/efeitos dos fármacos , Mifepristona/toxicidade , Nootrópicos/toxicidade , Animais , Condicionamento Psicológico/efeitos dos fármacos , Extinção Psicológica , Reação de Congelamento Cataléptica , Masculino , Pirrolidinonas/farmacologia , RatosRESUMO
Lesioning or inactivating the infralimbic (IL) subregion of the medial prefrontal cortex before acquisition produces more generalized and extinction-resistant fear memories. However, whether and how it modulates memory specificity and extinction susceptibility while consolidation takes place is still unknown. The present study aims to investigate these questions using muscimol-induced temporary inactivation and anisomycin-induced protein synthesis inhibition in the rat IL following contextual fear conditioning. Results indicate that the IL activity immediately after acquisition, but not six hours later, controls memory generalization over a week, regardless of its strength. Such IL function depends on the context-shock pairing since muscimol induced no changes in animals exposed to immediate shocks or the conditioning context only. Animals in which the IL was inactivated during consolidation extinguished similarly to controls within the session but were unable to recall the extinction memory the following day. Noteworthy, these post-acquisition IL inactivation-induced effects were not associated with changes in anxiety, as assessed in the elevated plus-maze test. Anisomycin results indicate that the IL protein synthesis during consolidation contributes more to producing extinction-sensitive fear memories than memory specificity. Collectively, present results provide evidence for the IL's role in controlling generalization and susceptibility to extinction during fear memory consolidation.
Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Generalização Psicológica/fisiologia , Lobo Límbico/fisiologia , Consolidação da Memória/fisiologia , Animais , Anisomicina/farmacologia , Condicionamento Clássico , Eletrodos Implantados , Generalização Psicológica/efeitos dos fármacos , Lobo Límbico/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Muscimol/farmacologia , Ratos , Ratos WistarRESUMO
RATIONALE: Studies point out a higher prevalence of posttraumatic stress disorder (PTSD) in individuals with diabetes mellitus. It is known that glucocorticoid (GR) and mineralocorticoid (MR) receptors are implicated in fear memory processes and PTSD. However, there is no preclinical studies addressing the involvement of these receptors on abnormal fear memories related to diabetic condition. OBJECTIVES: By inducing a contextual conditioned fear memory, we generate a suitable condition to investigate the extinction and the generalization of the fear memory in streptozotocin-induced diabetic (DBT) rats alongside the expression of the cytosolic and nuclear GR and MR in the hippocampus (HIP) and prefrontal cortex (PFC). Moreover, we investigated the involvement of the MR or GR on the acquisition of fear memory extinction and on the generalization of this fear memory. When appropriate, anxiety-related behavior was evaluated. METHODS: Male Wistar rats received one injection of steptozotocin (i.p.) to induce diabetes. After 4 weeks, the animals (DBTs and non-DBTs) were subjected to a conditioned contextual fear protocol. RESULTS: The expression of MR and GR in the HIP and PFC was similar among all the groups. The single injection of MR agonist was able to facilitate the acquisition of the impaired fear memory extinction in DBTs animals together with the impairment of its generalization. However, the GR antagonism impaired only the generalization of this fear memory which was blocked by the previous injection of the MR antagonist. All treatments were able to exert anxiolytic-like effects. CONCLUSIONS: The results indicate that MR activation in DBT animals disrupts the overconsolidation of aversive memory, without discarding the involvement of emotional behavior in these processes.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Extinção Psicológica/fisiologia , Medo/fisiologia , Generalização Psicológica/fisiologia , Memória/fisiologia , Receptores de Mineralocorticoides/metabolismo , Animais , Diabetes Mellitus Experimental/psicologia , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/psicologia , Fludrocortisona/farmacologia , Generalização Psicológica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Memória/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , Receptores de Mineralocorticoides/agonistasRESUMO
Exhibiting fear to non-threatening cues or contexts-generalized fear-is a shared characteristic of several anxiety disorders, which afflict women more than men. Female rats generalize contextual fear at a faster rate than males and this is due, in part, to actions of estradiol in the dorsal CA1 hippocampus (dCA1). To understand the mechanisms underlying estradiol's effects on generalization, we infused estradiol into the anterior cingulate cortex (ACC) or ventral CA1 hippocampus (vCA1) of ovariectomized (OVX) female rats. Estradiol acts within the ACC, but not the vCA1, to promote generalized fear. We next examined if AMPA or NMDA receptor antagonists (NBQX, APV) infused into the dCA1 or the ACC of female rats could block generalized fear induced by systemic injections of estradiol. Immediate pre-testing infusions of NBQX or APV into either region eliminated estradiol-induced generalization. Specific blockade of GluN2B receptors with infusions of Ro 25-6981 into the dCA1 or ACC also eliminated generalized fear. Our results suggest that in addition to the dCA1, the ACC is an important locus for the effects of estradiol on fear generalization. Moreover, within these regions, AMPA and NMDA-GluN2B receptors are necessary for estradiol-induced generalization of fear responses, suggesting a critical involvement of glutamatergic transmission. Furthermore, we identified a novel role for GluN2B in mediating the effects of estradiol on generalized fear in female rats. These data potentially implicate GluN2B receptors in more general forms of memory retrieval inaccuracies, and form the foundation for exploration of glutamate receptor pharmacology for treatments of anxiety disorders involving generalization.
Assuntos
Estradiol/metabolismo , Medo/fisiologia , Receptores de Glutamato/metabolismo , Animais , Região CA1 Hipocampal/metabolismo , Feminino , Generalização Psicológica/efeitos dos fármacos , Generalização Psicológica/fisiologia , Ácido Glutâmico/metabolismo , Ácido Glutâmico/fisiologia , Giro do Cíngulo/metabolismo , Hipocampo/metabolismo , Memória/fisiologia , Ovariectomia , Ratos , Ratos Long-Evans , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Fear memory overgeneralization contributes to the genesis and persistence of anxiety disorders and is a central hallmark in the pathophysiology of post-traumatic stress disorder (PTSD). Recent findings suggest that fear generalization is closely related to hippocampal dependency during retrieval. The selective serotonin reuptake inhibitor (SSRI) fluoxetine has been used as a first-line treatment for PTSD; however, how it exerts its therapeutic effect remains a matter of debate. Here, using contextual fear conditioning in rats, we show that chronic fluoxetine treatment prevents fear generalization and enhances subsequent extinction. Moreover, fluoxetine treatment after extinction prevents spontaneous recovery. The mechanism through which fluoxetine affects generalization and extinction seems to be through the postponement of systems consolidation, thereby maintaining hippocampal involvement during retrieval. Such an effect relies on a remodeling of dendritic spines in the hippocampus, as well as the number of mature, mushroom-type spines promoted by fluoxetine treatment. In order to further investigate whether fear generalization is a potential predictor of extinction effectiveness, we categorized a large naive population according to their generalization rate. We found that discriminator rats showed a better extinction profile compared to generalizers, suggesting that the generalization rate predicts extinction effectiveness. Hence, we propose that the therapeutic strategy of choice should take into account the extension of memory generalization, in which therapies based on extinction could induce a better outcome in patients who present less fear overgeneralization. These results open new avenues for the development of interventions that prevent fear generalization by maintaining memory dependency of the hippocampus.
Assuntos
Espinhas Dendríticas/efeitos dos fármacos , Medo/efeitos dos fármacos , Fluoxetina/administração & dosagem , Hipocampo/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Animais , Condicionamento Clássico , Espinhas Dendríticas/fisiologia , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Medo/fisiologia , Generalização Psicológica/efeitos dos fármacos , Generalização Psicológica/fisiologia , Hipocampo/fisiologia , Aprendizagem/fisiologia , Masculino , Consolidação da Memória/efeitos dos fármacos , Consolidação da Memória/fisiologia , Ratos WistarRESUMO
BACKGROUND: Fentanyl and its structurally related compounds have emerged as the most significant contributors to opioid overdose fatalities in recent years. While there is abundant information about the pharmacological effects of fentanyl, far less is known of its more recently abused analogs. The objective of this study was to determine whether fentanyl and several fentanyl-related substances would engender oxycodone-like responding in a mouse model of oxycodone discrimination. Oxycodone was selected as the training drug due to its high selectivity for mu opioid receptors. Compounds that elicited oxycodone-like responding in this procedure would likely evoke overlapping subjective experiences. METHODS: Adult male C57BL/6 mice were trained to discriminate 1.3â¯mg/kg oxycodone from vehicle in a food-reinforced, two-lever choice procedure. Generalization tests were conducted with fentanyl and the following fentanyl-related compounds: ocfentanil, 3-furanyl fentanyl, crotonylfentanyl, and valerylfentanyl. RESULTS: Fentanyl and each of its analogs completely generalized to the 1.3â¯mg/kg oxycodone discriminative stimulus and naltrexone pretreatment significantly decreased oxycodone-like responding for each compound. Rank order potency for engendering oxycodone-appropriate responding was ocfentanilâ¯>â¯fentanyl > 3-furanyl fentanylâ¯≈â¯crotonylfentanylâ¯>â¯oxycodoneâ¯>â¯valerylfentanyl. Drug doses that evoked full substitution also significantly suppressed response rates compared to vehicle. CONCLUSIONS: These results indicate that the discriminative stimulus, and by extension, the interoceptive and subjective effects of the tested fentanyl analogs, overlap with those of oxycodone. These observations consequentially support the prediction that they would also engender the likelihood for abuse similar to oxycodone. This article is part of the Special Issue entitled 'Opioid Neuropharmacology: Advances in treating pain and opioid addiction'.
Assuntos
Aprendizagem por Discriminação/efeitos dos fármacos , Fentanila/farmacologia , Generalização Psicológica/efeitos dos fármacos , Entorpecentes/farmacologia , Oxicodona/farmacologia , Animais , Fentanila/análogos & derivados , Furanos/farmacologia , Masculino , Camundongos , Piperidinas/farmacologiaRESUMO
Fear generalization is defined as the transferring of fear experienced during a traumatic event to safe conditions resembling or not the traumatic event. It has been related to several psychological disorders. Here we set out to determine whether novelty exposure can be effective to avoid fear generalization. We evaluated the effect of a novelty exposure on fear memory generalization using an aversive memory task, the inhibitory avoidance (IA). Male Wistar rats were trained in IA (day 1) and 24 h after (day 2) they were exposed to a new context similar to the original (modified IA - MIA), with some rats being exposed to a novelty just before the exposure to the MIA, while others were not (controls). On day 3, retention tests for IA and MIA contexts were performed. The control rats generalized the memory, expressing aversive behavioral in both contexts whereas rats exposed to novelty only expressed aversion on IA. Furthermore, both anisomycin, an inhibitor of ribosomal protein synthesis, and rapamycin, an inhibitor of mTOR-mediated protein synthesis, injected in the CA1 region of dorsal hippocampus blocked the novelty effect, promoting memory generalization. We conclude that novelty exposure hinders aversive memory generalization depending on hippocampal protein synthesis.
Assuntos
Aprendizagem da Esquiva/fisiologia , Generalização Psicológica/fisiologia , Hipocampo/metabolismo , Memória/fisiologia , Biossíntese de Proteínas , Animais , Anisomicina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Generalização Psicológica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Testes Neuropsicológicos , Biossíntese de Proteínas/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Ratos Wistar , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismoRESUMO
Dried bonito dashi is often used in Japanese cuisine with a number of documented positive health effects. Its major taste is thought to be umami, elicited by inosine 5'-monophosphate (IMP) and L-amino acids. Previously we found that lactic acid, a major component of dried bonito dashi, enhanced the contribution of many of these amino acids to the taste of dried bonito dashi, and reduced the contribution of other amino acids. In addition to amino acids, dried bonito dashi also has a significant mineral salt component. The present study used conditioned taste aversion methods with mice (all had compromised olfactory systems) to compare the taste qualities of dried bonito dashi with four salts (NaCl, KCl, CaCl2 and MgCl2), with and without lactic acid or citric acid. A conditioned taste aversion to 25% dried bonitio dashi generalized significantly to NaCl and KCl, with or without 0.9% lactic acid added but not when citric acid was added. Generalization of the CTA to dried bonito dashi was much stronger to the divalent salts, but when either lactic acid or citric acid was added, this aversion was eliminated. These results suggest that these salts contribute to the complex taste of dried bonito dashi and that both organic acids appear able to modify the tastes of divalent salts.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Aromatizantes/farmacologia , Generalização Psicológica/efeitos dos fármacos , Sais/farmacologia , Olfato/efeitos dos fármacos , Animais , Masculino , CamundongosRESUMO
The role of rodent hippocampus has been intensively studied in different cognitive tasks. However, its role in discrimination of objects remains controversial due to conflicting findings. We tested whether the number and type of features available for the identification of objects might affect the strategy (hippocampal-independent vs. hippocampal-dependent) that rats adopt to solve object discrimination tasks. We trained rats to discriminate 2D visual objects presented on a computer screen. The objects were defined either by their shape only or by multiple-features (a combination of filling pattern and brightness in addition to the shape). Our data showed that objects displayed as simple geometric shapes are not discriminated by trained rats after their hippocampi had been bilaterally inactivated by the GABAA-agonist muscimol. On the other hand, objects containing a specific combination of non-geometric features in addition to the shape are discriminated even without the hippocampus. Our results suggest that the involvement of the hippocampus in visual object discrimination depends on the abundance of object's features.
Assuntos
Condicionamento Operante/fisiologia , Aprendizagem por Discriminação/fisiologia , Percepção de Forma/fisiologia , Generalização Psicológica/fisiologia , Hipocampo/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Condicionamento Operante/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Percepção de Forma/efeitos dos fármacos , Agonistas de Receptores de GABA-A/farmacologia , Generalização Psicológica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Muscimol/farmacologia , Reconhecimento Visual de Modelos/efeitos dos fármacos , Ratos , Ratos Long-EvansRESUMO
In this study, we investigated: (1) the effect of fear on interval timing-time perception in the seconds-to-minutes range-and (2) the role of the insular cortex in the modulation of this effect. Rats were first trained on a temporal bisection task in which their response to a lever A was reinforced following a 2.00-s tone, whereas their response to a lever B was reinforced following an 8.00-s tone. After acquisition, the rats were also presented with intermediate-duration tones and pressed one of two levers to indicate whether tone duration was closer to 2.00 or 8.00s. Subsequently, the rats underwent differential fear conditioning in which one pitch tone (conditioned stimulus; CS+) was paired with an electric foot shock, while the other pitch tone (CS-) was presented alone. Either artificial cerebrospinal fluid (aCSF) or the GABAA agonist muscimol was then infused into the rats' bilateral insular cortex before the animals were tested on the bisection task using the CS+and CS- tones. We found that in the rats infused with aCSF, the point of subjective equality (PSE) of the CS+ was higher than that for CS-, suggesting that the duration for CS+ was perceived to be shorter than that of CS-. However, muscimol eliminated the difference in PSE between CS+ and CS- by generalizing of the effect from CS+to the CS-. Taken together, our results show that normal activity in the insular cortex is involved in fear-induced modulation of interval timing.
Assuntos
Córtex Cerebral/fisiologia , Medo/fisiologia , Generalização Psicológica/fisiologia , Percepção do Tempo/fisiologia , Animais , Córtex Cerebral/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Medo/efeitos dos fármacos , Medo/psicologia , Agonistas de Receptores de GABA-A/farmacologia , Generalização Psicológica/efeitos dos fármacos , Masculino , Muscimol/farmacologia , Testes Neuropsicológicos , Ratos Wistar , Percepção do Tempo/efeitos dos fármacosRESUMO
The novel potent analgesic cebranopadol is an agonist at nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors, with the highest in-vitro activity at NOP and mu-opioid peptide (MOP) receptors, and somewhat lower activity at kappa-opioid peptide (KOP) and delta-opioid peptide (DOP) receptors. We addressed the question of which of these pharmacological activities contribute to the stimulus properties of cebranopadol using a rat drug discrimination procedure. First, cebranopadol was tested in generalization tests against a morphine cue, including receptor-specific antagonism. Second, cebranopadol was established as a cue, and MOP, NOP, KOP and DOP receptor-selective agonists were tested in generalization tests. Third, cebranopadol in combination with receptor-selective antagonists was tested against the cebranopadol cue. Cebranopadol generalized to the morphine cue. Full generalization was only seen at clearly supra-analgesic doses. The effect of cebranopadol was reduced by naloxone, but was enhanced by the NOP receptor antagonist J-113397. In cebranopadol-trained rats, cebranopadol as well as morphine produced generalization. A NOP receptor agonist did not, while a DOP receptor agonist and a KOP receptor agonist weakly generalized to the cebranopadol cue. Conversely, generalization of cebranopadol was reduced by naloxone and J-113397, but not by a DOP or a KOP receptor antagonist. These results suggest a contribution of MOP receptor activity and a relative lack of contribution of DOP and KOP receptor activity to cebranopadol's stimulus properties. The findings regarding the contribution of NOP receptor activity were equivocal, but interestingly, the morphine-like stimulus property of cebranopadol appears to be reduced by its intrinsic NOP receptor activity.
Assuntos
Discriminação Psicológica/efeitos dos fármacos , Indóis/farmacologia , Peptídeos Opioides/farmacologia , Receptores Opioides mu/metabolismo , Receptores Opioides/metabolismo , Compostos de Espiro/farmacologia , Animais , Benzimidazóis/farmacologia , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Relação Dose-Resposta a Droga , Generalização Psicológica/efeitos dos fármacos , Masculino , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Piperidinas/farmacologia , Ratos , Ratos Long-Evans , Esquema de Reforço , Receptor de Nociceptina , NociceptinaRESUMO
Fear generalization occurs when a response, previously acquired with a threatening stimulus, is transferred to a similar one. However, it could be maladaptive when stimuli that do not represent a real threat are appraised as dangerous, which is a hallmark of several anxiety disorders. Stress exposure is a major risk factor for the occurrence of anxiety disorders and it is well established that it influences different phases of fear memory; nevertheless, its impact on the generalization of contextual fear memories has been less studied. In the present work, we have characterized the impact of acute restraint stress prior to contextual fear conditioning on the generalization of this fear memory, and the role of the GABAergic signaling within the basolateral amygdala complex (BLA) on the stress modulatory effects. We have found that a single stress exposure promoted the generalization of this memory trace to a different context that was well discriminated in unstressed conditioned animals. Moreover, this effect was dependent on the formation of a contextual associative memory and on the testing order (i.e., conditioning context first vs generalization context first). Furthermore, we observed that increasing GABA-A signaling by intra-BLA midazolam administration prior to the stressful session exposure prevented the generalization of fear memory, whereas intra-BLA administration of the GABA-A antagonist (Bicuculline), prior to fear conditioning, induced the generalization of fear memory in unstressed rats. We concluded that stress exposure, prior to contextual fear conditioning, promotes the generalization of fear memory and that the GABAergic transmission within the BLA has a critical role in this phenomenon.
Assuntos
Complexo Nuclear Basolateral da Amígdala/metabolismo , Medo/fisiologia , Generalização Psicológica/fisiologia , Memória/fisiologia , Receptores de GABA-A/metabolismo , Estresse Psicológico/metabolismo , Animais , Associação , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Bicuculina/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Medo/efeitos dos fármacos , Medo/psicologia , GABAérgicos/farmacologia , Generalização Psicológica/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Midazolam/farmacologia , Distribuição Aleatória , Ratos Wistar , Ácido gama-Aminobutírico/metabolismoRESUMO
Memory generalization is essential for adaptive decision-making and action. Our ability to generalize across past experiences relies on medial-temporal lobe structures, known to be highly sensitive to stress. Recent evidence suggests that stressful events may indeed interfere with memory generalization. Yet, the mechanisms involved in this generalization impairment are unknown. We tested here whether a pharmacological elevation of major stress mediators-noradrenaline and glucocorticoids-is sufficient to disrupt memory generalization. In a double-blind, placebo-controlled design, healthy men and women received orally a placebo, hydrocortisone, the α2-adrenoceptor antagonist yohimbine that leads to increased noradrenergic stimulation, or both drugs, before they completed an associative learning task probing memory generalization. Drugs left learning performance intact. Yohimbine, however, led to a striking generalization impairment in women, but not in men. Hydrocortisone, in turn, had no effect on memory generalization, neither in men nor in women. The present findings indicate that increased noradrenergic activity, but not cortisol, is sufficient to disrupt memory generalization in a sex-specific manner, with relevant implications for stress-related mental disorders characterized by generalization deficits.