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

Abstract

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(1 mg/kg); we found that opioid receptor antagonism increased AVP mRNA levels in cocaine-naive rats, but not in cocaine-withdrawn rats, suggesting less tonic opioid inhibition of PVN AVP neurons after chronic EDC.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.

Alcohol: A stimulant activating brain stress responsive systems with persistent neuroadaptation

“…Of interest, abnormal HPA activity in response to the dexamethasone test during alcohol withdrawal has also been found in humans (Hundt et al, 2001). This is further supported by the findings that an increase in AVP mRNA, but not CRF mRNA, was found in mice and rats during more than 2-week alcohol or cocaine withdrawal with HPA abnormal activation (Zhou et al, 2011b;Pang et al, 2013) (see more details in Section II). However, few studies have specifically addressed the involvement of AVP and V1b receptor systems in relapse-like drinking and the HPA modulation after chronic withdrawal from long-term alcohol exposure in rodent models, though AVP is a potent modulator of brain stress responsive systems and HPA axis.…”

“…The HPA hormones in response to chronic cocaine show a significant attenuation compared to the acute effects, indicating tolerance of HPA activity to chronic cocaine (Zhou et al, 1996a), as also found in cocaine dependent men (Mendelson et al, 1998). In early (1e2 days) cocaine withdrawal, there is a slight, but significant, increase in plasma ACTH levels at the nadir time point of circadian cycle (Zhou et al, 1996a(Zhou et al, , 2003a(Zhou et al, , 2003b(Zhou et al, , 2011b. During 14-day protracted withdrawal from chronic escalating-dose binge cocaine, there was a slight and persistent elevation of ACTH secretion, mediated through increased AVP activity in the paraventricular nucleus (Zhou et al, 2011b).…”

“…In early (1e2 days) cocaine withdrawal, there is a slight, but significant, increase in plasma ACTH levels at the nadir time point of circadian cycle (Zhou et al, 1996a(Zhou et al, , 2003a(Zhou et al, , 2003b(Zhou et al, , 2011b. During 14-day protracted withdrawal from chronic escalating-dose binge cocaine, there was a slight and persistent elevation of ACTH secretion, mediated through increased AVP activity in the paraventricular nucleus (Zhou et al, 2011b). In cocaine self-administration study, rats after escalating cocaine self-administration showed a blunted diurnal rhythm of circulating corticosterone levels during early withdrawal, with lower plasma corticosterone levels at the peak time point of the circadian cycle (Mantsch et al, 2003).…”

Opiate addiction and cocaine addiction: underlying molecular neurobiology and genetics

“…In early (1-2 day) cocaine withdrawal, there is a slight, but significant, increase in HPA hormones (68,69). During protracted withdrawal from chronic escalating-dose (but not steady-dose) "binge" cocaine, enhanced AVP/V1b expression was associated with persistent elevations of HPA activity (56).…”

“…Both CRF-R1 and AVP-V1b receptors are located on corticotropes in the anterior pituitary and drive the processing and release of ACTH and β-EP from the pro-opiomelanocortin (POMC) peptide, of particular interest for the field of addictive diseases (55,56). Endogenous opioids are critical in the control of the HPA axis.…”