A cross-talk between Transient Receptor Potential Vanilloid 1 and Cannabinoid Receptor 1 within the limbic system regulates depression and stress-induced anxiety-like behavior in rats.
AdvisorMaldonado Vlaar, Carmen S
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Clinical studies provide strong evidence that stress is an environmental risk factor that can trigger the onset of several neuropsychiatric disorders such as anxiety and depression in humans. Pre-clinical evidence suggests that the endovanilloid and the endocannabinoid systems within the brain are important neuronal substrates involved in emotional responses to stress. Specifically, studies have proposed that the Transient Receptor Potential Vanilloid 1 (TRPV1), a member of the Transient Receptor Potential (TRP) superfamily within the brain, regulates anxiety and depression behaviors through its interactions with the cannabinoid receptor 1 (CB1R). However, little is known about the cellular mechanisms that regulate the interaction of these receptors in the brain and their effects on neuropsychiatric disorders. We investigated the role of TRVP1 and CB1R within several brain regions, including the medial prefrontal cortex as part of the dopamine mesocorticolimbic system, the hippocampus, and the amygdala in anxiety and depression like-behaviors using rats as an animal model. To examine the role of these two receptors in depression like-behaviors, male and female Sprague Dawley rats were treated for 4 days with vehicle or fatty acid amid hydrolase inhibitor (FAAH) inhibitor URB597 [ 0; 0.1;0.2mg/kg.ip] 2 hours before testing in the forced swim test (FST) for 6 min the last day. Another group were treated for 4 days with either vehicle or Olvanil, a potent TRPV1 agonist [0; 0.3; 0.5 mg/kg.ip] 30 min before testing in the FST for 6 min, a third group of animals was treated for 4 days with either vehicle or URB597 [0; 0.1 ;0.2mg/kg.ip] and Olvanil [0; 0.3; 0.5 mg/kg.ip] 2 hours before testing in the FST for 6 min. Floating and swimming behaviors were observed during the FST session. In addition, animals were exposed for four days to evaluate anxiety-like behavior with either vehicle or URB597 at dose [0; 0.1mg;0.2mg/kg.ip] 90 minutes before placing in a restrainer for 30 mins, followed by a 15 mins light-dark box test. The second group of animals was treated with Olvanil at dose [0; 0.3; 0.5 mg/kg.ip] before exposure to 30 min acute restraint stress, followed by a 15 min light-dark box test. A third group of animals was treated simultaneously for four days with either vehicle or URB597 [0; 0.1;0.2mg/kg.ip] and Olvanil [0; 0.3; 0.5 mg/kg.ip] 90 minutes before placing in a restrainer for 30 mins, followed by a 15 min light-dark box test. Our results suggest that the combined treatment of URB597 and Olvanil significantly decreased depression and anxiety like-behaviors in male and female rats compared to the vehicle-treated groups. In addition, we found that combined treatment increased the expression of CB1 receptors in the medial prefrontal cortex (mPFC), but no changes were found in the hippocampus and amygdala in male rats previously exposed to the forced swim test. However, we found a decrease in CB1 receptor expression in male rats exposed to restraint stress. The manipulation of dual treatment also led to sex differences. For the first time, the present thesis presents new evidence that includes activating TRPV1 receptors with inhibition of FAAH to manage depression and anxiety-like behavior through CB1 receptors via different pathways.