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Background: Stress is a major risk factor for psychiatric disorders, particularly when occuring during the sensitive period of adolescence. We showed previously that male rats exposed to major stressors during prepuberty exhibit amygdala-driven loss of parvalbumin neurons in the ventral hippocampus, hippocampal hyperactivity, and an increase in ventral tegmental area (VTA) dopamine (DA) neuron activity. In contrast, we now find that female rats are resilient to the effects of prepubertal stress, but are uniquely sensitive to postpubertal (PostP) stress that impacts the system via a unique pathway involving the nucleus reuniens. Aims & Objectives: Using a combined stress paradigm, we examine the mechanism by which PostP stress in females activates medial VTA DA neuron activity, which are the DA neurons projecting to the affect-associated ventral nucleus accumbens. Method: Female rats were subjected to a combination of footshock/restraint stress during PostP (PD41-50). single-unit extracellular recordings of RE neurons 1-2 and 5-6 weeks were done after stress. RTN local field potentials were recorded in the RTN for at PD41, PD51, PD61, and PD85. Low (30-50Hz) and high gamma (60-120Hz) were analyzed. Immunohistochemistry analysis of PV/PNN content was evaluated in the posterior RTN one week after PostP stress (PD61). Another cohort of female rats received a retrograde inhibitory AAV-DREADDs virus (AAVrg-hSyn-hM4D(Gi)-mCherry, 500nL) at PD 31 followed by a cannula implantation in the nucleus reunions. Females were injected with Clozapine N-oxide (CNO, 1mM/200nL) in the nucleus reunions 15 min before stress during PD41-50. The rats were recorded for DA activity in the VTA during adulthood (PD>65). Results: Although female rats failed to show activation of the amygdala after PostP stress, another region that also projects to ventral hippocampal parvalbumin neurons, the nucleus reuniens, shows selective activation 1-2 weeks and 5-6 weeks after PostP stress only in females. This is accompanied by a loss of parvalbumin interneurons in the ventral hippocampus. This loss of hippocampal parvalbumin neurons leads to ventral hippocampal activation and DA neuron overdrive; an effect that is attenuated by inhibition of the reuniens-hippocampal pathway via inhibitory retrograde DREADD injection into the ventral hippocampus and CNO injection into the nucleus reuniens. One region that potently regulates primary thalamic nuclei, including the nucleus reuniens, is the reticular nucleus of the thalamus (RTN), a region consisting of parvalbumin-containing GABAergic neurons. We found that after postpubertal stress there is first an activation of low gamma oscillations one day after stress (consistent with parvalbumin neuron overdrive) followed one week later by a loss of parvalbumin neurons in the region of the RTN associated with the nucleus reuniens. Discussion & Conclusion: These data support that female rats that are resilient to prepubertal stress but show sensitivity to PostP stress that leads to parvalbumin loss in the RTN, decreased RTN inhibition of the nucleus reuniens, parvalbumin loss in the ventral hippocampus, and activation of the affect-related ventromedial striatum. These data are consistent with human studies, in which, females tend to be exposed more often to PostP stress in terms of e.g. sexual abuse, and are more susceptible to affect-related disorders. [ABSTRACT FROM AUTHOR]

Therapeutic intervention for schizophrenia relies on blockade of dopamine D2 receptors in the associative striatum; however, there is little evidence for baseline overdrive of the dopamine system. Instead, the dopamine system is in a hyper-responsive state due to excessive drive by the hippocampus. This causes more dopamine neurons to be in a spontaneously active, hyper-responsive state. Antipsychotic drugs alleviate this by causing depolarization block, or excessive depolarization-induced dopamine neuron inactivation. Indeed, both first- and second-generation antipsychotic drugs cause depolarization block in the ventral tegmentum to relieve positive symptoms, whereas first-generation drugs also cause depolarization in the nigrostriatal dopamine system to lead to extrapyramidal side effects. However, by blocking dopamine receptors, these drugs are activating multiple synapses downstream from the proposed site of pathology: the loss of inhibitory influence over the hippocampus. An overactive hippocampus not only drives the dopamine-dependent positive symptoms, but via its projections to the amygdala and the neocortex can also drive negative and cognitive symptoms, respectively. On this basis, a novel class of drugs that can reverse schizophrenia at the site of pathology, i.e., the hippocampal overdrive, could be effective in alleviating all three classes of symptoms of schizophrenia while also being better tolerated. [ABSTRACT FROM AUTHOR]

Animal models of psychiatric disorders have been highly effective in advancing the field, identifying circuits related to pathophysiology, and identifying novel therapeutic targets. In this review, we show how animal models, particularly those based on development, have provided essential information regarding circuits involved in disorders, disease progression, and novel targets for intervention and potentially prevention. Nonetheless, in recent years there has been a pushback, largely driven by the US National Institute of Mental Health (NIMH), to shift away from animal models and instead focus on circuits in normal subjects. This has been driven primarily from a lack of discovery of new effective therapeutic targets, and the failure of targets based on preclinical research to show efficacy. We discuss why animal models of complex disorders, when strongly cross-validated by clinical research, are essential to understand disease etiology as well as pathophysiology, and direct new drug discovery. Issues related to shortcomings in clinical trial design that confound translation from animal models as well as the failure to take patient pharmacological history into account are proposed to be a source of the failure of what are likely effective compounds from showing promise in clinical trials. [ABSTRACT FROM AUTHOR]

Stress exposure can result in several proinflammatory alterations in the brain, including overexpression of the inducible isoform of nitric oxide synthase (iNOS) in the medial prefrontal cortex (mPFC). These changes may be involved in the development of many psychiatric conditions. However, it is unknown if iNOS in mPFC plays a significant role in stress-induced behavioral changes. The endocannabinoid (ECB) system is also influenced by stress. Its activation seems to be a counter regulatory mechanism to prevent or decrease the stress-mediated neuroinflammatory consequences. However, it is unclear if the ECB system and iNOS interact to influence stress consequences. This study aimed to test the hypothesis that the anti-stress effect of iNOS inhibition in mPFC involves the local ECB system, particularly the CB1 cannabinoid receptors. Male Wistar rats with guide cannula aimed at the mPFC were submitted to acute restraint stress (RS) for 2 h. In the following morning, rats received bilateral microinjections of vehicle, AM251 (CB1 antagonist; 100 pmol), and/or 1400W(iNOS selective inhibitor; 10-4, 10-3, or 10-2 nmol) into the prelimbic area of mPFC (PL-mPFC) before being tested in the elevated plus-maze (EPM). iNOS inhibition by 1400Wprevented the anxiogenic-like effect observed in animals submitted to RS. The drug did not promote behavior changes in naive animals, demonstrating a stress-dependent effect. The 1400W-anti-stress effect was prevented by local pretreatment with AM251. Our data suggest that iNOS inhibition may facilitate the local endocannabinoid signaling, attenuating stress effects. [ABSTRACT FROM AUTHOR]

Background: Blockade of cannabinoid CB1 or vanilloid TRPV1 receptors in the ventromedial prefrontal cortex of rats respectively increases or decreases the conditioned emotional response during re-exposure to a context previously paired with footshocks. Although these mechanisms are unknown, they may involve local modulation of glutamatergic and nitrergic signaling.Aim: We investigated whether these mechanisms are involved in the reported effects of CB1 and TRPV1 modulation in the ventromedial prefrontal cortex.Methods: Freezing behavior and autonomic parameters were recorded during the conditioned response expression.Results: The CB1 receptors antagonist NIDA, or the TRPV1 agonist capsaicin (CPS) in the ventromedial prefrontal cortex increased the conditioned emotional response expression, and these effects were prevented by TRPV1 and CB1 antagonism, respectively. The increased conditioned emotional response evoked by NIDA and CPS were prevented by an NMDA antagonist or a neuronal nitric oxide synthase inhibitor. A nitric oxide scavenger or a soluble guanylate cyclase inhibitor prevented only the NIDA effects and the CPS effect was prevented by a non-selective antioxidant drug, as nitric oxide can also induce reactive oxygen species production.Conclusion: Our results suggest that CB1 and TRPV1 receptors in the ventromedial prefrontal cortex differently modulate the expression of conditioned emotional response through glutamatergic and nitrergic mechanisms, although different pathways may be involved. [ABSTRACT FROM AUTHOR]

We evaluate whether acute restraint stress may affect the oxidative state of the cardiorenal system and the possible contribution of angiotensin II/AT1 receptors in such response. Male Wistar rats were restrained for 60 min within wire mesh chambers. Some rats were treated with losartan (selective AT1 receptor antagonist, 10 mg/kg, p.o., gavage) 30 min before being stressed. Biochemical analyses were conducted after the 60-min period of restraint. Treatment with losartan prevented the increase in mean arterial pressure (MAP), but not heart rate (HR) induced by acute stress. Phenylephrine-induced contraction of endothelium-intact aortas was not affected by acute stress. Losartan prevented the increase in both superoxide anion (O2•−) and hydrogen peroxide (H2O2) levels induced by acute stress in the aorta and renal cortex. Similarly, the augmented activity of superoxide dismutase (SOD) induced by acute stress in the aorta and renal cortex was prevented by losartan. Enhanced levels of O2•− and thiobarbituric acid reactive species (TBARS) were detected in the left ventricle (LV) of stressed rats, but losartan did not prevent these responses. Similarly, losartan did not inhibited stress-induced decrease in the concentration of nitrate/nitrite (NOx) and H2O2 in the left ventricle. Stress increased ROS generation and affected the enzymatic antioxidant system in the cardiorenal system. In addition to its well-known cardiovascular changes during acute stress, angiotensin II also induces ROS generation in the cardiorenal system in a tissue-specific manner. The increase in oxidative stress mediated by angiotensin II/AT1 receptors could be one mechanism by which acute stress predisposes to cardiorenal dysfunctions. [ABSTRACT FROM AUTHOR]

Background: Inducible or neuronal nitric oxide synthase gene deletion increases or decreases anxiety-like behavior in mice, respectively. Since nitric oxide and endocannabinoids interact to modulate defensive behavior, the former effect could involve a compensatory increase in basal brain nitric oxide synthase activity and/or changes in the endocannabinoid system. Thus, we investigated the expression and extinction of contextual fear conditioning of inducible nitric oxide knockout mice and possible involvement of endocannabinoids in these responses. Methods: We evaluated the effects of a preferential neuronal nitric oxide synthase inhibitor, 7-nitroindazol, nitric oxide synthase activity, and mRNA changes of nitrergic and endocannabinoid systems components in the medial prefrontal cortex and hippocampus of wild-type and knockout mice. The effects of URB597, an inhibitor of the fatty acid amide hydrolase enzyme, which metabolizes the endocannabinoid anandamide, WIN55,212-2, a nonselective cannabinoid agonist, and AM281, a selective CB1 antagonist, on contextual fear conditioning were also evaluated. Results: Contextual fear conditioning expression was similar in wild-type and knockout mice, but the latter presented extinction deficits and increased basal nitric oxide synthase activity in the medial prefrontal cortex. 7-Nitroindazol decreased fear expression and facilitated extinction in wild-type and knockout mice. URB597 decreased fear expression in wild-type and facilitated extinction in knockout mice, whereas WIN55,212-2 and AM281 increased it in wild-type mice. Nonconditioned knockout mice showed changes in the mRNA expression of nitrergic and endocannabinoid system components in the medial prefrontal cortex and hippocampus that were modified by fear conditioning. Conclusion: These data reinforce the involvement of the nitric oxide and endocannabinoids (anandamide) in stress-related disorders and point to a deregulation of the endocannabinoid system in situations where nitric oxide signaling is increased. [ABSTRACT FROM AUTHOR]

Stress exposure can result in several proinflammatory alterations in the brain, including overexpression of the inducible isoform of nitric oxide synthase (iNOS) in the medial prefrontal cortex (mPFC). These changes may be involved in the development of many psychiatric conditions. However, it is unknown if iNOS in mPFC plays a significant role in stress-induced behavioral changes. The endocannabinoid (ECB) system is also influenced by stress. Its activation seems to be a counter regulatory mechanism to prevent or decrease the stress-mediated neuroinflammatory consequences. However, it is unclear if the ECB system and iNOS interact to influence stress consequences. This study aimed to test the hypothesis that the anti-stress effect of iNOS inhibition in mPFC involves the local ECB system, particularly the CB 1 cannabinoid receptors. Male Wistar rats with guide cannula aimed at the mPFC were submitted to acute restraint stress (RS) for 2 h. In the following morning, rats received bilateral microinjections of vehicle, AM251 (CB 1 antagonist; 100 pmol), and/or 1400W (iNOS selective inhibitor; 10 -4 , 10 -3 , or 10 -2 nmol) into the prelimbic area of mPFC (PL-mPFC) before being tested in the elevated plus-maze (EPM). iNOS inhibition by 1400W prevented the anxiogenic-like effect observed in animals submitted to RS. The drug did not promote behavior changes in naive animals, demonstrating a stress-dependent effect. The 1400W-anti-stress effect was prevented by local pretreatment with AM251. Our data suggest that iNOS inhibition may facilitate the local endocannabinoid signaling, attenuating stress effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Coelho, Vila-Verde, Sartim, Uliana, Braga, Guimarães and Lisboa.)