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Biomedical subjects

J H Mendelson

Publications and source records attributed to J H Mendelson.

At least 73 records · Page 4Linked to original sources
PubMed1993

Naltrexone-buprenorphine interactions: effects on cocaine self-administration.

An opioid mixed agonist-antagonist analgesic, buprenorphine, significantly reduces cocaine self-administration by rhesus monkeys, but the relative contribution of buprenorphine's agonist and antagonist properties to this effect is unclear. This study examined the effects of concurrent treatment with naltrexone, a long-acting mu opioid antagonist, on buprenorphine's effects on cocaine and food self-administration by five rhesus monkeys. Cocaine (0.5 mg/kg per injection) and food self-administration (1 gm banana pellet) were maintained on a second order fixed ratio 4 (FR4) variable ratio (VR) 16:S schedule of reinforcement. Buprenorphine treatment alone (0.40 mg/kg/day) and in combination with ascending doses of naltrexone (0.05, 0.10, 0.20, and 0.40 mg/kg/day) was compared with naltrexone alone (0.40 mg/kg/day) and saline control treatment. Naltrexone was administered simultaneously or 20 minutes before buprenorphine administration. Each treatment condition was in effect for 10 days. Buprenorphine alone significantly reduced cocaine self-administration by an average of 53% in comparison to the saline treatment baseline (p < .01). When saline was substituted for buprenorphine, each monkey rapidly returned to its prebuprenorphine level of cocaine self-administration. Food self-administration in all conditions was equivalent to or significantly higher (p < .05) than food-maintained responding during the saline baseline. When buprenorphine and naltrexone were administered simultaneously, naltrexone significantly attenuated buprenorphine's suppressive effects on cocaine self-administration (p < .05 to .01). When naltrexone was administered 20 minutes before buprenorphine, there was a significant naltrexone dose-dependent (p < .01) decrease in buprenorphine's reduction of cocaine self-administration in comparison to the initial saline baseline. These data suggest that naltrexone antagonizes the partial mu agonist component of buprenorphine, which may be important for buprenorphine's effects on cocaine self-administration. Moreover, the addition of an opioid antagonist to reduce illicit diversion of buprenorphine might also compromise its effectiveness for treatment of dual dependence on cocaine and opiates.

Animals↗
PubMed1993

The effects of nalbuphine and butorphanol treatment on cocaine and food self-administration by rhesus monkeys.

This study was designed to determine whether opioid mixed agonist-antagonist analgesics other than buprenorphine also selectively reduce cocaine self-administration by rhesus monkeys. The effects of daily treatment with nalbuphine (0.1 to 3 mg/kg/day) or (0.254 to 7.62 mumol/kg/day), butorphanol (0.01 to 0.3 mg/kg/day) or (0.0209 to 0.628 mumol/kg/day), and saline on cocaine and food self-administration were each studied for 40 sessions over 10 consecutive days. Cocaine (0.05 or 0.10 mg/kg/inj) and food (1-gm banana pellets) self-administration were maintained on a fixed ratio 4 (variable ratio 16:S) schedule of reinforcement. Both nalbuphine and butorphanol reduced cocaine self-administration (p < 0.0001) but this effect was not selective since food self-administration also decreased in a dose-dependent manner (p < 0.0001). Nalbuphine administration (1 to 3 mg/kg/day) decreased cocaine injections to 40% to 60% below baseline (p < 0.01) and food pellets 30% to 68% below baseline (p < 0.01). Lower doses of nalbuphine (0.10 and 0.30 mg/kg) did not change cocaine- or food-maintained responding significantly. All doses of butorphanol (0.01 to 0.3 mg/kg/day) reduced cocaine injections to 16% to 58% below baseline (p < 0.01). Food self-administration decreased to 21% to 70% below baseline (p < 0.01) at butorphanol doses of 0.03 to 0.3 mg/kg/day). These data suggest that these opioid mixed agonist-antagonist analgesics may not be useful as pharmacotherapies for the treatment of cocaine abuse.

Analysis of Variance↗
PubMed1993

Pituitary volume in men with concurrent heroin and cocaine dependence.

Pituitary gland volume was measured in 16 men between the ages of 26-33 with magnetic resonance imaging. Eight male patients had a Diagnostic and Statistical Manual III-Revised, American Psychiatric Association Axis I diagnosis of concurrent opioid and cocaine dependence. The average duration of opioid and cocaine abuse was 7.8 +/- 2.0 and 6.9 +/- 1.4 yr, respectively. All patients were in good physical health as determined by physical examination, blood chemistry, hemogram and hormone analysis, and all tested negatively for the HIV antibody. No patient had any other Diagnostic and Statistical Manual III-Revised Axis I diagnosis or neurological disorder. Eight healthy males served as age-matched control subjects. None of the control subjects had any past or current history of substance abuse or any clinical indication for magnetic resonance imaging. Opioid and cocaine dependent men had significantly larger pituitary gland volumes (730.0 +/- 24.4 mm3) than control subjects (540.0 +/- 26.6 mm3) (P < 0.01). The significant increase in pituitary gland volume in men who abuse opiates and cocaine may be antecedent to detection of abnormal anterior pituitary hormone function.

Adult↗
PubMed1993

Acute effects of cocaine on anterior pituitary hormones in male and female rhesus monkeys.

The effects of acute cocaine administration (0.4 or 0.8 mg/kg) on anterior pituitary hormones were studied in four male and six female adult rhesus monkeys during the midluteal phase of the menstrual cycle (days 20-23). Progesterone levels averaged 15.7 +/- 3 and 10.6 +/- 2.8 ng/ml before low and high dose cocaine administration. Integrated plasma samples were collected every 10 min for 40 min before i.v. administration of cocaine, and 11 postcocaine samples were collected over 110 min. Cocaine (0.8 mg/kg) stimulated a significant increase in luteinizing hormone (LH) within 10 to 20 min (P < .01) and LH reached peak levels (59-60% above base line) within 30 min after cocaine administration in both males and females. Plasma cocaine levels averaged 289 +/- 23 and 346 +/- 73 ng/ml at 10 min after i.v. cocaine (0.8 mg/kg) administration in males and females, respectively. Follicle stimulating hormone levels were unchanged in midluteal females. Male testosterone increased by 50% above average base-line levels 50 min after the LH peak (80 min postcocaine). These data are consistent with our previous findings that cocaine increased LH and enhanced luteinizing hormone-releasing hormone-stimulated LH in early follicular females. The low dose of cocaine did not change basal levels of LH and follicle stimulating hormone in midluteal females and both LH and testosterone were unaffected in males. Cocaine plasma levels averaged 97.6 +/- 29 and 68.3 +/- 9.1 ng/ml at 10 min after 0.4 mg/kg of cocaine in males and females, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effects of intermittent buprenorphine administration on cocaine self-administration by rhesus monkeys.

In previous studies, daily buprenorphine administration significantly reduced cocaine self-administration by rhesus monkeys over 15 to 120 days (Mello et al., 1990, 1992). This report describes the effects of 60 days of intermittent buprenorphine (0.40 mg/kg) treatment once every 48 hr or 72 hr on cocaine and food self-administration by six rhesus monkeys. Cocaine (0.05 or 0.10 mg/kg/injection) and food (1-g banana pellet) self-administration were maintained on a fixed ratio 4, (variable ratio 16:S) reinforcement schedule. Intermittent buprenorphine treatment reduced cocaine self-administration significantly below saline treatment levels (P < .01). On the first day of buprenorphine treatment, cocaine self-administration averaged 53 and 60% below base line (P < .01-.0001). Cocaine self-administration remained significantly below base line on day 2 (P < .02-.0001) but usually returned to base-line levels by day 3. During buprenorphine treatment once every 48 hr, cocaine self-administration gradually increased over time in four monkeys (P < .001-.0005). These data suggest that intermittent buprenorphine treatment is less effective than daily buprenorphine treatment in reducing cocaine self-administration by rhesus monkeys. Food self-administration decreased by 23.6 and 12.7% from the saline base line during buprenorphine treatment every 48 and 72 hr, respectively. On the day of buprenorphine treatment, food self-administration was usually significantly lower than during the saline base line (P < .05-.0001), but usually returned to or exceeded base line levels by days 2 and 3. There were no significant changes in food self-administration over time with intermittent buprenorphine treatment every 48 hr.

Animals↗
PubMed1993

Acute interactions of buprenorphine with intravenous cocaine and morphine: an investigational new drug phase I safety evaluation.

Recent preclinical and clinical studies suggest that buprenorphine, an opioid mixed agonist-antagonist, may be useful for the treatment of dual dependence on cocaine and opiates. This report describes an inpatient clinical evaluation of the safety of buprenorphine alone and in combination with single doses of cocaine and morphine. Twenty subjects with a DSM-III-R diagnosis of concurrent cocaine and opioid dependence were randomly assigned to maintenance treatment with single daily doses of 4 or 8 mg of sublingual buprenorphine for 21 days. Side effects and vital signs were evaluated every day once every 8 hours and for 2 hours after daily buprenorphine administration. The physiologic effects of a single-blind challenge dose of cocaine (30 mg intravenously), morphine (10 mg intravenously), and intravenous saline placebo were measured before and during buprenorphine maintenance. Before buprenorphine maintenance, subjects underwent methadone detoxification followed by a 9-day drug-free period. Three baseline single-blind challenge dose studies were conducted on study days 7, 8, and 9 during the drug-free period. Cardiovascular responses to cocaine and to morphine were equivalent under drug-free and buprenorphine maintenance conditions. Respiration and temperature changes in response to cocaine were also equivalent before and during buprenorphine maintenance. Respiratory rates were slightly lower after morphine administration during maintenance on 8 mg of buprenorphine, but this was not statistically significant. Mild opioid agonist-like side effects were reported during buprenorphine induction and maintenance. These included headache, sedation, nasal discharge, abdominal discomfort, and anxiety. Most opioid agonist side effects decreased within 12 to 14 days. An electrocardiogram and blood chemistry measures were normal before and during buprenorphine maintenance. These data suggest that daily maintenance on buprenorphine is not associated with adverse side effects or toxic interactions with a single acute dose of intravenous cocaine or morphine.

Administration, Sublingual↗
PubMed1992

Quantitative magnetic resonance imaging in heroin- and cocaine-dependent men: a preliminary study.

Quantitative magnetic resonance imaging (MRI) of the brain was performed in nine drug-dependent men with a primary diagnosis of opioid and/or cocaine dependence, and 10 age-matched, non-drug-dependent controls. Individuals were screened for the presence of gross cerebral abnormalities before T1 and T2 analyses. Regional T1 and T2 times were calculated on a single 5-mm thick axial slice positioned just below the caudal margin of the lateral ventricles, passing through the caudate and putamen. A voxel of interest (VOI) cursor was placed bilaterally within the putamen, caudate, frontal gray matter, frontal white matter, or posterior white matter. T1 and T2 values were determined for each VOI using an iterative chi 2 minimization program. T1 and T2 relaxation times did not differ significantly between the subject groups in any brain region studied. These results suggest that T1 and T2 relaxation times may not identify microstructural central nervous system changes resulting from chronic opiate and cocaine abuse.

Adult↗
PubMed1992

Hyperprolactinemia and macrocytosis in women with alcohol and polysubstance dependence.

Chronic alcoholism and drug abuse are often associated in women with derangements of reproductive function such as amenorrhea, anovulation, luteal phase dysfunction and early menopause. Endocrine profiles were studied of the first 18 women (aged 17-58) admitted consecutively to a Massachusetts hospital for treatment of alcohol/polysubstance dependence under civil commitment. Twelve women were diagnosed as alcohol dependent according to criteria established in DSM-III-R. Their daily alcohol consumption ranged from 42-324 grams. Six women were diagnosed as polysubstance dependent. In addition to alcohol (84-831 g/day), cocaine was the most frequently abused drug followed by tranquilizers, marijuana and opiates. Over 60% of alcohol-dependent women of reproductive age had either hyperprolactinemia or macrocytosis (increased mean corpuscular volume, MCV), or both. Over 60% of the polysubstance-dependent women of reproductive age had either hyperprolactinemia or increased MCV. Over 80% of alcohol-dependent women of postmenopausal age had either hyperprolactinemia or increased MCV, or both. We conclude that evaluation of plasma prolactin levels and MCV may be useful as biological state markers for alcoholism and polysubstance abuse in women.

Adolescent↗
PubMed1992

Marihuana attenuates the rise in plasma ethanol levels in human subjects.

This study was conducted to determine if plasma ethanol levels are altered as a result of smoking marihuana. Fifteen healthy adult male volunteers who used ethanol and marihuana on a casual basis participated in this study. Subjects were randomly assigned to one of three groups: placebo, low-dose, or high-dose marihuana. The marihuana dose was held constant and each subject drank three different doses of ethanol on 3 separate days spaced at least 1 week apart. Subjects drank either placebo or ethanol at doses of 0.35 g/kg (7.60 mmol/kg) or 0.70 g/kg (15.19 mmol/kg). Thirty minutes after drinking they smoked either a placebo marihuana cigarette, or one containing either 1.26% or 2.53% delta 9-tetrahydrocannabinol. Plasma ethanol levels rose sharply after the 0.7 g/kg dose and peaked at 50 minutes after drinking began (78.25 +/- 4.95 mg/dl). When subjects smoked the high-dose marihuana cigarettes after the 0.7 g/kg dose of ethanol, peak plasma ethanols levels were only 54.80 +/- 8.32 mg/dl at 105 minutes after drinking began. These alterations in plasma ethanol levels paralleled a reduction in the duration of ethanol- and marihuana-induced subjective effects after high doses of both drugs. These data suggest that marihuana may alter ethanol bioavailability.

Adult↗
PubMed1992

Buprenorphine attenuates the effects of cocaine on adrenocorticotropin (ACTH) secretion and mood states in man.

Adrenocorticotropin (ACTH) levels in plasma increased rapidly to 105% above baseline within 5 minutes after intravenous injection of cocaine (30 mg) in cocaine-dependent men. The time course of ACTH stimulation paralleled increases in plasma cocaine levels and self-reports of salient drug effects on mood states and did not occur after placebo administration. An opioid mixed agonist-antagonist, buprenorphine (4 mg/day sublingually), suppressed the acute cocaine-induced stimulation of both ACTH and euphoria. Buprenorphine's suppression of postcocaine ACTH and euphoria were not related to differences in plasma cocaine levels or cocaine-induced alterations of cardiovascular function.

Adrenocorticotropic Hormone↗
PubMed1992

Acute effects of cocaine on plasma adrenocorticotropic hormone, luteinizing hormone and prolactin levels in cocaine-dependent men.

Acute cocaine administration alters secretion of anterior pituitary hormones in experimental animals, and cocaine abuse may compromise neuroendocrine function in humans. The goal of this study was to examine cocaine's acute effects on neuroendocrine hormones in cocaine-dependent men. Plasma adrenocorticotropic hormone (ACTH), luteinizing hormone and prolactin levels were measured in 18 men before and after i.v. administration of cocaine (30 mg) or placebo. Each subject served as his own control during the i.v. placebo and cocaine administration conditions. Plasma cocaine levels peaked at 260 ng/ml within 5 min after the i.v. injection. Plasma ACTH levels increased significantly above base-line levels at 5, 15, 30 (P < .01) and 45 min (P < .05) after i.v. cocaine. Plasma luteinizing hormone levels increased significantly above base-line levels at 5 (P < .05) and at 15 min (P < .01) after i.v. cocaine. No changes in plasma ACTH or luteinizing hormone levels were found after i.v. placebo injection. Plasma prolactin levels decreased significantly at 30, 45, 60, 90 and 120 min (P < .01) after both i.v. cocaine and placebo administration. Cocaine-induced increases in plasma ACTH levels may be due to its effects on dopaminergic systems which modulate corticotropin-releasing factor release in brain.

Adrenocorticotropic Hormone↗
PubMed1992

Effects of alcohol on E2 beta-stimulated luteinizing hormone in ovariectomized rhesus monkeys.

Anovulation is a frequent concomitant of alcohol abuse, but it has been difficult to assess the acute effects of alcohol on ovulation. Estradiol benzoate (E2 beta) can stimulate a luteinizing hormone (LH) surge in ovariectomized monkeys that appears to be associated with increased luteinizing hormone-releasing hormone (LHRH) pulse frequency and amplitude. The acute effects of alcohol (2.5 and 3.5 g/kg) and an isocaloric sucrose control solution on LH and follicle-stimulating hormone (FSH) secretory activity were studied in five ovariectomized monkeys 41 to 51 hours after administration of E2 beta (42 micrograms/kg, IM). Integrated plasma samples were collected at 20-minute intervals over 10 hours. Under sucrose control conditions, LH increased to 445 and 584 ng/ml within 46 to 49.3 hours after E2 beta administration in two monkeys and high-amplitude LH pulses were evident in three monkeys. Alcohol (2.5 and 3.5 g/kg) significantly decreased the number of LH peaks and valleys (p < 0.01). Peak blood alcohol levels averaged 195 and 291 mg/dl. After 2.5 g/kg alcohol, there was no LH surge or LH pulses in four of five monkeys. A delayed LH surge occurred in one monkey 48 to 50.6 hours after E2 beta when blood alcohol levels decreased to 62 mg/dl. After 3.5 g/kg alcohol, no monkey had an LH surge and pulsatile LH release was significantly reduced in comparison to control conditions (p < 0.01). FSH levels remained stable across alcohol and control conditions. These data suggest that alcohol attenuates pituitary release of LH in response to E2 beta stimulation. These findings are consistent with menstrual cycle disruptions observed in alcohol-dependent women, social drinkers, and in a primate model of alcoholism.

Animals↗
PubMed1992

The effects of chronic buprenorphine treatment on cocaine and food self-administration by rhesus monkeys.

The goal of this study was to determine if buprenorphine continues to reduce cocaine self-administration over long periods of treatment, or if tolerance develops to this effect. The effects of 30 to 120 days of buprenorphine treatment (0.32 mg/kg/day) on cocaine and food self-administration were examined in six rhesus monkeys. Saline control treatment was studied for 15 days before and after buprenorphine treatment. Intravenous cocaine (0.05 or 0.10 mg/kg) and food (1 g banana pellet) self-administration were maintained on a FR 4 (VR 16:S) schedule of reinforcement. Cocaine self-administration decreased significantly (P less than .0001) and remained 60 to 97% below saline treatment baseline levels (52 +/- 2 injections/day) throughout 120 days of buprenorphine treatment (P less than .01). After substitution of saline for buprenorphine, cocaine self-administration resumed and averaged between 21 (+/- 3.6) and 56 (+/- 6.5) injections per day over 20 days. Buprenorphine plasma levels averaged 18 (+/- 2.84) ng/ml (range 10.9-30 ng/ml) during buprenorphine treatment. Buprenorphine plasma levels usually decreased by 50% or more within 27 hr after the last buprenorphine dose. Low levels of buprenorphine (0.10-0.19 ng/ml) were measured for 30 to 74 days after abrupt termination of daily buprenorphine treatment. Food self-administration was initially reduced (P less than .01-.05), but tolerance to buprenorphine's suppression of food-maintained responding developed over 30 to 70 days of treatment. Food self-administration returned to and significantly exceeded (P less than .05-.01) saline treatment base-line levels, whereas cocaine self-administration remained significantly suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Protection of participants and experimental design in clinical abuse liability testing.

The protection of participants in clinical abuse liability testing requires adherence to the basic practices of respect for persons, beneficence and justice. Informed consent procedures must ensure protection of confidentiality, specification of potential risk and benefits, and careful explanation of the nature of the research project and the procedures of the study. All participants should be assured that their participation is voluntary, and that they may freely decline or withdraw from the study. The selection of subjects for participation in clinical abuse liability testing should involve consideration of social and behavioral factors which may co-vary with risk for substance abuse. Protection of participants also involves attempts to achieve excellence in the design and conduct of the research in order to enhance the contribution of such studies to science and humanity.

Behavioral Research↗