CRF dependent sensitization of VTA

CRF-dependent sensitization of VTA glutamate release after repeated administration of cocaine has also been documented in an electrophysiological study recording from glutamatergic synapses in VTA containing slices from mice repeatedly treated with cocaine [44]. In this case, both pre and postsynaptic modifications were reported. However, the CRF receptor type involved in presynaptic modifications was not analyzed further. Interestingly, a non-contingent administration of cocaine was used suggesting that the CRF-mediated sensitization of VTA glutamate release reported in cocaine-experienced rats [26], [34] is not related to the contingency of the auto-administration process, but to the repeated presence of cocaine itself.
Possible role of CRF-BP in CRF/CRF2 receptor actions in the VTA An intriguing feature of the pre and postsynaptic processes at the level of the VTA that have been shown to be mediated by CRF2 receptors [9], [34] is that they are exerted only by agonists with high affinity for both CRF2 receptors and CRF-BP. The four endogenous peptides of the CRF system have high affinity for CRF2 receptors, but only CRF and urocortin-1 have high affinity for CRF-BP. Thus, CRF and/or urocortin-1 could be acting in the VTA. It is important to note that urocortin-1 is expressed in VTA dopaminergic neurons [45]. It has also been shown that CRF-BP is expressed in a subset of VTA dopaminergic neurons [46]. Our recent report [47] showing that CRF-BP readily enters the regulated secretory pathway in neuronal and endocrine cells suggests that the regulation of CRF-BP release from nerve terminals/dendrites of CRF-BP containing neurons may be an additional factor that should be considered in further studies. Interestingly, CRF-BP has been linked to alcoholism in human genetic studies [48], [49], [50].
How does footshock activate CRF-mediated transmission in the extended amygdala? The BNST is the Meropenem region with the highest concentration of noradrenaline in the brain [51] especially in its most anterior pole [52]. This rich noradrenergic innervation to the BNST originates mainly from A1 ventrolateral medulla (VML) and A2 hindbrain noradrenergic nuclei [53], [54]. The CeA also receives noradrenergic innervation from the A1 noradrenergic nucleus [53]. Several studies have shown that exposure to fear-related stimuli activate these noradrenergic neurons [55], [56]. The neurochemical consequences of increasing noradrenaline levels in the BNST have led us to propose that the BNST plays a key role relaying and integrating limbic and autonomic information related to stress responses [57]. Recently, Rinaman [58] has thoroughly reviewed existing evidence showing the role of A2 noradrenergic neurons in physiological processes that once imbalanced could account for pathological processes such as drug addiction. The activation of α2-adrenergic receptors decreases electrical [59] and K+-induced release of noradrenaline in the BNST [60], [61], [62]. Interestingly, it has been shown that systemic administration of clonidine, a selective α2-adrenergic agonist attenuates stress- but not cocaine-induced relapse to cocaine seeking [63]. This observation was also extended to stress-induced relapse to heroin-seeking [64] suggesting the existence of a common mechanism explaining stress-induced relapse to addictive drugs. A functional interaction between noradrenaline and CRF has been shown, and that CRF acts downstream of noradrenaline [65]. Noradrenaline increases GABA-IPSCs in the BNST [66] and it was suggested that this was due to noradrenaline-induced depolarization of local GABA neurons that could in turn control BNST output neurons innervating the VTA. However, this hypothesis awaits further clarification of the differences in the existing anatomical evidence regarding the innervation between the extended amygdala and the VTA [33].