RESUMEN
RATIONALE: Aversive learning and memory are essential to cope with dangerous and stressful stimuli present in an ever-changing environment. When this process is dysfunctional, however, it is associated with posttraumatic stress disorder (PTSD). The endocannabinoid (eCB) system has been implicated in synaptic plasticity associated with physiological and pathological aversive learning and memory. OBJECTIVE AND METHODS: The objective of this study was to review and discuss evidence on how and where in the brain genetic or pharmacological interventions targeting the eCB system would attenuate aversive/traumatic memories through extinction facilitation in laboratory animals and humans. The effect size of the experimental intervention under investigation was also calculated. RESULTS: Currently available data indicate that direct or indirect activation of cannabinoid type-1 (CB1) receptor facilitates the extinction of aversive/traumatic memories. Activating CB1 receptors around the formation of aversive/traumatic memories or their reminders can potentiate their subsequent extinction. In most cases, the effect size has been large (Cohen's d ≥ 1.0). The brain areas responsible for the abovementioned effects include the medial prefrontal cortex, amygdala, and/or hippocampus. The potential role of cannabinoid type-2 (CB2) receptors in extinction learning is now under investigation. CONCLUSION: Drugs augmenting the brain eCB activity can temper the impact of aversive/traumatic experiences by diverse mechanisms depending on the moment of their administration. Considering the pivotal role the extinction process plays in PTSD, the therapeutic potential of these drugs is evident. The sparse number of clinical trials testing these compounds in stress-related disorders is a gap in the literature that needs to be addressed.
Asunto(s)
Reacción de Prevención/efectos de los fármacos , Cannabinoides/uso terapéutico , Trastornos por Estrés Postraumático/tratamiento farmacológico , Trastornos por Estrés Postraumático/psicología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Reacción de Prevención/fisiología , Cannabinoides/farmacología , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología , Miedo/efectos de los fármacos , Miedo/fisiología , Miedo/psicología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Trastornos por Estrés Postraumático/metabolismoRESUMEN
The results of this study show that the oral administration of ivermectin (48 mg/L) repeatedly for 72 h used in accordance with the present protocol is a safe and highly effective treatment for Giardia spp. and Hymenolepis nana in laboratory rat colonies. The drug can be easily and safely administered using drinking water. This simple regimen should control pinworm infection (Syphacia muris), a problem that can be endemic in laboratory colonies. Experiments using healthy animals are likely to generate more consistent results, thereby requiring a reduced number of animals per group.
Asunto(s)
Antiparasitarios/uso terapéutico , Giardiasis/veterinaria , Himenolepiasis/veterinaria , Ivermectina/uso terapéutico , Oxiuriasis/veterinaria , Ratas , Enfermedades de los Roedores/tratamiento farmacológico , Administración Oral , Animales , Antiparasitarios/farmacología , Femenino , Tracto Gastrointestinal/parasitología , Giardia/efectos de los fármacos , Giardiasis/tratamiento farmacológico , Giardiasis/parasitología , Himenolepiasis/tratamiento farmacológico , Himenolepiasis/parasitología , Hymenolepis nana/efectos de los fármacos , Ivermectina/farmacología , Masculino , Oxiuriasis/tratamiento farmacológico , Oxiuriasis/parasitología , Oxyuroidea/efectos de los fármacos , Recuento de Huevos de Parásitos/veterinaria , Ratas Wistar , Enfermedades de los Roedores/parasitología , RoedoresRESUMEN
Tolerance to the anxiolytic-like effect of drugs may develop because of a memory derived from prior experience in certain apparatuses such as the elevated plus-maze (EPM). Activity in basolateral amygdala was shown to be required for consolidating this knowledge. The dorsal hippocampus (DH) is also implicated in long-term memory consolidation, a process relying on new protein synthesis. It is unknown, however, whether the DH protein synthesis disruption would prevent the phenomenon rendering animals unresponsive to benzodiazepines in the EPM retest. To address this, we bilaterally infused the protein synthesis inhibitor anisomycin (ANI) into the rat DH 0, 3 or 6 h after, or 15 min before, the EPM test. DH infusion of ANI (80 µg) around the time of EPM testing preserved the anxiolysis of the midazolam (MDZ; 0.5 mg/kg, i.p.) in rats retested in the EPM 24 h later, suggesting that information consolidated by DH protein synthesis impacts on the subsequent animal's responsiveness to this drug. To examine whether impaired memory acquisition could also contribute to the prevention of MDZ tolerance seen in EPM-experienced animals infused with ANI before testing, the EPM retest was performed 3 h after testing to coincide with the temporal window in which short-term memory remains, for the reason that this process does not require protein synthesis for its formation. The pretest DH anisomycin infusion's ability to prevent the MDZ tolerance on retesting was now missing. This result confirms a specific action of the ANI on memory consolidation. We also found that rats express further avoidance to open-arms in the EPM retest. However, neither pretest nor posttest DH ANI infusion interfered with this pattern of results exhibited by EPM-experienced rats.
Asunto(s)
Tolerancia a Medicamentos/fisiología , Hipocampo/fisiología , Aprendizaje por Laberinto/fisiología , Biosíntesis de Proteínas/fisiología , Animales , Anisomicina/farmacología , Ansiolíticos/farmacología , Hipocampo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Memoria/fisiología , Midazolam/farmacología , Biosíntesis de Proteínas/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/farmacología , Ratas , Ratas WistarRESUMEN
The prelimbic (PL) subregion of medial prefrontal cortex has been implicated in anxiety regulation. It is unknown, however, whether PL cortex also serves to fine-tuning the level of anxiety-related behavior exhibited on the next exposure to the same potentially threatening situation. To address this, we infused cobalt (1.0 mM) to temporarily inactivate the PL cortex during testing, post-testing or retesting in the elevated plus-maze (EPM). This protocol was chosen because it allowed us to concurrently investigate anxiety and the process of aversive learning and memory. PL cortex inactivation during the EPM testing increased the exploration of open-arms, substantiating its role in anxiety. PL cortex inactivation during the EPM retesting counteracted the further avoidance to open-arms exhibited by rats. Interestingly, as evidenced by min-by-min analysis, the cobalt-treated group behaved on EPM retesting as did the vehicle-treated group on EPM testing. This result may imply that activity in PL cortex is necessary for retrieving previously learned information that adjusts the anxiety response level on EPM retesting. Alternatively, a simple reduction in anxiety could explain the cobalt-induced increase in retest open-arms exploration. Neither test nor post-test PL cortex inactivation affected the further avoidance to open-arms observed on EPM retesting. To extend the investigation of PL cortex role in the regulation of open-arms avoidance, we infused other drugs prior to testing or retesting in the EPM. Antagonism of PL cortex adrenergic beta-1 receptors with atenolol (10 nmol), cholinergic muscarinic receptors with scopolamine (20 nmol) or glutamatergic N-methyl-d-aspartic acid (NMDA) receptors with AP5 (6.0 nmol) interfered with the level of open-arms exploration on testing, but not on retesting.
Asunto(s)
Ansiedad/metabolismo , Sistema Límbico , Aprendizaje por Laberinto/fisiología , Corteza Prefrontal/metabolismo , Animales , Ansiedad/psicología , Reacción de Prevención/fisiología , Conducta Exploratoria/fisiología , Sistema Límbico/metabolismo , Masculino , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Rodents re-exposed to the elevated plus-maze no longer respond to anxiolytic-like drugs, such as benzodiazepines. This phenomenon is thought to be due to retrieval of aversive learning associated with the initial exploration of this potentially dangerous environment Based on this assumption, one might expect the maintenance of the drug's anxiolytic-like effect in rodents already experienced in the elevated plus-maze if the acquisition and/or consolidation of this learning were impaired. Using male Wistar rats, we investigated whether the systemic administration of propranolol, at putative learning-impairing doses, prior to or immediately after the first (Trial 1) elevated plus-maze exposure would retain the midazolam anxiolytic-like effect on the second (Trial 2) exposure to this apparatus. There was an anxiolytic-like effect, characterized by an increase in the open-arms exploration, in response to 0.25 mg/kg of midazolam on Trial 2 only in rats administered with 20 mg/kg of propranolol before Trial 1. Although propranolol had a dose-dependent and behaviorally-selective anti-anxiety effect (significant at 20 mg/kg) on Trial 1, further minute-by-minute analysis confirmed the propranolol-induced learning acquisition deficit in this group on Trial 2. The knowledge of the environment actually contributes to the unresponsiveness to anxiolytic-like drugs observed in rats re-exposed to the elevated plus-maze.