urb-597 and Memory-Disorders

Patients diagnosed with fetal alcohol spectrum disorder (FASD) show persistent cognitive disabilities, including memory deficits. However, the neurobiological substrates underlying these deficits remain unclear. Here, we show that prenatal and lactation alcohol exposure (PLAE) in mice induces FASD-like memory impairments. This is accompanied by a reduction of N-acylethanolamines (NAEs) and peroxisome proliferator-activated receptor gamma (PPAR-γ) in the hippocampus specifically in a childhood-like period (at post-natal day (PD) 25). To determine their role in memory deficits, two pharmacological approaches were performed during this specific period of early life. Thus, memory performance was tested after the repeated administration (from PD25 to PD34) of: i) URB597, to increase NAEs, with GW9662, a PPAR-γ antagonist; ii) pioglitazone, a PPAR-γ agonist. We observed that URB597 suppresses PLAE-induced memory deficits through a PPAR-γ dependent mechanism, since its effects are prevented by GW9662. Direct PPAR-γ activation, using pioglitazone, also ameliorates memory impairments. Lastly, to further investigate the region and cellular specificity, we demonstrate that an early overexpression of PPAR-γ, by means of a viral vector, in hippocampal astrocytes mitigates memory deficits induced by PLAE. Together, our data reveal that disruptions of PPAR-γ signaling during neurodevelopment contribute to PLAE-induced memory dysfunction. In turn, PPAR-γ activation during a childhood-like period is a promising therapeutic approach for memory deficits in the context of early alcohol exposure. Thus, these findings contribute to the gaining insight into the mechanisms that might underlie memory impairments in FASD patients.

Topics: Animals; Child; Female; Fetal Alcohol Spectrum Disorders; Humans; Lactation; Memory Disorders; Mice; Pioglitazone; PPAR gamma; Pregnancy; Thiazolidinediones

Inhibitors of the endocannabinoid metabolic enzyme fatty acid amide hydrolase exert therapeutic effects, but might also be associated with some of the adverse effects of cannabis. However, at least one fatty acid amide hydrolase inhibitor, URB597, has beneficial effects without signs of abuse or dependence. Although previous investigations have evaluated URB597-morphine interactions, the effects of URB597 on morphine tolerance and cognition deficits have not been studied previously. Rats were rendered tolerant to or dependent on morphine by an injection of morphine (10 mg/kg, subcutaneous) twice daily, respectively, for 7 or 10 days. URB597 (1 mg/kg, intraperitoneal) was administered before morphine. The tail-flick and passive avoidance learning tests were used to evaluate tolerance and cognition. Chronic morphine injection led to significant tolerance to the antinociceptive effect on days 5 and 7. URB597 completely prevented the development of morphine tolerance. URB597 also enhanced memory acquisition in the passive avoidance learning test, and although morphine impaired memory, URB597 alleviated this effect. These data show that URB597 protects against tolerance and memory deficits in chronic usage of morphine and suggests URB597 as a promising candidate for the treatment of adverse effects of opioids.

Topics: Amidohydrolases; Analgesics, Opioid; Animals; Avoidance Learning; Benzamides; Carbamates; Cognition Disorders; Drug Tolerance; Enzyme Inhibitors; Male; Memory Disorders; Morphine; Morphine Dependence; Nociception; Psychotropic Drugs; Random Allocation; Rats, Wistar

Cannabinoid and endocannabinoid systems have been implicated in several physiological functions including modulation of cognition. In this study we evaluated the effects and interaction between fatty-acid amide hydrolase (FAAH) inhibitor URB597 and CB1 receptor agonist WIN55, 212-2 on memory using object recognition and passive avoidance learning (PAL) tests. Learning and memory impairment was induced by WIN 55, 212-2 administration (1mg/kg, i.p.) 30min before the acquisition trial. URB597 (0.1, 0.3 and 1mg/kg, i.p.) or SR141716A (1mg/kg, i.p.) was injected to rats 10min before WIN 55, 212-2 or URB597 respectively. URB597 (0.3 and 1mg/kg) but not 0.1mg/kg induced higher discrimination index (DI) in object recognition test and enhanced memory acquisition in PAL test. The cognitive enhancing effect of URB597 was blocked by a CB1 receptor antagonist, SR141716A which at this dose alone had no effect on cognition. WIN55, 212-2 caused cognition deficits in both tests. URB597 (0.3 and 1mg/kg) treatment could alleviate the negative influence of WIN 55, 212-2 on cognition and memory. These results indicate URB597 potential to protect against memory deficits induced by cannabinoid. Therefore, in combination with URB597 beneficial effects, this study suggests that URB597 has recognition and acquisition memory enhancing effects. It may also constitute a novel approach for the treatment of cannabinoid induced memory deficits and lead to a better understanding of the brain mechanisms underlying cognition.

Topics: Amidohydrolases; Animals; Benzamides; Benzoxazines; Carbamates; Learning; Male; Memory Disorders; Morpholines; Naphthalenes; Nootropic Agents; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Retention, Psychology; Rimonabant