Corticotropin-releasing factor-1 receptor involvement in behavioral neuroadaptation to ethanol: A urocortin ₁ -independent mechanism

Abstract

A common expression of neuroadaptations induced by repeated exposure to addictive drugs is a persistent sensitized behavioral response to their stimulant properties. Neuroplasticity underlying drug-induced sensitization has been proposed to explain compulsive drug pursuit and consumption characteristic of addiction. The hypothalamic-pituitary-adrenal (HPA) axis-activating neuropeptide, corticotropin-releasing factor (CRF), may be the keystone in drug-induced neuroadaptation. Corticosterone-activated glucocorticoid receptors (GRs) mediate the development of sensitization to ethanol (EtOH), implicating the HPA axis in this process. EtOHinduced increases in corticosterone require CRF activation of CRF1 receptors. We posited that CRF1 signaling pathways are crucial for EtOH-induced sensitization. We demonstrate that mice lacking CRF1 receptors do not show psychomotor sensitization to EtOH, a phenomenon that was also absent in CRF 1 ؉ 2 receptor doubleknockout mice. Deletion of CRF2 receptors alone did not prevent sensitization. A blunted endocrine response to EtOH was found only in the genotypes showing no sensitization. The CRF1 receptor antagonist CP-154,526 attenuated the acquisition and prevented the expression of EtOH-induced psychomotor sensitization. Because CRF1 receptors are also activated by urocortin-1 (Ucn1), we tested Ucn1 knockout mice for EtOH sensitization and found normal sensitization in this genotype. Finally, we show that the GR antagonist mifepristone does not block the expression of EtOH sensitization. CRF and CRF1 receptors, therefore, are involved in the neurobiological adaptations that underlie the development and expression of psychomotor sensitization to EtOH. A CRF/CRF1-mediated mechanism involving the HPA axis is proposed for acquisition, whereas an extrahypothalamic CRF/CRF1 participation is suggested for expression of sensitization to EtOH.addiction ͉ CP-154,526 ͉ HPA axis ͉ knockout mice ͉ psychomotor sensitization

Mifepristone in the Central Nucleus of the Amygdala Reduces Yohimbine Stress-Induced Reinstatement of Ethanol-Seeking

“…Importantly, Wulsin and co-workers also found no effect of mifepristone on the stress-induced response in the paraventricular nucleus of the hypothalamus, which points to extrahypothalamic site of action for its anti-stress and anti-depressant effects. CORT binding has been shown to negatively regulate HPA axis function in the hypothalamus, while it has stimulatory effects in extrahypothalamic regions, including the CeA (Makino et al, 1994;Pastor et al, 2008). Furthermore, inactivation of the CeA, but not the BLA, has been shown to block footshock-induced reinstatement of cocaine-seeking (McFarland et al, 2004).…”

Role of Corticotropin-Releasing Factor and Corticosterone in Behavioral Sensitization to Ethanol

“…Behavioral sensitization induced by ethanol (EtOH) has been largely studied in mice (Masur and Boerngen, 1980;Phillips et al, 1997;Broadbent et al, 2003;Pastor et al, 2008), but also demonstrated in rats (Correa et al, 2003) and humans (Newlin and Thomson, 1999). However, the neurobiological determinants of EtOH sensitization remain to be entirely elucidated.…”

“…Results pertaining to the participation of dopamine (Broadbent et al, 1995;Palmer et al, 2003), opioid (Pastor and Aragon, 2006;Abrahao et al, 2008), ␥-aminobutyric acid (Chester and Cunningham, 1999;Meyer et al, 2005), and glutamate (Broadbent et al, 2003;Meyer and Phillips, 2007) systems in ethanol sensitization have not provided consistent support. It is noteworthy that manipulation of hypothalamic-pituitary-adrenal (HPA)-axis components, such as corticotropin-releasing factor (CRF) or glucocorticoids, has been shown to critically modulate EtOH-induced behavioral sensitization (Roberts et al, 1995;Phillips et al, 1997;Fee et al, 2007;Pastor et al, 2008).…”

“…EtOH sensitization critically depends on CRF 1 activation; it is absent in CRF 1 knockout (KO) mice (Pastor et al, 2008) and reduced by the CRF 1 antagonist N-butyl-N-ethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine (CP-154,526) (Fee et al, 2007;Pastor et al, 2008). CRF 2 KO mice show normal EtOH sensitization (Pastor et al, 2008). CRF 1 is endogenously activated by CRF, but also by urocortin-1.…”

“…CRF 1 is endogenously activated by CRF, but also by urocortin-1. That EtOH sensitization is not absent in urocortin-1 KO animals (Pastor et al, 2008) suggests that CRF is the necessary ligand for EtOH sensitization to develop. However, combined CRF and urocortin-1 actions could still account for the involvement of CRF 1 .…”