A Role for Brain Stress Systems in Addiction

Arginine vasopressin (AVP) from the paraventricular nucleus (PVN) of hypothalamus has important roles in regulation of the hypothalamic-pituitary-adrenal (HPA) axis and stress-related behaviors during chronic stress. It is unknown, however, whether AVP in the PVN is involved in the modulation of HPA activity after chronic cocaine exposure. Here, we examined the gene expression alterations of AVP in the hypothalamus, and V1b receptor and pro-opiomelanocortin (POMC) in the anterior pituitary, as well as HPA hormonal changes, in Fischer rats after chronic cocaine and withdrawal, using two different chronic (14-day) 'binge' pattern administration regimens: steady-dose cocaine (SDC, 45 mg/kg/day) and escalating-dose cocaine (EDC, 45 up to 90 mg/kg/day). There was a significant (7-fold) plasma adrenocorticotropic hormone (ACTH) elevation after chronic EDC (but not SDC), coupled with increased V1b and POMC mRNA levels in the anterior pituitary. From acute (1-day) to protracted (14-day) withdrawal from chronic EDC (but not from SDC), we found persistent elevations of both plasma ACTH and corticosterone levels and AVP mRNA levels in the PVN. Selective V1b antagonist SSR149415 (5 mg/kg) attenuated acute withdrawal-induced HPA activation after EDC. To study potential roles of endogenous opioids in modulating the AVP gene, we administered naloxone (1 mg/kg); we found that opioid receptor antagonism increased AVP mRNA levels in cocaine-naive rats, but not in cocaine-withdrawn rats, suggesting less tonic opioid inhibition of PVN AVP neurons after chronic EDC. To assess the effects of cocaine withdrawal on sub-populations of PVN AVP neurons, we utilized AVP-enhanced green fluorescent protein (EGFP) promoter transgenic mice and found that acute withdrawal following chronic EDC increased the number of AVP-EGFP neurons in the parvocellular PVN (pPVN). These results suggest that during protracted withdrawal, enhanced pPVN AVP gene expression is associated with persistent elevations of basal HPA activity; a hyposensitivity of PVN AVP gene expression to naloxone is indicative of reduced opioidergic tone. Our studies indicate that the AVP and its V1b receptor system may be a potential therapeutic target for treating anxiety and depressive symptoms associated with cocaine addiction.

Section: Discussionmentioning

confidence: 60%

Persistent Increase in Hypothalamic Arginine Vasopressin Gene Expression During Protracted Withdrawal from Chronic Escalating-Dose Cocaine in Rodents

Zhou

Litvin

Piras

et al. 2011

“…Chronic exposure to high levels of GCs in the brain, similar to that caused by long-term ethanol exposure, has been shown to upregulate CRF expression in the amygdala (Koob, 2008;Makino et al, 1994Makino et al, , 2002Shepard et al, 2000;Swanson and Simmons, 1989). Blocking GRs in the amygdala prevents the excitation of CRF-containing neurons (Gray and Bingaman, 1996), which may decrease the CRF activation necessary for reinstatement.…”

Section: Discussionmentioning

confidence: 99%

“…Upon ligand binding, GR translocates to the nucleus, and regulates neuronal target gene expression (Beato and Sanchez-Pacheco, 1996), including downregulation of the GR itself. However, under chronic stress this feedback becomes deregulated, leading to the variety of maladaptive syndromes such as anxiety and various forms of depressive disorders (Sapolsky, 2000) and addiction, including alcohol dependence (Koob, 2008). Indeed, chronic ethanol intake leads to alterations in the homeostatic functioning of GCs (cortisol in humans, corticosterone (CORT) in rodents), which can lead to neuroadaptations that increase susceptibility to AUDs (Koob, 2008;Shaham and Hope, 2005).…”

Section: Introductionmentioning

confidence: 99%

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

Simms

Haass‐Koffler

Bito-Onon

et al. 2011

Chronic ethanol exposure leads to dysregulation of the hypothalamic-pituitary-adrenal axis, leading to changes in glucocorticoid release and function that have been proposed to maintain pathological alcohol consumption and increase vulnerability to relapse during abstinence. The objective of this study was to determine whether mifepristone, a glucocorticoid receptor antagonist, plays a role in ethanol self-administration and reinstatement. Male, Long-Evans rats were trained to self-administer either ethanol or sucrose in daily 30 min operant self-administration sessions using a fixed ratio 3 schedule of reinforcement. Following establishment of stable baseline responding, we examined the effects of mifepristone on maintained responding and yohimbine-induced increases in responding for ethanol and sucrose. Lever responding was extinguished in separate groups of rats and animals were tested for yohimbine-induced reinstatement and corticosterone release. We also investigated the effects of local mifepristone infusions into the central amygdala (CeA) on yohimbine-induced reinstatement of ethanol-and sucrose-seeking. In addition, we infused mifepristone into the basolateral amygdala (BLA) in ethanol-seeking animals as an anatomical control. We show that both systemic and intra-CeA (but not BLA) mifepristone administration suppressed yohimbine-induced reinstatement of ethanol-seeking, while only systemic injections attenuated sucroseseeking. In contrast, baseline consumption, yohimbine-induced increases in responding, and circulating CORT levels were unaffected. The data indicate that the CeA plays an important role in the effects of mifepristone on yohimbine-induced reinstatement of ethanolseeking. Mifepristone may be a valuable pharmacotherapeutic strategy for preventing relapse to alcohol use disorders and, as it is FDA approved, may be a candidate for clinical trials in the near future.

“…To further investigate the neural substrates underlying the CRF 2 receptor-mediated vulnerability, in situ hybridization studies are also carried out. In particular, expression of the key catecholamine and γ-aminobutyric acid (GABA) synthesis enzymes tyrosine hydroxylase (TH) and glutamic acid decarboxylase (GAD 67 ) is assessed in stress-and drug dependence-relevant brain regions, such as the ventral tegmental area (VTA), the locus coeruleus (LC), the central (CeA), and the basolateral (BLA) nucleus of the amygdala (Esclapez et al, 1994;Ingallinesi et al, 2012;Koob, 2008;Papaleo et al, 2007;Phelps and LeDoux, 2005;Vrana et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal

Morisot

Rouibi

Contarino

2015

Vulnerability to stressful life events is a hallmark of drug dependence that may persist long after cessation of drug intake and dramatically fuel key clinical features, such as deregulated up-shifted motivational states and craving. However, to date, no effective therapy is available for reducing vulnerability to stressful events in former drug users and drug-dependent patients, mostly because of poor knowledge of the mechanisms underlying it. In this study, we report that genetic inactivation of the stress-responsive corticotropin-releasing factor receptor-2 (CRF 2 − / − ) completely eliminates the reemergence of increased nonrewarded nose-pokes, reflecting up-shifted motivational states, triggered by ethological environmental stressors long after cessation of morphine administration in mice. Accordingly, CRF 2 receptor deficiency completely abolishes the increase in biomarkers of synthesis of major brain motivational substrates, such as ventral tegmental area (VTA) dopamine (DA) and amygdala γ-aminobutyric acid (GABA) systems, associated with the stress-induced reemergence of upshifted motivational states long after opiate withdrawal. Nevertheless, neither CRF 2 receptor deficiency nor long-term opiate withdrawal affects amygdala CRF or hypothalamus CRF expression, indicating preserved brain stress-coping systems. Moreover, CRF 2 receptor deficiency does not influence the locomotor or the anxiety-like effect of long-term opiate withdrawal. Thus, the present results reveal an essential and specific role for the CRF 2 receptor in the stress-induced reemergence of up-shifted motivational states and related alterations in brain motivational systems long after opiate withdrawal. These findings suggest new strategies for the treatment of the severe and longlasting vulnerability that inexorably follows drug withdrawal and hinder drug abstinence.