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Extant data, mostly from studies in vitro, suggest that coumarin and nicotine are both metabolized by CYP2A6, a cytochrome P450 isozyme. In order to investigate this issue further, the activity of this enzyme in vivo was measured in 37 non-smokers and 37 smokers using coumarin (2.0 mg, PO) as the metabolic probe. The percentage of coumarin metabolized to 7-hydroxycoumarin in 8 h was measured in urine by high-pressure liquid chromatography. There was more than 10-fold variability in coumarin metabolism in both groups. Coumarin metabolism was significantly reduced in smokers (46.6 +/- 4.4%) as compared to non-smokers (66.4 +/- 3.5%; p < or = .001). The results support previous in vitro findings that both coumarin and nicotine are metabolized, at least in part, by a common pathway, which most likely is CYP2A6. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to compare the effects of contingent and noncontingent cocaine administration on plasma levels of corticosterone in rats. Male rats were trained to self-administer cocaine under a fixed-ratio 5 schedule. The rats were yoked such that the delivery of cocaine (0.25 mg/kg/infusion) to one rat (contingent cocaine) produced the simultaneous noncontingent delivery of the same dose of cocaine (noncontingent cocaine) or saline (noncontingent saline) to other rats. Although saline administration had no effect, plasma corticosterone levels were significantly higher in rat receiving contingent cocaine compared to those receiving noncontingent cocaine. These results demonstrate that the active vs. passive administration of cocaine can differentially affect this neuroendocrine response.

The present study examined the persistent functional consequences associated with exposure to single and multiple doses of (+/-) 3,4-methylenedioxymethamphetamine (MDMA) as reflected by the neuroendocrine responses to d,l-fenfluramine (FEN). Adult male rats were administered a single dose of MDMA (20 mg/kg, s.c.) and challenged 2 weeks later with saline or FEN (2, 4, 6 and 8 mg/kg, s.c.). The corticotropin (ACTH) response to FEN (6 and 8 mg/kg) was blunted and the prolactin response to FEN (4 and 6 mg/kg) was enhanced in MDMA pre-treated rats. The ACTH and prolactin responses to FEN (6 mg/kg, s.c.) were then evaluated 4, 8 and 12 months after exposure to single and multiple doses MDMA (20 mg/kg, s.c. and 20 mg/kg, s.c., bid, x 4 days, respectively). The ACTH response to FEN was significantly reduced at 4 and 8 months in both MDMA treatment groups, and at 12 months in the multiple dose group only. In contrast, the prolactin response to FEN was enhanced in both groups of MDMA treated rats at 4 months, but only in the multiple dose group at 8 months. By 12 months, the prolactin response to FEN had normalized. Following multiple doses of MDMA, 5-HT concentrations were reduced significantly in the frontal cortex at 4 and 12 months. The results indicate that exposure to single or multiple doses of MDMA can produce functional alterations which can persist for months, whereas the biochemical sequelae were less robust and shorter lived.

The present study characterized the response of the hypothalamo-pituitary-adrenal axis after the acute administration of enantiomeric pairs of drugs that bind to phencyclidine (PCP) and sigma receptors. Rats were injected with the enantiomers of 1-(1-phenylcyclohexyl)-3-methylpiperidine (PCMP), N-allylnormetazocine (SKF 10,047), dioxadrol (dexoxadrol and levoxadrol) or pentazocine, and plasma levels of adrenocorticotropin (ACTH) and corticosterone were determined by radioimmunoassay. The effects of the enantiomers of PCMP and dioxadrol showed stereospecificity as both (+)-PCMP and dexoxadrol increased plasma levels of ACTH and corticosterone but (-)-PCMP and levoxadrol had no effect. Whereas (-)-pentazocine produced greater responses than (+)-pentazocine, the two enantiomers of SKF 10,047 did not show stereoselectivity. Although the potency of the enantiomers of PCMP and dioxadrol parallel their affinity for binding to PCP receptors, the potency of the enantiomers of pentazocine did not. These results suggest that although the stimulation of the hypothalamo-pituitary-adrenal axis by PCP and drugs with PCP-like activity might be due to interactions with PCP receptors, the effects of pentazocine also involve interactions at other sites.

The authors present an innovative approach for providing freshman and sophomore medical students with their initial exposure to the problems of alcohol and other drug abuse. Students in small interactive group seminars teach each other about the major areas of substance abuse: treatment, prevention/education, research, and law enforcement. They are aided by group moderators, by resource professionals, and by recovery teachers as they make field trips, attend 12-step meetings, and get background material. They utilize audiovisuals, role-plays, and programmed patients in a report/debate format. Effects of this seminar on their attitudes have been measured and are presented.

The characterization of the sigma receptor has been hampered by the lack of a functional bioassay system. Drugs that bind to sigma receptors have been reported to inhibit carbachol-induced phosphatidylinositol turnover in rat brain; however, these drugs might directly affect muscarinic acetylcholine receptors. The purpose of the present study was to determine the affinity for muscarinic receptors and the antimuscarinic activity of sigma and phencyclidine receptor ligands. All of the drugs tested inhibited the binding of [3H]N-methylscopolamine to guinea pig cerebral cortical membranes with KI values in the micromolar range and also inhibited carbachol-induced contractions in the guinea pig ileum. These results demonstrate that these compounds have substantial antimuscarinic activity which might limit the use of the inhibition of carbachol-induced phosphatidylinositol turnover as a functional assay system for studying sigma ligands. Furthermore, this antimuscarinic activity must be considered when evaluating the effects of these compounds after in vivo administration.

Multiple opiate receptor agonists and antagonists have been found to produce different patterns of anterior pituitary hormone release. The present studies examined the pattern of anterior pituitary hormone release produced by buprenorphine. The effects of the kappa agonist ethylketocyclazocine on thyroid stimulating hormone release were also examined. Following buprenorphine, serum levels of corticosterone and luteinizing hormone were not changed while growth hormone release was stimulated in a dose-dependent manner. Prolactin release was stimulated after the lowest dose of buprenorphine while the highest dose induced a fall in serum prolactin. Similar biphasic effects on thyroid stimulating hormone were seen after either buprenorphine or ethylketocyclazocine. The results provide support for the role of multiple opiate receptors in opiate-induced changes in anterior pituitary hormone release.

Naloxone-induced hypothermia is a sensitive indicator of mu-type opiate dependence in the rat. The present study investigated whether naloxone produces hypothermia in chronically PCP-treated rats. Rats were given daily injections of saline or PCP (10.0 mg/kg s.c.) for 7 days, and on day 8 challenged with naloxone (2.0 mg/kg s.c.). There were no differences between chronic saline- and PCP-treated subjects, indicating that the repeated administration of 10.0 mg/kg per day of PCP does not produce mu-type opiate dependence as reflected by naloxone-precipitated hypothermia.

Analgesia and cardiovascular changes produced by electrical stimulation of the midbrain periaqueductal gray matter were examined in the lightly pentobarbital-anesthetized rat. The current intensity required to elicit analgesia was first determined, using the tail-flick test, after which the effects on arterial pressure and heart rate were recorded from stimulating at the same intensity. Intensity thresholds for decreases and/or increases in arterial pressure were also ascertained at the same sites. Although stimulation at the analgesia threshold produced increases in arterial pressure at more than 60% of the sites within the periaqueductal gray, decreases, no change, and mixed responses were also observed. Below the periaqueductal gray, increases in arterial pressure occurred at analgesia threshold for more than 70% of the sites studied, and no cardiovascular changes were found for 20% of the sites. Above the periaqueductal gray, no change and mixed responses were the predominant effects at analgesia threshold. A correlation across sites within the periaqueductal gray was found between the threshold for stimulation-produced analgesia and the threshold for a change in arterial pressure. No reliable alterations in heart rate were observed at any stimulation site. These results are in agreement with the existence of a common midbrain substrate for both the regulation of pain inhibition and cardiovascular function. However, they indicate that analgesia resulting from stimulation of the periaqueductal gray matter does not necessarily occur concurrently with an increase in arterial pressure.

The acute administration of phencyclidine (PCP) causes hypothermia in the rat. Metaphit (1-[1-(3-isothiocyanatophenyl)cyclohexyl]-piperidine) is a derivative of PCP that has been shown to irreversibly acylate PCP receptors in vitro and in vivo and can antagonize the behavioral and electrophysiological effects of PCP in the rat. The purpose of the present study was to determine whether pretreatment with metaphit can block the hypothermic effects of PCP in the rat. Metaphit or PCP (1.0 mumol/rat) were injected into the lateral ventricles of rats, and 24 hr later the subjects were challenged with PCP (20.0 mg/kg s.c.). Pretreatment with metaphit blocked PCP-induced hypothermia; however, pretreatment with PCP did not affect the subsequent hypothermic response to PCP. These results indicate that the antagonism of PCP-induced hypothermia by metaphit was a specific effect and not due to PCP receptor desensitization.

Either opioid or nonopioid forms of stress-induced analgesia can be elicited depending on the intensity or duration of the stressor. Several forms of stress have also been shown to cause hyperthermia in the rat. The present study investigated whether opioid and nonopioid forms of such stress-induced hyperthermia can be elicited in the rat as a function of footshock current intensity. Rats were given footshock after pretreatment with saline or naltrexone, or chronic morphinization. Footshock produced hyperthermia, the degree of which was found to be a function of current intensity. While the peak rise in temperature was not affected by naltrexone or chronic morphine administration, the rate of return to baseline temperature was slowed by these treatments. Thus, the endogenous opioid system appears to be involved in the return to normal body temperature following footshock, but not in the footshock-induced rise in temperature.

Male rats injected with pentobarbital (50.0 mg/kg i.p.) showed increased sleeping time after the acute administration of morphine (5.0 or 10.0 mg/kg s.c.). This effect was antagonized by naltrexone (2.0 mg/kg s.c.). The enhancement displayed stereoselectivity as levorphanol greatly lengthened the sleeping time induced by pentobarbital while dextrophan only produced a slight increase. Rats implanted for 3 days with pellets of morphine base (75.0 mg) were tolerant to the analgesic effects of morphine (2.5 mg/kg s.c.) but showed an even greater increase in pentobarbital-induced sleeping time than rats treated acutely. No potentiation was observed in subjects that were also implanted with a pellet of naltrexone (30.0 mg). It is concluded that the potentiation of pentobarbital-induced sleeping time produced by opiates is mediated by opiate receptors, but fails to show the development of tolerance.

The acute administration of morphine elicits changes in the release of anterior pituitary hormones. The locus of this action is thought to be in the central nervous system, specifically the hypothalamus. There are some data suggesting that systemically administered opiates and opioid peptides can act outside of the blood-brain barrier to influence anterior pituitary hormone release. To test this hypothesis we examined the effects of the systemic administration of N-methylmorphine chloride, a quaternary analogue of morphine that does not cross the blood-brain barrier, on the release of corticosterone, growth hormone, prolactin, luteinizing hormone, and thyroid stimulating hormone in the rat. N-methylmorphine caused increases in the release of growth hormone and prolactin, but serum levels of corticosterone, luteinizing hormone and thyroid stimulating hormone were unaffected. These results indicate that the opiate-induced release of growth hormone and prolactin may be mediated in part by sites outside of the blood-brain barrier.

Some of the dioxolanes produce pharmacological effects that have much in common with phencyclidine and phencyclidine-like drugs. Dioxadrol can be resolved into two enantiomers, dexoxadrol and levoxadrol. Dexoxadrol has an affinity for phencyclidine receptors that is much greater than that of levoxadrol, but dexoxadrol and levoxadrol have nearly equal affinities for sigma receptors. The systematic analysis of the relative potencies of dexoxadrol and levoxadrol can be used as an approach to define effects mediated by phencyclidine vs sigma receptors. Compounds that act on phencyclidine receptors, as well as affecting behavior, alter body temperature in the rat. The purpose of the present study was to compare and contrast the effects of the acute administration of dexoxadrol, levoxadrol, MK-801 and phencyclidine on body temperature in the rat. Dexoxadrol and levoxadrol (5.0, 10.0, 20.0 or 40.0 mg/kg), MK-801 (0.12, 0.6 or 1.2 mg/kg) or phencyclidine (5.0, 10.0 or 20.0 mg/kg) were administered subcutaneously and body temperature was measured. Both dexoxadrol and MK-801 produced hyperthermia but levoxadrol did not affect body temperature. In contrast to the hyperthermic effects of dexoxadrol and MK-801, phencyclidine produced hypothermia. These findings indicate that hypothermia induced by phencyclidine is not due to interactions with phencyclidine receptors and, while dexoxadrol, MK-801 and phencyclidine may share some similar receptor binding and behavioral characteristics, they can be differentiated on the basis of their effects on body temperature.

Phencyclidine (PCP) has been shown to stimulate the pituitary-adrenal axis in the rat. The purpose of the present study was to determine whether opiate receptors are involved in this effect by testing whether pretreatment with the opiate antagonist naloxone can antagonize PCP-induced ACTH and corticosterone release. PCP (10.0 mg/kg) produced increases in plasma ACTH and corticosterone 60 min after s.c. administration. Pretreatment with naloxone (2.0 mg/kg s.c.) did not reduce the rise in plasma levels of ACTH or corticosterone produced by PCP. These results indicate that naloxone-sensitive opiate receptors are not involved in the PCP-induced stimulation of the pituitary-adrenal axis in rats.

In addition to its producing profound changes in behavior, phencyclidine (PCP) disrupts neuroendocrine function in the rat. Because PCP binds to PCP as well as sigma receptors, it is not known which receptor type mediates the various effects of the drug. The purpose of the present study was to characterize the effects of the acute administration of enantiomers of MK-801, a compound with a high degree of selectivity for PCP over sigma receptors, on the release of ACTH, corticosterone and prolactin in the rat. In addition, MK-801 was administered daily for eight days in order to test whether tolerance develops to MK-801-induced ACTH and corticosterone release after repeated administration. While both enantiomers of MK-801 markedly increased plasma levels of ACTH and corticosterone, the (+) enantiomer was more potent. Tolerance developed to MK-801-induced increases in ACTH and corticosterone after repeated administration. Plasma prolactin levels were not affected by either the acute or the repeated administration of MK-801. These results suggest that the decrease in plasma levels of prolactin produced by PCP-like drugs is not mediated by PCP receptors, and may be a marker for a sigma receptor-mediated effect.

There is little information on the neuroendocrine effects of PCP. The present study examined the effects of the acute subcutaneous administration of PCP on serum levels of corticosterone, growth hormone and prolactin in the male rat. PCP increased serum levels of corticosterone, decreased serum levels of prolactin and failed to affect growth hormone levels. The results indicate that, like other drugs of abuse, PCP alters neuroendocrine function.