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  • An intriguing feature of the


    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 Cytidine 5-triphosphate 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 Cytidine 5-triphosphate 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].
    Conclusions New and exciting evidence supports the proposal that both CRF1 and CRF2 receptors play a relevant role in CRF-dependent neuroadaptations determining stress-induced relapse to drug seeking behaviour. Fig. 1 depicts the basic neuronal circuit involved in stress-induced relapse to drug seeking. Most of the available evidence supporting the existence of this circuit has been obtained in cocaine experienced rats. However, there is evidence to suggest that this may be a general circuit associated with stress-induced relapse to most drugs of abuse. As shown in Fig. 1, stressful stimuli such as footshock activate noradrenergic neurons in the brain stem A1 (ventrolateral medulla, VLM) and A2 (nucleus of the solitary tract, NTS) noradrenergic neuronal groups. A1 noradrenergic neurons have axon collaterals innervating the BNST and the CeA [53]. Thus, the activation of these neurons impacts the neuronal activity of both subnuclei of the extended amygdala. It has been shown that noradrenaline increases the activity of CeA CRF neurons that innervate the BNST. Thus, CRF is released in the BNST by the activation of CeA neurons and by the direct action of noradrenaline in the BNST. The precise mechanisms by which noradrenaline activates the release of BNST CRF is unknown. It is proposed that released CRF activates BNST CRF containing neurons projecting to the VTA by acting on CRF1 receptors. As a result of this activation, CRF is released in the VTA. An alternative pathway could be an indirect connection with the VTA through the lateral hypothalamus and/or the pedunculopontine nucleus (PPT) [32], [67]. In cocaine-experienced rats, but not in naïve rats, the CRF released in the VTA induces VTA glutamate release by activating CRF2 receptors located presynaptically in glutamatergic nerve terminals. As shown [26], [34] this VTA glutamate sensitization leads to the activation of VTA dopaminergic neurons. As a result of this dopaminergic activation, increases in the activity of the prefrontal cortex, via the nucleus accumbens core, trigger motor behaviour and relapse to drug seeking [12], [13].