James Schluger

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

In humans, mu- and kappa-opioid receptor agonists lower tuberoinfundibular dopamine, which tonically inhibits prolactin release. Serum prolactin is, therefore, a useful biomarker for tuberoinfundibular dopamine. The current study evaluated the unexpected finding that the relative mu- and kappa-opioid receptor selective antagonist nalmefene increases serum prolactin, indicating possible kappa-opioid receptor agonist activity. In all, 33 healthy human volunteers (14 female) with no history of psychiatric or substance use disorders received placebo, nalmefene 3 mg, and nalmefene 10 mg in a double-blind manner. Drugs were administered between 0900 and 1000 on separate days via 2-min intravenous infusion. Serial blood specimens were analyzed for serum levels of prolactin. Additional in vitro studies of nalmefene binding to cloned human kappa-opioid receptors transfected into Chinese hamster ovary cells were performed. Compared to placebo, both doses of nalmefene caused significant elevations in serum prolactin (p<0.002 for nalmefene 3 mg and p<0.0005 for nalmefene 10 mg). There was no difference in prolactin response between the 3 and 10 mg doses. Binding assays confirmed nalmefenes affinity at kappa-opioid receptors and antagonism of mu-opioid receptors. [35S]GTPγS binding studies demonstrated that nalmefene is a full antagonist at mu-opioid receptors and has partial agonist properties at kappa-opioid receptors. Elevations in serum prolactin following nalmefene are consistent with this partial agonist effect at kappa-opioid receptors. As kappa-opioid receptor activation can lower dopamine in brain regions important to the persistence of alcohol and cocaine dependence, the partial kappa agonist effect of nalmefene may enhance its therapeutic efficacy in selected addictive diseases.

Hypothalamic-pituitary-adrenocortical (HPA) axis response and biotransformation of oral naltrexone: preliminary examination of relationship to family history of alcoholism.

We examined HPA axis response to 50 mg oral naltrexone compared with placebo in 17 healthy male and female nonalcoholic subjects, approximately half of whom had a positive family history of alcoholism (FH+) and half of whom who did not (FH−). Mood response and naltrexone biotransformation were also examined at various intervals. Subjects participated in two morning test sessions (50 mg naltrexone or identical placebo pill) after an overnight stay in the Rockefeller University GCRC. For the total sample, ACTH and cortisol significantly increased after naltrexone compared with placebo (p < .05). Secondary analyses showed the FH+ subgroup had a different pattern of response over time compared with the FH− subgroup, with heightened ACTH and cortisol, and decreased vigor ratings, during naltrexone (p < .05). The results demonstrate that orally administered naltrexone acutely disinhibits the HPA axis, and that individuals with an assumed greater biological vulnerability to addiction, by virtue of familial alcoholism, had altered regulation of the HPA axis in part under the control of the endogenous opioid system. 166 words.

Altered HPA Axis Responsivity to Metyrapone Testing in Methadone Maintained Former Heroin Addicts with Ongoing Cocaine Addiction

Metyrapone testing, a provocation of hypothalamic-pituitary-adrenocortical (HPA) axis function, was performed in 39 in-patient subjects: 10 stable methadone-maintained former heroin addicts without ongoing drug or alcohol abuse or dependence (MM), eight methadone- maintained former heroin addicts without ongoing drug or alcohol abuse or dependence other than ongoing cocaine dependence (C-MM), and 21 normal volunteers (NV). Plasma adrenocorticotrophic hormone (ACTH) levels were determined in samples drawn at 9 A.M., just before administration of 2.25 g metyrapone orally and 4 and 8 hours afterward. Following metyrapone, C-MM had levels of ACTH that were significantly higher than both MM (p < .05) and NV (p < .01); whereas, MM and NV had levels that were comparable. Area under the plasma ACTH curves yielded similar results. This study documents hyper-responsivity to removal of glucocorticoid negative feedback associated with cocaine addiction, even in the setting of methadone maintenance for heroin addiction, which here and previously has been shown to be associated with normalization of HPA axis function.

Corticotropin-releasing factor testing reveals a dose-dependent difference in methadone maintained vs control subjects.

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 μg/kg) and one dose higher (2.0 μg/kg) than the dose used in standard clinical diagnostics (100 μg), 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 (p<0.05). 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.

DOWNREGULATION OF 5-HT1A RECEPTORS IN RAT HYPOTHALAMUS AND DENTATE GYRUS AFTER BINGE PATTERN COCAINE ADMINISTRATION

The effect of chronic cocaine exposure on the central serotonergic system in the rat was investigated using a selective 5‐HT1A receptor agonist, [3H]8‐hydroxy‐2‐(di‐N‐propylamino) tetralin (8‐OH‐DPAT), and a 5‐HT2A receptor antagonist, [3H]ketanserin, as tritiated ligands in a quantitative autoradiography study. Rats were administered cocaine in a “binge” pattern, 15 mg/kg/injection, three times a day, at 1‐h intervals for 14 days to mimic the pattern often seen in human cocaine addicts. A significant decrease in the binding of [3H]8‐OH‐DPAT was found in the ventromedial hypothalamus (P < 0.001) and the dorsal dentate gyrus (P < 0.01) in rats administered cocaine as compared with rats injected with saline. No significant difference in the binding of [3H]ketanserin was found in frontal, parietal, agranular insular, and piriform cortices, caudate‐putamen, olfactory tubercle, nucleus accumbens, thalamus, septohippocampal nucleus, and claustrum. Several studies have shown that 5‐HT1A receptor agonists have antidepressant properties. Other studies, in animal models, have shown that 5‐HT1A receptor agonists stimulate the hypothalamic–pituitary–adrenal axis, which is of interest, since chronic activation of this axis has been related to anxiety and depression. Our data show that the 5‐HT1A component of the serotonergic system is altered following chronic “binge” pattern cocaine administration in an animal model and may be related to changes in the HPA axis and behavior. Synapse 30:166–171, 1998.

Glucocorticoid negative feedback in methadone-maintained former heroin addicts with ongoing cocaine dependence: dose-response to dexamethasone suppression.

Combined cocaine and illicit opiate use is common. This study aimed to test the hypothesis that cocaine dependence in former heroin‐addicted patients maintained on methadone treatment is associated with enhanced glucocorticoid negative feedback. Multiple dose dexamethasone suppression tests, using a conventional 2.0 mg dose, and two lower doses, 0.5 mg and 0.125 mg, were performed in 10 methadone‐maintained former heroin addicts with ongoing cocaine dependence (C‐MM), 10 stabilized methadone‐maintained former heroin addicts with no ongoing drug or alcohol use (MM), and 22 normal volunteers (NV). At 9 hours, there was no difference in plasma adrenocorticotropin hormone (ACTH) and/or cortisol levels among groups on the baseline day, as well as after the two lower doses of dexamethasone. At 17 hours, C‐MM and MM had significantly lower plasma ACTH and/or cortisol levels than NV. However, C‐MM did not significantly differ from MM in their hormonal levels. When the hormonal responses to dexamethasone are expressed as magnitude of lowering from baseline, there was no significant difference at any dose among groups. Therefore, C‐MM exhibited a normal glucocorticoid negative feedback in the morning. Using the standard interpretation of dexamethasone suppression testing based on the examination of the actual hormonal levels rather than the difference from baseline condition, C‐MM appear to have glucocorticoid effects similar to MM, yet were both greater than NV in the late afternoon. Thus, further studies are needed to know whether altered glucocorticoid negative feedback is related to chronic cocaine exposure, or is the result of former heroin addiction and/or its long‐term treatment with methadone.

Acute subjective effects of dynorphin A(1-13) infusion in normal healthy subjects

Twelve healthy subjects with no history of substance abuse participated in a placebo-controlled single-blinded study of subjective response to acute i.v. administration of placebo and two doses of the natural shortened peptide sequence of the kappa-opioid agonist, dynorphin A(1-13) (low dose 120 micrograms/kg, high dose 500 micrograms/kg). Visual analog scales showed small but significant negative mood and positive drug effect 10 min post infusion in the high dose dynorphin compared to placebo infusion. The differences were no longer apparent at 30 min. These results show that dynorphin A(1-13), shown previously to have both neuroendocrine and modest analgesic effects, was well tolerated and produced modest transient subjective responses.

Relationships between Endocrine Functions and Substance Abuse Syndromes

Publisher Summary This chapter discusses the relationships between endocrine functions and substance-abuse syndromes. Important possible relationships between endocrine function, substance abuse, and addiction syndromes in general, including the early hypothesis that abnormalities in stress responsivity might contribute to the pathophysiology of these disorders, were first formally recognized in the late 1960s. Research reports that focused on the impact of one of the most devastating illicit drugs of abuse, heroin, on various specific components of endocrine function during cycles of addiction, as well as the very early reports on normalization of the perturbations caused by this short-acting opiate on endocrine function during long-term pharmacotherapy with the long-acting opioid agonist, methadone, first appeared in the early 1970s. Studies of both heroin addicts and former addicts in methadone maintenance treatment have been conducted in various therapeutic settings over the ensuing 30 years.