Fine-tuning of defensive behaviors in the dorsal periaqueductal gray by atypical neurotransmitters

Abstract

This paper presents an up-to-date review of the evidence indicating that atypical neurotransmitters such as nitric oxide (NO) and endocannabinoids (eCBs) play an important role in the regulation of aversive responses in the periaqueductal gray (PAG). Among the results supporting this role, several studies have shown that inhibitors of neuronal NO synthase or cannabinoid type 1 (CB1) receptor agonists cause clear anxiolytic responses when injected into this region. The nitrergic and eCB systems can regulate the activity of classical neurotransmitters such as glutamate and γ-aminobutyric acid (GABA) that control PAG activity. We propose that they exert a ‘fine-tuning’ regulatory control of defensive responses in this area. This control, however, is probably complex, which may explain the usually bell-shaped dose-response curves observed with drugs that act on NO- or CB1-mediated neurotransmission. Even if the mechanisms responsible for this complex interaction are still poorly understood, they are beginning to be recognized. For example, activation of transient receptor potential vanilloid type-1 channel (TRPV1) receptors by anandamide seems to counteract the anxiolytic effects induced by CB1 receptor activation caused by this compound. Further studies, however, are needed to identify other mechanisms responsible for this fine-tuning effect.

The endocannabinoid, endovanilloid and nitrergic systems could interact in the rat dorsolateral periaqueductal gray matter to control anxiety-like behaviors

“…However, this anxiolytic-like response is lost after the injection of higher AEA doses, characterizing an inverted U-shaped curve [20,29]. This finding agrees with other observations indicating that the emotional effects of cannabinoids compounds occur in a biphasic dose-dependent way, inducing anxiolytic-like effects at lower doses and no response, or even an anxiogenic one, at higher doses [5,12,15,17,19,33]. This profile could be explained by the capacity of cannabinoids to bind to different classes of receptors, such as CB 1 and TRPV 1 , and influencing the release of neurotransmitters such as GABA, glutamate and NO, which may have distinct roles in the modulation emotional responses [14,16,33,34,35].…”

“…This profile could be explained by the capacity of cannabinoids to bind to different classes of receptors, such as CB 1 and TRPV 1 , and influencing the release of neurotransmitters such as GABA, glutamate and NO, which may have distinct roles in the modulation emotional responses [14,16,33,34,35]. In opposition to CB 1 receptor activation, TRPV 1 receptor activity could facilitate defensive behaviors by increasing calcium influx and stimulation of NO production, which, in turn, could act presynaptically as a retrograde messenger stimulating glutamate release [5,12,36].…”

“…Since NO is a highly diffusible gas that easily penetrate into subjacent neurons, it can modulate several neurotransmitters, including the endocannabinoid, endovanilloid, glutamatergic and GABAergic systems [5]. Thus, it is plausible that the anxiolytic-or pro-aversive-like effects induced by NO could be due to complex interactions between these systems.…”

“…Specifically, the dorsolateral (dlPAG) column has been proposed as one of the main neural substrate for the control of fear-and anxiety-related behaviors [3,4]. These responses are modulated by different brain systems and involve both typical (glutamate, GABA, serotonin, neuropeptides) and atypical neurotransmitters, such as nitric oxide (NO) and endocannabinoids [5].…”

Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey

“…Finding an appropriate antibody against TRPV1 to use in the western blotting study was a challenge. A number of papers have questioned the presence of TRPV1 in the brain (Fogaça et al, 2012;Madasu et al, 2015;Martins et al, 2014). However, recently, Navarria et al, demonstrated that TRPV1 is present in the hippocampus, and is upregulated in Wistar rats exposed to restraint stress (Navarria et al, 2014).…”