Hypercortisolemia decreases dexamethasone half-life in rabbit.

The pharmacokinetics of dexamethasone have been found to be related to endogenous hypothalamic-pituitary-adrenal (HPA) axis activity. Lower plasma dexamethasone levels in psychiatric patients (especially depressed) who are dexamethasone suppression test (DST) nonsuppressors have previously been reported. Since DST nonsuppression is one measure of HPA axis hyperactivity and is usually associated with relatively increased plasma cortisol levels and lower post dose plasma dexamethasone levels, we hypothesized that hypercortisolemia can induce a more rapid disappearance of dexamethasone from plasma. We therefore studied the kinetics of dexamethasone in rabbits before and after a period of sustained hypercortisolemia produced by administration of IM hydrocortisone acetate, a slowly absorbed salt of cortisol. Mean dexamethasone half-life decreased significantly from baseline of 1.92 h on day zero in seven rabbits to 1.17 h on experimental day 17 of induced hypercortisolemia (P < 0.001), while there was no significant change in saline treated controls (n = 3). Dexamethasone half-life had returned to the baseline levels when retested 88 days later on experimental day 105. The results indicate that pronounced hypercortisolemia decreases dexamethasone half-life in rabbits, and support the concept that increased circulating cortisol levels induce hepatic enzymes that metabolize dexamethasone. Thus, the lower postdexamethasone plasma dexamethasone levels and decreased dexamethasone half-life in DST nonsuppressors may in part reflect the effect of prior or coincident hypercortisolemia.

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 9A.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.

Nalmefene causes greater hypothalamic-pituitary-adrenal axis activation than naloxone in normal volunteers: implications for the treatment of alcoholism.

Among other actions, opioid antagonists modulate the control endogenous opioids exert on the hypothalamic-pituitary-adrenal (HPA) axis. Naloxone, nalmefene, and naltrexone are the opioid antagonists approved for use in man and are primarily mu-opioid selective. Naltrexone and nalmefene have been demonstrated to be useful in the treatment of alcoholism. Compared with naloxone, nalmefene has a longer half-life, is more potent at the mu-receptor, and has a higher affinity for kappa- and delta-opioid receptors. We conducted an inpatient study comparing the effects of 10 and 30 mg doses of intravenous naloxone and nalmefene in normal, nonsubstance nor alcohol-abusing, volunteers. Significant increases in ACTH and cortisol were observed after both antagonists, without an apparent dose-response relationship; however, both doses of nalmefene resulted in greater HPA axis activation than either dose of naloxone (ACTH: p <0.005). These results indicate that kappa- and delta-opioids may play important roles in the regulation of the HPA axis; nalmefene may be useful as both a probe to explore the HPA axis physiology and as a pharmacotherapeutic agent.

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.

Electric fish approach stationary signal sources by following electric current lines.

African electric fish of a pulse species, Brienomyrus brachyistius (Mormyridae), housed singly in a large, circular arena, were presented with electrical stimuli which mimicked a conspecific intruder. Stimuli were produced with either dipolar or bipolar electrodes in three different geometries. We tracked the unconditioned approach response paths taken by the fish and compared tracks for each of the geometries. The results suggest that B. brachyistius can determine neither the distance nor the direction of an electric dipole from afar, but that they do manage to find the source by maintaining a precise alignment of their body axis parallel to the direction of the local electric field vector (parallel to current lines) while swimming. This behaviour ultimately leads to the current source. We propose that this behaviour may be a simple mechanism mediating the approach response of one electric fish to another.