Corticotropin-Releasing Factor (CRF) Sensitization of Ethanol Withdrawal-Induced Anxiety-Like Behavior is Brain Site Specific and Mediated by CRF-1 Receptors: Relation to Stress-Induced Sensitization

Abstract

In abstinent alcoholics, stress induces negative affect-a response linked to craving and relapse. In rats, repeated stresses at weekly intervals before 5-day ethanol diet sensitize withdrawalinduced anxiety-like behavior ("anxiety") that is blocked by a corticotrophin-releasing factor 1 (CRF-1)-receptor antagonist. Current experiments were performed to identify brain sites that support CRF involvement in stress sensitization of ethanol withdrawal-induced anxiety-like behavior. First, different doses of CRF microinjected weekly into the central amygdala (CeA) before ethanol exposure produced a dose-related sensitization of anxiety during ethanol withdrawal. Subsequently, CRF microinjection into the basolateral amygdala, dorsal raphe nucleus (DRN), or dorsal bed nucleus of the stria terminalis (d-BNST) also sensitized ethanol withdrawal-induced anxiety. In contrast, sensitization of ethanol withdrawal-induced anxiety was not observed after weekly CRF administration into the ventral-BNST, CA1-hippocampal region, or hypothalamic-paraventricular nucleus. Then, experiments documented the CRF receptor subtype responsible for CRF and stress sensitization of withdrawal-induced anxiety. Systemic administration of a CRF-1 receptor antagonist before CRF microinjection into the CeA, DRN, or d-BNST prevented CRF-induced sensitization of anxiety during ethanol withdrawal. Furthermore, repeated microinjections of urocortin-3, a CRF-2 receptor agonist, into the CRF-positive sites did not sensitize anxiety after withdrawal from ethanol. Finally, microinjection of a CRF-1 receptor antagonist into the CeA, DRN, or d-BNST before stress blocked sensitization of anxiety-like behavior induced by the repeated stress/ethanol withdrawal protocol. These results indicate that CRF released by stress acts on CRF-1 receptors within specific brain regions to produce a cumulative adaptation that sensitizes anxiety-like behavior during withdrawal from chronic ethanol exposure.

Stress-Induced Cocaine Seeking Requires a Beta-2 Adrenergic Receptor-Regulated Pathway from the Ventral Bed Nucleus of the Stria Terminalis That Regulates CRF Actions in the Ventral Tegmental Area

“…to (1) confirm the neurochemical phenotype of VTA-projecting vBNST CRF-positive neurons, (2) clarify the mechanism through which ␤-2 ARs regulate these neurons and determine how this regulation might change following cocaine exposure, and (3) examine the likelihood that ␤-2 AR in the vBNST may also regulate CRF and/or CRF actions in the VTA via parallel multisynaptic pathways. Consistent with the last possibility, BNST efferents can influence the VTA through multisynaptic pathways that include regions, such as the lateral habenula and rostromedial tegmental area (Dong and Swanson, 2006;Kaufling et al, 2009;Lammel et al, 2012).…”

“…Although it is likely that the mechanisms through which stress promotes relapse are not identical across drug classes, both CRF-R1 receptor activation (Shaham et al, 1997;Lê et al, 2000;Bruijnzeel et al, 2009) and central noradrenergic signaling Lê et al, 2005;Yamada and Bruijnzeel, 2011) Huang et al, 2010;Silberman et al, 2013) and opioids (Delfs et al, 2000;Fuentealba et al, 2000), suggesting that this pathway to the VTA, or parallel pathways originating in other BNST subregions may also contribute to withdrawal-related drug seeking.…”

“…In light of these findings, it is surprising that vBNST ␤-ARs have been found to exert inhibitory effects on neurons that project to the VTA, likely via stimulation of local GABA release (Dumont and Williams, 2004). Both GABAergic and glutamatergic projections from the BNST to the VTA have been identified (Georges andAston-Jones, 2001, 2002;Kudo et al, 2012;. Moreover, CRFpositive terminals within the VTA coexpress either the glutamatergic neuronal marker, vesicular glutamate transporter 2, or the GABAergic neuronal marker, glutamic acid decarboxylase, and make contacts that have morphological characteristics of either excitatory or inhibitory synapses, suggesting that CRF can be coreleased into the VTA along with either GABA or glutamate (Tagliaferro and Morales, 2008).…”

Prevention of Alcohol-Heightened Aggression by CRF-R1 Antagonists in Mice: Critical Role for DRN-PFC Serotonin Pathway

“…We also recently observed that CP-154,526 microinjected in the DRN reduced alcohol drinking CRF-R1 and 5-HT on alcohol-heightened aggression IM Quadros et al in rats and mice that drank excessively, but not in those animals that showed low-level or moderate alcohol drinking (Hwa et al, 2013). Sensitized anxiety-like behavior and increased drinking, in the context of withdrawal from alcohol, can also be prevented by CRF-R1 antagonists in the DRN and other sites (Huang et al, 2010;Knapp et al, 2011). Together, these results and ours indicate that CRF appears to play a role in excessive alcohol-related behaviors, whether it is escalated drinking leading to dependence, or escalated aggression caused by an acute, moderate dose of ethanol.…”

Transtornos relacionados ao uso de álcool e as mulheres: impacto nos circuitos integrativos e de neurorregulação do estresse

“…O álcool, tanto em curto como em logo prazo, promove profunda alteração no eixo HHA. O uso agudo de álcool ativa o eixo HHA, resultando em níveis elevados de glicocorticoides e diminuindo a ansiedade, ao passo que a exposição prolongada ao álcool promove hipertrofia adrenal e embotamento da resposta ao estresse, tendo efeito ansiogênico 20,21 . Também tem sido demonstrado que a desregulação do eixo HHA permanece mesmo após longos períodos de abstinência, interferindo nos mecanismos de coping frente a novos estressores e facilitando a recaída 22 .…”