RESUMO
Activity in the rodent prelimbic (PL) cortex contributes to consolidation, retrieval and reconsolidation of learned fear. The PL cortex is considered homologous to the primate dorsal anterior cingulate cortex (dACC). In patients with post-traumatic stress disorder (PTSD), the dACC is often reported to be hyperactive after acquisition and/or around the retrieval of the traumatic memory. It is still unknown, however, whether there is a relationship between altered dACC functioning at these time points and PTSD-associated behavioral outcomes, such as fear overgeneralization. The present study sought to investigate this matter by associating contextual fear conditioning with bilateral and selective activation of PL cortex N-methyl-D-aspartate (NMDA) glutamate receptors with NMDA (0.03-0.3nmol) while the learned fear was being consolidated, retrieved or reconsolidated. We report that this pharmacological intervention induced generalized fear expression and/or extinction deficits in animals subjected to a strong contextual fear conditioning protocol when conducted post-acquisition, pre-retrieval or post-retrieval. These results suggest that newly acquired and reactivated fear memories undergo abnormal consolidation or reconsolidation after PL cortex NMDA receptor activation. The consolidation or reconsolidation of a contextual fear memory trace induced by a weak fear training protocol was also potentiated by PL cortex NMDA receptor activation. Altogether, the present findings connect altered PL cortex activity with changes in specificity and/or intensity of a contextual fear memory, which might shed light on the PTSD neurobiology and related behavioral outcomes.
Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Generalização Psicológica/efeitos dos fármacos , Memória/efeitos dos fármacos , N-Metilaspartato/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/agonistas , Animais , Extinção Psicológica/efeitos dos fármacos , Masculino , Ratos , Ratos WistarRESUMO
BACKGROUND: Traumatic memories have been resilient to therapeutic approaches targeting their permanent attenuation. One of the potentially promising pharmacological strategies under investigation is the search for safe reconsolidation blockers. However, preclinical studies focusing on this matter have scarcely addressed abnormal aversive memories and related outcomes. METHODS: By mimicking the enhanced noradrenergic activity reported after traumatic events in humans, here we sought to generate a suitable condition to establish whether some clinically approved drugs able to disrupt the reconsolidation of conditioned fear memories in rodents would still be effective. RESULTS: We report that the α2-adrenoceptor antagonist yohimbine was able to induce an inability to restrict behavioral (fear) and cardiovascular (increased systolic blood pressure) responses to the paired context when administered immediately after acquisition, but not 6h later, indicating the formation of a generalized fear memory, which endured for over 29 days and was less susceptible to suppression by extinction. It was also resistant to reconsolidation disruption by the α2-adrenoceptor agonist clonidine or cannabidiol, the major non-psychotomimetic component of Cannabis sativa. Since signaling at N-methyl-D-aspartate (NMDA) receptors is important for memory labilization and because a dysfunctional memory may be less labile than is necessary to trigger reconsolidation on its brief retrieval and reactivation, we then investigated and demonstrated that pre-retrieval administration of the partial NMDA agonist D-cycloserine allowed the disrupting effects of clonidine and cannabidiol on reconsolidation. CONCLUSIONS: These findings highlight the effectiveness of a dual-step pharmacological intervention to mitigate an aberrant and enduring aversive memory similar to that underlying the post-traumatic stress disorder.
Assuntos
Medo/efeitos dos fármacos , Memória/efeitos dos fármacos , Psicotrópicos/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Canabidiol/farmacologia , Clonidina/farmacologia , Ciclosserina/farmacologia , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Extinção Psicológica/efeitos dos fármacos , Medo/fisiologia , Masculino , Distribuição Aleatória , Ratos Wistar , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Ioimbina/farmacologiaRESUMO
The prelimbic cortex has been implicated in the consolidation of previously learned fear. Herein, we report that temporarily inactivating this medial prefrontal cortex subregion with the GABAA agonist muscimol (4.0 nmol in 0.2 µL per hemisphere) was able to equally disrupt 1-, 7-, and 21-d-old contextual fear memories after their brief retrieval in rats. In all cases, this effect was prevented when memory reactivation was omitted. These results indicate that recent and remote fear memories are susceptible to reconsolidation blockade induced by prelimbic cortex inactivation. It was also demonstrated that the disrupting effect of prelimbic cortex inactivation on fear memory persisted over 11 d, and did not show extinction-related features, such as reinstatement. Infusing the same dose and volume of muscimol bilaterally into the infralimbic cortex after brief retrieval/reactivation of the fear memory did not disrupt it, as seen in prelimbic cortex-inactivated animals. The expression of Zif268/Egr1, the product of an immediate early gene related to memory reconsolidation, was also less pronounced in the infralimbic cortex than in prelimbic cortex following memory retrieval/reactivation. Altogether, the present findings highlight that activity in the prelimbic cortex may reestablish reactivated aversive memories and, therefore, contribute to their maintenance over time.
Assuntos
Córtex Cerebral/fisiologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Memória/fisiologia , Análise de Variância , Animais , Córtex Cerebral/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Lateralidade Funcional , Agonistas de Receptores de GABA-A/farmacologia , Masculino , Memória/efeitos dos fármacos , Muscimol/farmacologia , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Fear conditioning and avoidance tasks usually elicit adaptive aversive memories. Traumatic memories are more intense, generalized, inflexible, and resistant to attenuation via extinction- and reconsolidation-based strategies. Inducing and assessing these dysfunctional, maladaptive features in the laboratory are crucial to interrogating posttraumatic stress disorder's neurobiology and exploring innovative treatments. Here we analyze over 350 studies addressing this question in adult rats and mice. There is a growing interest in modeling several qualitative and quantitative memory changes by exposing already stressed animals to freezing- and avoidance-related tests or using a relatively high aversive training magnitude. Other options combine aversive/fearful tasks with post-acquisition or post-retrieval administration of one or more drugs provoking neurochemical or epigenetic alterations reported in the trauma aftermath. It is potentially instructive to integrate these procedures and incorporate the measurement of autonomic and endocrine parameters. Factors to consider when defining the organismic and procedural variables, partially neglected aspects (sex-dependent differences and recent vs. remote data comparison) and suggestions for future research (identifying reliable individual risk and treatment-response predictors) are discussed.
Assuntos
Extinção Psicológica , Transtornos de Estresse Pós-Traumáticos , Ratos , Camundongos , Animais , Extinção Psicológica/fisiologia , Roedores , Condicionamento Psicológico , Medo/fisiologiaRESUMO
Growing evidence indicates that cannabidiol (CBD), a substance present in the Cannabis sativa plant, has potential therapeutic value to regulate abnormal emotional memories associated with post-traumatic stress and drug use disorders. CBD can attenuate their valence after retrieval (i.e., during reconsolidation) or potentiate their suppression by extinction. Pharmacological research has now focused on elucidating how it acts. Systemic antagonism of cannabinoid type-1 (CB1) receptors has often prevented the abovementioned effects of CBD. However, it is unknown in which brain regions CBD stimulates CB1 receptors and how it interferes with local activity-related plasticity to produce these effects. The present study addressed these questions considering the reconsolidation of contextual fear memories in rats. We focused on the medial prefrontal cortex (mPFC), which comprises the anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) subregions, as local activity or plasticity has been associated with the process to-be-investigated. Animals that received post-retrieval systemic CBD treatment presented relatively fewer cells expressing Zif268/Egr1 protein, a proxy for synaptic plasticity related to reconsolidation, in the AC and PL. At the same time, there were no significant differences in the IL. Pretreatment with the CB1 receptor antagonist/inverse agonist AM251 into the AC, PL, or IL prevented the impairing effects of systemic CBD treatment on reconsolidation. CBD also caused reconsolidation impairments when injected directly into the AC or PL but not the IL. Together, these findings show complementary mechanisms through which CBD may hinder the reconsolidation of destabilized aversive memories along the dorsoventral axis of the mPFC.
Assuntos
Canabidiol/efeitos adversos , Agonistas de Receptores de Canabinoides/efeitos adversos , Antagonistas de Receptores de Canabinoides/farmacologia , Consolidação da Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Ratos , Receptor CB1 de Canabinoide/antagonistas & inibidoresRESUMO
BACKGROUND AND PURPOSE: In preclinical studies, cannabidiol (CBD) mitigates fear memories by facilitating their extinction or interfering with their generalization and reconsolidation. The brain regions and mechanisms underlying these effects, and their temporal window, are still poorly understood. Here, we have investigated related questions in the dorsal hippocampus (DH) during contextual fear consolidation. EXPERIMENTAL APPROACH: Adult male Wistar rats received CBD (10-30 pmol) intra-DH immediately, 1 or 3 hr after fear conditioning. Effects of CBD on consolidation were inferred behaviourally and by analysing expression of the activity-regulated, cytoskeleton-associated (Arc) protein. The contribution of anandamide, CB1 , CB2 , 5-HT1A , A2A , and PPARγ receptors was also assessed. KEY RESULTS: CBD impaired memory consolidation when given immediately or 1 hr after fear conditioning, but not after 3 hr. Expression of Arc protein in DH was reduced by systemic CBD treatment in both cases. Immediately after fear conditioning, CBD effects were abolished by CB1 or CB2 receptor blockade, partly reduced by 5-HT1A or A2A antagonism, and remained unchanged after antagonism of PPARγ receptors. One hour after fear conditioning, CBD effects were prevented only by PPARγ receptor antagonism. Also, inhibition of fatty acid amide hydrolase by URB597, impaired memory consolidation when infused immediately, but not 1 hr after fear conditioning. CONCLUSIONS AND IMPLICATIONS: CBD disrupts memory consolidation up to 1 hr after fear conditioning, allowing an extended window of opportunity to mitigate aversive memories after their acquisition. Our results suggest time-dependent participation of anandamide, CB1 , CB2 and PPARγ receptors in the DH, during this process.
Assuntos
Canabidiol , Consolidação da Memória , Animais , Canabidiol/farmacologia , Medo , Hipocampo , Masculino , PPAR gama , Ratos , Ratos Wistar , Receptor CB1 de CanabinoideRESUMO
Posttraumatic stress and drug use disorders may stem from aberrant memory formation. As the endocannabinoid (eCB) system has a pivotal role in emotional memory processing and related synaptic plasticity, here we seek to review and discuss accumulating evidence on how and where in the brain interventions targeting the eCB system would attenuate outcomes associated with traumatic events and/or drug addiction through memory extinction facilitation or reconsolidation disruption. Currently available data from mouse, rat, monkey and healthy human studies investigating the effects of cannabinoid drugs on extinction and reconsolidation of aversive memories are more consistent than those related to rewarding drug-associated memories. Interventions able to attenuate aversive memories by extinction facilitation or reconsolidation disruption have boosted the anandamide-induced activation of cannabinoid type-1 (CB1) receptors. A still limited number of studies report that CB1 receptor activation could also be effective in facilitating the extinction or disrupting the reconsolidation of rewarding drug-associated memories. The reinstatement of extinguished drug memories (relapse) is reduced by CB1 receptor antagonism. The cannabidiol has shown to be effective in any of the aforementioned cases, albeit its mechanism of action is not fully understood. Brain areas in which cannabinoid drugs induce these effects include the prefrontal cortex, amygdala, hippocampus, and/or nucleus accumbens. The potential role of 2-arachidonoylglycerol (2-AG) and cannabinoid type-2 (CB2) receptors in emotional memory extinction and reconsolidation is currently under investigation. Overall, preclinical data support a closer look into certain cannabinoid drugs owing to their safety and potential therapeutic value against stress-related and drug use disorders.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Moduladores de Receptores de Canabinoides/farmacologia , Extinção Psicológica/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , Recompensa , Transtornos Relacionados ao Uso de Substâncias/psicologia , Animais , Aprendizagem da Esquiva/fisiologia , Extinção Psicológica/fisiologia , Humanos , Consolidação da Memória/fisiologia , Receptores de Canabinoides/metabolismo , Transtornos Relacionados ao Uso de Substâncias/metabolismoRESUMO
Pharmacological interventions able to modulate a fear memory while it is consolidated could have therapeutic value in tempering those maladaptively overconsolidated. Animal and human studies have shown the intensity of unconditioned stimulus delivered during fear conditioning influences qualitative and quantitative aspects of the memory to be established. By varying the shock intensity used for contextual pairing in rats, here we induced specific and more generalized long-term fear memories to investigate whether, how and where in the brain the cannabidiol (CBD; 3.0-30 mg/kg i.p.) could impair their consolidation and related outcomes. When given immediately after their acquisition, it reduced respectively the conditioned fear expression, and fear generalization, ultrasonic vocalizations at 22-kHz and the relative resistance to extinction. CBD had no effects on short-term fear memory, and its delayed treatment no longer affected the consolidation process. As the dorsal hippocampus (DH) modulates fear memory specificity and generalization, and cannabinoid type-1 (CB1) and type-2 (CB2) receptors contribute to consolidation, we investigated their involvement in CBD effects. Both systemic and intra-DH treatment with the CB1 receptor antagonist/inverse agonist AM251 or the CB2 receptor antagonist/inverse agonist AM630 prevented the disrupting CBD effects on consolidation. Since the CBD effects on the endocannabinoid transmission are probably indirect, we investigated and demonstrated the FAAH inhibitor URB597 induced effects similar to those of CBD when given systemically or intra-DH. Altogether, the present results suggest the CBD disrupts the consolidation of different fear memories via anandamide-mediated activation of DH CB1 and CB2 receptors.
Assuntos
Canabidiol/farmacologia , Moduladores de Receptores de Canabinoides/farmacologia , Medo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , Psicotrópicos/farmacologia , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Animais , Ácidos Araquidônicos/metabolismo , Benzamidas/farmacologia , Carbamatos/farmacologia , Endocanabinoides/metabolismo , Inibidores Enzimáticos/farmacologia , Medo/fisiologia , Hipocampo/metabolismo , Indóis/farmacologia , Masculino , Consolidação da Memória/fisiologia , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/metabolismo , Pirazóis/farmacologia , Distribuição Aleatória , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismoRESUMO
The mechanisms underpinning the persistence of emotional memories are inaccurately understood. Advancing the current level of understanding with regards to this aspect is of potential translational value for the treatment of post-traumatic stress disorder (PTSD), which stems from an abnormal aversive memory formation. Tamoxifen (TMX) is a drug used in chemotherapy for breast cancer and associated with poor cognitive performances. The present study investigated whether the systemic administration of TMX (1.0-50mg/kg) during and/or beyond the reconsolidation time-window could attenuate a reactivated contextual fear memory in laboratory animals. When administered 0, 6 or 9h (but not 12h) post-memory retrieval and reactivation, TMX (50mg/kg) reduced the freezing behavior in male rats re-exposed to the paired context on day 7, but not on day 1, suggesting a specific impairing effect on memory persistence. Importantly, this effect lasts up to 21 days, but it is prevented by omitting the memory retrieval or memory reactivation. When female rats in the diestrous or proestrous phase were used, the administration of TMX 6h after retrieving and reactivating the fear memory also impaired its persistence. Altogether, regardless of the gender, the present results indicate that the TMX is able to disrupt the persistence of reactivated fear memories in an expanded time-window, which could shed light on a new promising therapeutic strategy for PTSD.
Assuntos
Antineoplásicos Hormonais/efeitos adversos , Medo/psicologia , Tamoxifeno/efeitos adversos , Animais , Condicionamento Psicológico/efeitos dos fármacos , Ciclo Estral/fisiologia , Feminino , Masculino , Memória/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Ratos , Ratos Wistar , Caracteres Sexuais , Fatores de TempoRESUMO
Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the major constituents of the Cannabis sativa plant, which is frequently consumed by subjects exposed to life-threatening situations to relief their symptomatology. It is still unknown, however, whether THC could also affect the maintenance of an aversive memory formed at that time when taken separately and/or in conjunction with CBD. The present study sought to investigate this matter at a preclinical level. We report that THC (0.3-10mg/kg, i.p.) was able to disrupt the reconsolidation of a contextual fear memory, resulting in reduced conditioned freezing expression for over 22 days. This effect was dependent on activation of cannabinoid type-1 receptors located in prelimbic subregion of the medial prefrontal cortex and on memory retrieval/reactivation. Since CBD may counteract the negative psychotropic effects induced by THC and has been shown to be a reconsolidation blocker, we then investigated and demonstrated that associating sub-effective doses of these two compounds was equally effective in attenuating fear memory maintenance in an additive fashion and in a dose ratio of 10 to 1, which contrasts with that commonly found in C. sativa recreational samples. Of note, neither THC alone nor CBD plus THC interfered with anxiety-related behaviors and locomotor activity, as assessed in the elevated plus-maze test, at a time point coinciding with that used to evaluate their effects on memory reconsolidation. Altogether, present findings suggest a potential therapeutic value of using THC and/or CBD to mitigate a dysfunctional aversive memory through reconsolidation disruption in post-traumatic stress disorder patients.
Assuntos
Canabidiol/farmacologia , Dronabinol/farmacologia , Medo/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Memória/efeitos dos fármacos , Análise de Variância , Animais , Canabidiol/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Dronabinol/efeitos adversos , Combinação de Medicamentos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de TempoRESUMO
The search for reconsolidation blockers may uncover clinically relevant drugs for disrupting memories of significant stressful life experiences, such as those underlying the posttraumatic stress disorder. Considering the safety of systemically administered cannabidiol (CBD), the major non-psychotomimetic component of Cannabis sativa, to animals and humans, the present study sought to investigate whether and how this phytocannabinoid (3-30 mg/kg intraperitoneally; i.p.) could mitigate an established memory, by blockade of its reconsolidation, evaluated in a contextual fear-conditioning paradigm in rats. We report that CBD is able to disrupt 1- and 7-days-old memories when administered immediately, but not 6 h, after their retrieval for 3 min, with the dose of 10 mg/kg being the most effective. This effect persists in either case for at least 1 week, but is prevented when memory reactivation was omitted, or when the cannabinoid type-1 receptors were antagonized selectively with AM251 (1.0 mg/kg). Pretreatment with the serotonin type-1A receptor antagonist WAY100635, however, failed to block CBD effects. These results highlight that recent and older fear memories are equally vulnerable to disruption induced by CBD through reconsolidation blockade, with a consequent long-lasting relief in contextual fear-induced freezing. Importantly, this CBD effect is dependent on memory reactivation, restricted to time window of <6 h, and is possibly dependent on cannabinoid type-1 receptor-mediated signaling mechanisms. We also observed that the fear memories disrupted by CBD treatment do not show reinstatement or spontaneous recovery over 22 days. These findings support the view that reconsolidation blockade, rather than facilitated extinction, accounts for the aforementioned CBD results in our experimental conditions.
Assuntos
Canabidiol/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Medo/efeitos dos fármacos , Memória/efeitos dos fármacos , Animais , Condicionamento Psicológico/fisiologia , Medicina Baseada em Evidências/métodos , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Medo/fisiologia , Masculino , Memória/fisiologia , Distribuição Aleatória , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/fisiologiaRESUMO
The neurochemical mechanisms supporting the role of the ventral hippocampus in anxiety are now under investigation. To address this issue, we examined whether the pharmacological blockade of transient receptor potential vanilloid type 1 (TRPV1) channels in the ventral hippocampus would attenuate anxiety-related behaviour. Rats infused with the TRPV1 channel antagonist capsazepine (2.0 nmol) showed less inhibitory avoidance than controls in the elevated plus-maze test. This result indicates an anxiolytic-like effect, and suggests a role for TRPV1 channels in regulating anxiety.