Altered HPA Axis Responsivity to Metyrapone Testing in Methadone Maintained Former Heroin Addicts with Ongoing Cocaine 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(1 mg/kg); we found that opioid receptor antagonism increased AVP mRNA levels in cocaine-naive rats, but not in cocaine-withdrawn rats, suggesting less tonic opioid inhibition of PVN AVP neurons after chronic EDC.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: Interaction Between Ppvn Avp and Opioid Receptorsmentioning

confidence: 78%

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

Zhou

Litvin

Piras

et al. 2011

“…Similarly, responses to other probes of HPA axis function, such as ACTH infusion or metyrapone (an oral 11-b-hydroxylase inhibitor that blocks the final step in cortisol synthesis in the adrenal glands) testing have been found to be within normal limits in stabilized methadone-maintained subjects (Kreek, 1972(Kreek, , 1973aCushman Jr and Kreek, 1974;Kreek et al, 1984). In recent studies, we have also shown normal HPA response to metyrapone in stable-dose methadone-maintained subjects but not in methadone-maintained subjects with ongoing cocaine dependence (Schluger et al, 2001).…”

Section: Introductionmentioning

confidence: 77%

“…Positron emission tomography (PET) studies performed in stable-dose methadone-maintained subjects have shown that only 19-32% of m-opiate receptors are occupied during steady-state methadone therapy thereby allowing the remaining receptors to function in their normal physiologic capacity modulating pain and analgesia, immune function, and the HPA axis (Kling et al, 2000). The return of normal HPA axis responsivity during stable-dose methadone maintenance is likely due to this and, in part, to the normalization of opioidergic tone evidenced by the normalization of HPA responsivity to the removal of the other, and major, modulator of HPA axis response, glucocorticoid negative feedback, using metyrapone (an inhibitor of cortisol synthesis) (Kreek, 1972(Kreek, , 1973aKreek et al, 1984;Kennedy et al, 1990;Schluger et al, 2001). Further supporting the hypothesis of normalized opioidergic tone in methadone maintenance, former heroin addicts in long- term abstinence without methadone pharmacotherapy have increased HPA responsivity to metyrapone testing (Kreek et al, 1984).…”

Section: Discussionmentioning

confidence: 99%

“…In human studies, during acute, subacute, and chronic self-administration of drugs of abuse such as opiates, cocaine, and alcohol, evolving changes with time of exposure are observed in HPA axis stress response, hormone production, and also gene expression (Kreek, 1972;Gianoulakis et al, 1996;Mendelson et al, 1998;Wand et al, 1998;Schluger et al, 2001;Schuckit et al, 2001;O'Malley et al, 2002). In animal models, for instance, decreased hypothalamic CRF mRNA was found following 14-day binge pattern cocaine in rats; however, levels returned to normal 10 days following the final cocaine administration (Zhou et al, 1996a).…”

Section: Discussionmentioning

confidence: 99%

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Corticotropin-Releasing Factor Testing Reveals a Dose-Dependent Difference in Methadone Maintained Vs Control Subjects

Schluger

Bart

Green

et al. 2003

Opiate addiction is associated with abnormal function of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis. In general, addiction and withdrawal are associated with abnormal HPA responsivity as demonstrated by baseline, dexamethasone, and metyrapone testing. Following stabilization in methadone maintenance treatment, normalization of HPA axis responsivity is observed. To further investigate HPA axis function associated with heroin addiction and its treatment, saline placebo and human corticotropin-releasing factor (hCRF) were administered intravenously in two doses, one dose lower (0.5 mg/kg) and one dose higher (2.0 mg/kg) than the dose used in standard clinical diagnostics (100 mg), to 16 normal male volunteer controls (NV) and eight male stable-dose methadone-maintained former heroin addicts without ongoing drug or alcohol abuse or dependence (MM). Plasma adrenocorticotrophic hormone (ACTH) and cortisol levels were determined at serial time points. There was no difference in hormonal measurements between the two groups following placebo. NV as well as MM displayed a dose-response effect in plasma ACTH and cortisol levels. MM displayed a significantly greater increase in plasma ACTH levels than the NV following high-dose but not low-dose hCRF (po0.05). There was no significant difference in plasma cortisol levels between the two groups following high-dose hCRF. Thus, despite earlier documented normalization of behavioral function and of several measures of neuroendocrine function during long-term methadone maintenance, some abnormalities in HPA axis responsivity that may be a consequence of heroin exposure, or that may have existed prior to the addiction, can persist during stable methadone treatment.

“…We assessed plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) because they are known to be altered by chronic exposure to opiates and cocaine (Schluger et al, 2001;Zhou et al, 1999Zhou et al, , 2003. Finally, because glucocorticoids exert a negative feedback control on the release of ACTH and beta-endorphins by the anterior pituitary, we quantified mRNA expression of their precursor (POMC) in this region.…”

Section: Introductionmentioning

confidence: 99%

Effects of High-Dose Methadone Maintenance on Cocaine Place Conditioning, Cocaine Self-Administration, and Mu-Opioid Receptor mRNA Expression in the Rat Brain

Leri

Zhou

Goddard

et al. 2005

Methadone maintenance at appropriate doses can effectively reduce cocaine abuse in heroin-dependent individuals. In the present studies, we investigated the effect of high-dose methadone maintenance cocaine conditioned place preference (CPP) and cocaine intravenous self-administration. Rats implanted with methadone-filled osmotic mini-pumps (20 and 55 mg/kg/day, SC) and conditioned with cocaine (1, 5, and 20 mg/kg, i.p.) did not express cocaine CPP. Similarly, rats implanted with methadone pumps (55 mg/kg/day) after cocaine conditioning (20 mg/kg) displayed neither spontaneous nor cocaine-precipitated (20 mg/kg, i.p.) CPP. In contrast, methadone maintenance (30 and 55 mg/kg/day, SC) did not alter the intravenous self-administration (continuous schedule of reinforcement) of various doses of cocaine (0.1, 0.5, and 2.0 mg/kg/inf). To explore neuropharmacological interactions between methadone maintenance and cocaine conditioning, we quantitatively measured mRNA levels of mu-opioid receptor (MOR) and proopiomelanocortin genes 10 days after methadone maintenance. MOR mRNA levels in both the nucleus accumbens core and frontal cortex were significantly elevated in rats exposed to cocaine during CPP conditioning. However, upregulation of MOR mRNA levels in the nucleus accumbens core were reduced by methadone maintenance in a dose-dependent manner. In conclusion, our results suggest that high-dose methadone maintenance does not alter the direct reinforcing effect of cocaine, but blocks spontaneous and cocaine-precipitated cocaine-seeking, possibly by preventing MOR alterations in the nucleus accumbens core induced by cocaine conditioning.