Anxiety disorders are the most common mental illness in the USA affecting 18% of the population. The cause(s) of anxiety disorders is/are not completely clear, and research in the neurobiology of anxiety at the molecular level is still rather limited. Although mounting clinical and preclinical evidence now indicates that oxidative stress may be a major component of anxiety pathology, whether oxidative stress is the cause or consequence remains elusive. Studies conducted over the past few years suggest that anxiety disorders may be characterised by lowered antioxidant defences and increased oxidative damage to proteins, lipids, and nucleic acids. In particular, oxidative modifications to proteins have actually been proposed as a potential factor in the onset and progression of several psychiatric disorders, including anxiety and depressive disorders. Oxidised proteins are normally degraded by the proteasome proteolytic complex in the cell cytoplasm, nucleus, and endoplasmic reticulum. The Lon protease performs a similar protective function inside mitochondria. Impairment of the proteasome and/or the Lon protease results in the accumulation of toxic oxidised proteins in the brain, which can cause severe neuronal trauma. Recent evidence points to possible proteolytic dysfunction and accumulation of damaged, oxidised proteins as factors that may determine the appearance and severity of psychotic symptoms in mood disorders. Thus, critical interactions between oxidative stress, proteasome, and the Lon protease may provide keys to the molecular mechanisms involved in emotional regulation, and may also be of great help in designing and screening novel anxiolytics and antidepressants.

[481][482][483][484][485][486][487][488] 2006) have shown that glutamatergic synapses in the ventral portion of the medial prefrontal cortex (vMPFC) modulate baroreflex activity. Moreover, glutamatergic neurotransmission in the vMPFC can be modulated by the endocannabinoids system (eCBs), particularly the endocannabinoid anandamide, through presynaptic CB 1 receptor activation. Therefore, in the present study, we investigated eCBs receptors that are present in the vMPFC, and more specifically whether CB1 receptors modulate baroreflex activity. We found that bilateral microinjection of the CB 1 receptor antagonist AM251 (100 or 300 pmol/200 nl) into the vMPFC increased baroreflex activity in unanesthetized rats. Moreover, bilateral microinjection of either the anandamide transporter inhibitor AM404 (100 pmol/200 nl) or the inhibitor of the enzyme fatty acid amide hydrolase that degrades anandamide, URB597 (100 pmol/200 nl), into the MPFC decreased baroreflex activity. Finally, pretreatment of the vMPFC with an ineffective dose of AM251 (10 pmol/200 nl) was able to block baroreflex effects of both AM404 and URB597. Taken together, our results support the view that the eCBs in the vMPFC is involved in the modulation of baroreflex activity through the activation of CB1 receptors, which modulate local glutamate release.anandamide; autonomic system; cannabinoids; infralimbic cortex; prelimbic cortex THE MEDIAL PREFRONTAL CORTEX (MPFC) is a limbic structure that is involved in the modulation of autonomic responses exerting influence on the cardiovascular system in rats (44, 57). The ventral portion of the MPFC (vMPFC), which is compounded by the infralimbic (IL), prelimbic (PL), and dorsal peduncular cortexes (41, 61), is involved in the modulation of baroreflex activity (49,56).Glutamatergic terminals and ionotropic glutamate receptors were reported in the vMPFC of rats (18,36). Furthermore, a previous study from our group showed that local injection of L-glutamate into the vMPFC evokes an activation of both sympathetic and parasympathetic activities on the heart of unanesthetized rats (48). Moreover, the glutamatergic system present in the vMPFC is involved in baroreflex modulation (45).In the central nervous system (CNS), the endocannabinoid anandamide is synthesized on demand in postsynaptic neurons, after calcium influx increase (13,42). Anandamide immediately diffuses to the synaptic cleft, activating CB 1 cannabinoid receptors, which are located in presynaptic terminals (59). The action of anandamide is limited by its reuptake through a putative anandamide transporter, being subsequently metabolized by the intracellular enzyme fatty acid amide hydrolase (FAAH) that is located in postsynaptic neurons (14, 43). These two mechanisms, which cooperate to attenuate anandamide signaling in the CNS, can be pharmacologically inhibited by drugs such as AM404 (anandamide re-uptake inhibitor) and URB597 (FAAH inhibitor).The CB 1 cannabinoid receptor is one of the most abundant G protein-coupled receptors in the brain and ...