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    • br Conclusions New and exciting

    2020-07-27


    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 CPI-455 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].
    Introduction The dorsal periaqueductal gray matter (dPAG) is a midbrain site markedly involved in fear/anxiety-evoked responses as well as in nociception (see, for example, Bandler and Carrive, 1988, Deakin and Graeff, 1991, Fardin et al., 1984a, Fardin et al., 1984b, Litvin et al., 2007). Chemical or electrical stimulation of dPAG elicits defensive behavior such as freezing, flight and fight reaction, escalation of risk assessment behavior and arousal (e.g., Bandler and Carrive, 1988, Schenberg et al., 2005) and autonomic activation (e.g., tachycardia, hypertension, tachypnea — Bandler et al., 1991, Hayward et al., 2003, McDougall et al., 1985). These responses are generally accompanied by antinociception (e.g., Coimbra and Brandão, 1997, Fanselow, 1991). Among the various neurotransmitter systems pointed out to play a role in the mediation of defensive and antinociceptive responses elicited by environmentally aversive stimuli, the neuropeptide corticotropin-releasing factor or hormone (CRF or CRH) has attracted the interest of many researchers investigating its role in the modulation of defensive reactions (Baldwin et al., 1991, Berridge and Dunn, 1989, Carvalho-Netto et al., 2007, Litvin et al., 2007, Stenzel-Poore et al., 1994). CRF is a 41-amino acid peptide that activates the hypothalamo–pituitary–adrenal (HPA) axis, releasing, at the end of a cascade, glucocorticoids from the adrenal gland. HPA axis hyperactivation has been related to several brain disturbances such as anxiety disorders, depression, epilepsy and drug addiction (Allen et al., 2011, Kanner, 2011, Lim et al., 2011, Pariante and Lightman, 2008). Besides its action on the HPA axis, CRF also acts in other brain areas such as the amygdala (Carrasco and Van de Kar, 2003, Shekhar et al., 2005), bed nucleus of stria terminalis (Sahuque et al., 2006), locus coeruleus (Chen et al., 1992), dorsal raphe nucleus (Carrasco and Van de Kar, 2003) and PAG (Borelli and Brandão, 2008, Martins et al., 1997) increasing anxiety-like responses in various animal tests.