Desipramine treatment for relapse prevention in cocaine dependence.
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Adult↗
Biomedical subjects
J H Mendelson
Publications and source records attributed to J H Mendelson.
Electroencephalographic activity and plasma ACTH during ethanol-induced euphoria.
Covariance of brain electrical activity (EEG), plasma adrenocorticotrophic hormone (ACTH) and cortisol levels, and mood states were determined for healthy adult men during the first 2 hr after ingestion of ethanol or ethanol placebo under controlled double-blind conditions. Analysis of integrated plasma ACTH and cortisol levels at 5-min intervals, EEG power spectral analysis during consecutive 2-min epochs, and continuous assessment of mood states with a nonverbal instrumental device were carried out during the ascending phase of the blood ethanol curve. Ethanol induced rapid changes in brain electrical activity and plasma ACTH levels that were significantly correlated with subjective perception of changes in mood. The paroxysmal short epochs of euphoria associated with electroencephalographic and ACTH responses during the ascending phase of the blood ethanol curve may reflect physiological concomitants of pharmacological and behavioral reinforcers that enhance risk for perpetuation of drinking and alcohol abuse.
Adrenocorticotropic Hormone↗
Acute alcohol effects on plasma estradiol levels in women.
Acute administration of alcohol (0.695 g/kg) to healthy adult women resulted in peak blood alcohol levels between 70 and 75 mg/dl within 50-60 min after initiation of drinking. Alcohol induced a significant increase (means = 18 pg/ml) in plasma estradiol levels (P less than 0.01). In contrast, after placebo ingestion, plasma estradiol levels did not change significantly. After alcohol intake, plasma estradiol levels reached peak values at 25 min following initiation of drinking when blood alcohol levels averaged 34 mg/ml. It is postulated that the alcohol-induced increase in plasma estradiol is due to changes in hepatic redox states associated with the catabolism of ethanol.
Adult↗
Blood ethanol levels, self-rated ethanol effects and cognitive-perceptual tasks.
Family history of alcoholism influences the acute effects of ethanol in young men. We expanded these findings by concomitantly measuring plasma ethanol levels (BALs), subjective intoxication effects, and task performance in young women. Healthy subjects with no familial alcoholism provided informed consent and received 0.75 ml/kg ethanol or isocaloric placebo (n = 10 per group) under randomized double-blind conditions. Assessments were made at 90, 60 and 30 min before, and 15, 30, 45, 60, 90, 120, 150 and 180 min after beverage administration. BALs reached 80 mg/dl 45-60 min following ethanol. Dizziness and clumsiness ratings correlated strongly with BAL, but clumsiness and confusion were the strongest effects associated with placebo. Impaired visual selectivity and hand-eye coordination covaried with BAL (p less than 0.05) on written tests. Deficits in abstract instruction and symbol comprehension almost attained statistical significance (p less than 0.06). Compared with previous findings for males, data from the present report suggest that ethanol may have gender-related effects.
Adult↗
Differential tolerance development to buprenorphine-, diprenorphine-, and heroin-induced disruption of food-maintained responding in macaque monkeys.
Single daily subcutaneous injections of buprenorphine (1.0 mg/kg), diprenorphine (1.0 mg/kg), or heroin (1.0 mg/kg) were given over 25 consecutive days to examine the degree and the rate of tolerance development to drug-induced suppression of food maintained responding. One gram food pellets were available on a second order schedule (FR 4 VR 16: S) during the 1-hr sessions three times a day. All drug and saline control injections were given at 10:00 a.m., 1 hr before a food session. During the first three days of treatment all three drugs produced marked suppression of food-maintained performance. Recovery from buprenorphine- and diprenorphine-induced suppression of food-maintained responding occurred within four and eight days, respectively. By the 25th day of buprenorphine and diprenorphine treatment, operant responding for food increased significantly above control levels (p less than 0.01). In contrast, the significant heroin-induced disruption of food-maintained responding (p less than 0.01) persisted throughout the 25-day treatment period. Saline substitution for all three drugs resulted in a gradual return to control levels of food pellets earned. Linear regression analysis of the linear portion of the time-effect curve revealed significant differences in both the rate and the degree of tolerance development to these three drugs. These differences in tolerance development may reflect pharmacokinetic differences between the relatively short-acting heroin and the longer-acting diprenorphine and buprenorphine.
Animals↗
Naltrexone effects on pituitary and gonadal hormones in male and female rhesus monkeys.
The long-acting opioid antagonist, naltrexone, stimulates LH and FSH in women during the early follicular phase of the menstrual cycle and is a new provocative test of hypothalamic-pituitary function (42,63). The acute effects of naltrexone (0.25, 0.50 and 1.0 mg/kg IV) on anterior pituitary (LH, FSH, PRL) and gonadal steroid (T or E2) hormones were studied in 7 female and 4 male rhesus monkeys (Macaca mulatta). Integrated plasma samples were collected at 20 min intervals for 60 min before and for 300 min after intravenous infusion of naltrexone over 10 min. In females studied during the early follicular phase (cycle days 1-3), naltrexone did not stimulate LH and significantly suppressed E2 (p less than 0.0003-0.0001) and FSH (p less than 0.006-0.0001). Naltrexone (0.50 and 1.0 mg/kg) also did not stimulate LH release in late follicular phase females (cycle days 10-12) when estradiol levels were in the peri-ovulatory range. FSH and E2 were significantly suppressed (p less than 0.01-0.05) after 1.0 mg/kg naltrexone, but not after 0.5 mg/kg naltrexone. However, in males all doses of naltrexone significantly stimulated LH (p less than 0.003-0.0001) and T (p less than 0.001-0.0001) but not FSH. LH increased significantly above baseline within 20 to 40 min and T increased significantly within 60 min. These gender differences in naltrexone's effects on pituitary gonadotropins and gonadal steroid hormones were unanticipated. These data are not concordant with clinical studies which report significant naltrexone stimulation of LH in men and in women during the early follicular phase.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Progressive ratio performance maintained by buprenorphine, heroin and methadone in Macaque monkeys.
The relative reinforcing efficacy of buprenorphine (0.01-0.10 mg/kg/inj.), heroin (0.01-0.10 mg/kg/inj.), methadone (0.03-0.25 mg/kg/inj.) and saline were compared in Macaque male monkeys using progressive ratio procedures. Responding for drugs and food (1 g banana pellet) was maintained on a second order FR 4 (VR 16:S) schedule of reinforcement that required an average of 64 responses for each injection or food pellet. After 40 sessions (10 days) of stable performance, the number of responses for each drug injection was systematically increased until monkeys reached a breakpoint defined by 2 consecutive days of no drug injections. Progressive ratio breakpoints for heroin at intermediate and high doses (0.05 and 0.10 mg/kg/inj.) were two to three times higher than for any other drug (P less than 0.05). Breakpoints for buprenophine (0.01-0.10 mg/kg/inj.) were higher than for a low dose of methadone (0.03 mg/kg/inj.) but were equivalent to an intermediate methadone dose (0.10 mg/kg/inj.). Breakpoints for both low (0.01 mg/kg/inj.) and high (0.10 mg/kg/inj.) buprenorphine doses were greater than for intermediate doses (0.03 and 0.05 mg/kg/inj.) but these differences were not statistically significant. Linear regression and area under the curve analyses were used to quantify the rate at which drug maintained responding decreased by 30% of control levels as response requirements were increased. Extrapolated breakpoints derived from linear regression analyses were significantly correlated (P less than 0.05-0.01) with actual breakpoints for buprenorphine, heroin and methadone. The concordance between 'extrapolated' and traditional breakpoint ranking of these drugs suggests that regression analysis techniques can be used to predict traditional breakpoints.
Animals↗
Anterior pituitary, adrenal, and gonadal hormones during cocaine withdrawal.
Plasma luteinizing hormone (LH), prolactin, testosterone, and cortisol levels were determined in 16 patients after hospital admission for cocaine abuse, during the course of 4 weeks of hospitalization, and before discharge. Hyperprolactinemia was found at admission (mean +/- SD, 27.5 +/- 10.2 ng/ml) and persisted until discharge (mean +/- SD, 28.7 +/- 10.8 ng/ml). Plasma LH, testosterone, and cortisol levels were within normal limits. These findings suggest that persistent elevation of plasma prolactin levels after cocaine withdrawal may reflect a chronic cocaine-induced derangement in neural dopaminergic regulatory systems.
Adult↗
Alcohol effects on naltrexone-induced stimulation of pituitary, adrenal, and gonadal hormones during the early follicular phase of the menstrual cycle.
Chronic alcohol abuse in women is associated with severe derangements of menstrual cycle regularity. However, acute alcohol ingestion has no effect on pituitary-gonadal secretory function. The purpose of this study was to determine whether acute alcohol ingestion altered the effects of naltrexone, a long-acting opioid antagonist, on pituitary, adrenal, and gonadal hormones in normal women. Fourteen women were studied during the early follicular phase (between days 2 and 4) of their menstrual cycle. Plasma LH, PRL, estradiol, progesterone, and cortisol concentrations were measured before and after administration of 50 mg naltrexone, orally, and alcohol or placebo solution given 1 h after naltrexone, under double blind conditions. Naltrexone significantly increased mean plasma LH (P = 0.02), PRL (P = 0.003), E2 (P less than 0.03), and cortisol (P less than 0.001) levels. Alcohol significantly augmented the naltrexone-stimulated increases in plasma LH (P = 0.006), estradiol (P less than 0.004), and cortisol (P less than 0.001) levels and significantly decreased plasma progesterone levels (P = 0.001). Plasma PRL increased (P = 0.001) to the same extent after naltrexone and alcohol ingestion or naltrexone and placebo. We conclude that alcohol enhances naltrexone-induced increases in plasma gonadotropins and adrenal and gonadal steroid hormones in women during the early follicular phase of the menstrual cycle.
Adrenal Cortex Hormones↗
Alcohol-induced changes in body sway in women at risk for alcoholism: a pilot study.
Family history of alcoholism appears to influence acute alcohol responses in young men. We report pilot data from a study designed to expand these observations by measuring blood alcohol levels (BALs), subjective intoxication effects, body sway and cognitive-motor task performance in women. Six young women with (FHP) and six without (FHN) alcoholic first degree relatives provided informed consent and were given 0.56 g/kg ethanol under double-blind conditions. Groups were matched for age, drinking history and height-weight ratio. Subjects performed tasks in random order at 90, 60 and 30 min before drinking alcohol, and 15, 30, 45, 60, 90, 120, 150 and 180 min after drinking alcohol. BALs peaked at 80 mg/dl 30 to 60 min after drinking alcohol. BALs were comparable and disappearance rates were similar for both groups. BALs and intoxication ratings for both FHP and FHN women had highly significant correlations. Alcohol decreased accuracy on an automated version of the Digit Symbol Substitution Test (DSST) for both groups, but FHN women made significantly more errors 30 min after alcohol. Significantly greater alcohol effects on body sway were apparent in FHN women 15, 30, 60, 90 and 120 min after alcohol. Compared with previous findings for men, both FHP and FHN women reported less intoxication at similar BALs, but body sway in FHN women was more affected by alcohol. Small sample size limits generalization of these findings but suggests that some effects of familial alcoholism in women are similar to those observed in men.
Adult↗
Alcohol self-administration by female macaque monkeys: a model for study of alcohol dependence, hyperprolactinemia and amenorrhea.
Chronic alcohol dependence produces persistent amenorrhea in alcoholic women and female Macaque monkeys but the mechanism is unknown. In one amenorrheic alcohol-dependent monkey, prolactin levels increased from 16.5 to 63 ng/ml during chronic, high-dose alcohol self-administration (3.4 g/kg/day) and immunocytochemical examination of the anterior pituitary showed apparent hyperplasia of the lactotrophs. These data suggested that hyperprolactinemia might contribute to alcohol-induced amenorrhea. Four amenorrheic cycles (85-194 days) from two other alcoholic female monkeys that self-administered an average of 2.97 to 4.4 g/kg/day of alcohol were also studied. Each monkey became amenorrheic during the first menstrual cycle that alcohol was available. One monkey developed galactorrhea during a 97-day amenorrheic cycle when alcohol self-administration averaged 3.35 g/kg/day. Although prolactin levels were intermittently elevated above 20 ng/ml, average levels during these amenorrheic cycles (14.7 +/- 1.8 to 19.6 +/- 1.5 ng/ml) did not differ significantly from prolactin levels during normal ovulatory menstrual cycles when no alcohol was available (19.7 +/- 0.36 ng/ml). There was a negative correlation between daily alcohol dose and prolactin levels (p less than .01). High-dose alcohol self-administration was often associated with low normal prolactin levels, but a relative fall in alcohol dose was usually associated with elevated prolactin levels. These data suggest that both alcohol intoxication and relative alcohol withdrawal may alter basal prolactin levels. LH levels were significantly lower during amenorrheic cycles (16.9 +/- 1.2 to 24 +/- 1.4 ng/ml) than during nonalcohol control cycles (28 +/- 1.2 to 30 +/- 2.2 ng/ml) (p less than .001). These data are consistent with clinical data that suggest that hypothalamic amenorrhea is associated with suppression of gonadotropin secretory activity.
Alcohol Drinking↗
Alcohol effects on naloxone-stimulated luteinizing hormone, follicle-stimulating hormone and prolactin plasma levels in female rhesus monkeys.
Alcohol's effects on hypothalamic function were examined under conditions of opioid antagonist stimulation. The effects of naloxone (0.5 mg/kg i.v.) on anterior pituitary hormone plasma levels after alcohol (2.5 and 3.5 g/kg) or sucrose control administration were studied in 10 normal female monkeys (Macaca mulatta) during the luteal phase of the menstrual cycle. Naloxone was administered 60 or 90 min after nasogastric alcohol administration when blood alcohol levels were above 120 and 140 mg/dl. The rate of naloxone infusion (i.v. bolus or slowly over 10 min) and basal levels of progesterone were critical determinants of the anterior pituitary response to opioid antagonist stimulation. Bolus administration of naloxone did not stimulate luteinizing hormone (LH) or follicle-stimulating hormone (FSH) under control or alcohol conditions. Slow naloxone infusion significantly stimulated LH (P less than .01-.05), but not FSH, in monkeys with high basal progesterone levels (14.1-15.8 ng/ml) under both control and alcohol conditions. Naloxone stimulation of LH was equivalent under control and 2.5 g/kg alcohol conditions (60 and 53% above base line). The LH response to naloxone was enhanced after administration of 3.5 g/kg alcohol and increased to 151% above base line (P less than .01) in monkeys with high progesterone levels. In monkeys with low progesterone levels (3.6-4.6 ng/ml), slow naloxone infusion did not stimulate LH or FSH after sucrose control or 3.5 g/kg alcohol administration, but LH increased (P less than .05) after 2.5 g/kg alcohol administration. A slow infusion of naloxone suppressed PRL levels significantly below base line after sucrose and alcohol administration in monkeys with high (P less than .01-.0002) and low progesterone levels (P less than .0001). Naloxone suppression of PRL was equivalent after alcohol and sucrose control administration. Alcohol alone did not suppress PRL levels significantly. We conclude that acute alcohol administration, with peak blood alcohol levels above 240 and 300 mg/dl, does not attenuate hypothalamic and pituitary responsivity to naloxone stimulation.
Animals↗
Chronic alcohol effects on anterior pituitary and ovarian hormones in healthy women.
The effects of chronic alcohol intake on menstrual cycle status and hormonal function were studied in 26 healthy, adult women under controlled research ward conditions. Women were classified as heavy, social or occasional alcohol users on the basis of the actual number of drinks consumed during 3 consecutive weeks of alcohol availability. Heavy, social and occasional users drank an average of 7.81 ( +/- 0.69), 3.84 ( +/- 0.19) and 1.22 ( +/- 0.21) drinks/day, respectively. This drinking pattern was highly consistent with subjects' self-reports of alcohol use before the study. No evidence of menstrual cycle dysfunction or abnormality in reproductive hormone levels was found in the occasional drinkers or in two of the social drinkers who consumed less than an average of three drinks/day. In contrast, 50% of the social drinkers who consumed more than three drinks/day and 60% of the heavy drinkers had significant derangements of menstrual cycle and reproductive hormone function. The major abnormality found in social drinkers was anovulatory cycles, and three of the five women who were heavy drinkers had persistent hyperprolactinemia. These findings suggest that alcohol-related menstrual cycle and reproductive hormone dysfunction may be more prevalent among women who are social and heavy drinkers than has been assumed previously.
Adult↗
Perinatal effects of drugs of abuse.
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Alcoholic Beverages↗
Cigarette smoking by women: interactions with alcohol use.
Cigarette smoking increased during alcohol self-administration in comparison to an alcohol-free baseline in 24 women given access to alcohol for 21 days. Heavy smokers (25 or more cigarettes per day) increased smoking significantly during drinking (P less than 0.05). Analysis of tobacco smoking by level of alcohol consumption showed that both heavy and moderate alcohol users increased smoking significantly during alcohol availability (P less than 0.05, 0.01). The heavy and moderate smokers smoked significantly more between noon and midnight (P less than 0.001) than at other times when alcohol was available. The rate of cigarette smoking (defined by inter-cigarette intervals) was faster during alcohol self-administration than during the alcohol-free baseline. Heavy smokers smoked most cigarettes at intervals of 11-20 min during heavy or moderate drinking. During the pre-alcohol baseline, these women smoked most cigarettes at intervals of 21-30 or 31-40 min. Most women (70-74%) also increased tobacco smoking at the premenstruum. Both heavy and occasional smokers increased smoking at the premenstruum significantly more than the moderate smokers (P less than 0.05). All women reported increased psychological discomfort at the premenstruum on the Premenstrual Assessment Form (PAF) but reports of physical discomfort were more marked in women who smoked less at the premenstruum. These data extend previous findings in men that alcohol consumption is associated with increased cigarette smoking to female social drinkers.
Alcohol Drinking↗
Acute ethanol administration enhances plasma testosterone levels following gonadotropin stimulation in men.
Plasma levels of LH, FSH, prolactin (PRL), and testosterone (T) were assessed in six normal men following administration of a pharmacologic dose of gonadotropin releasing hormone (GnRH) (500 micrograms iv over a one-min period) with concomitant oral administration of either ethanol (0.695 g/kg of body weight over a 15-min period) or ethanol placebo. Acute ethanol administration had no effect on the response of either LH or FSH to GnRH. PRL levels increased following GnRH and administration of both ethanol and ethanol placebo. Ethanol administration enhanced the T response to GnRH (p less than 0.001 vs placebo). During the placebo condition, T levels did not rise significantly until 100 min after GnRH administration, at which time the mean increment over baseline was 101 +/- 20 ng/dl (+/- SEM). In contrast, following ethanol intake, T levels were significantly elevated within 30 min after GnRH administration, at which time the mean increment over baseline was 187 +/- 42 ng/dl. The mean T increments were 304 +/- 62 and 472 +/- 77 ng/dl, respectively, 60 and 105 min following GnRH and ethanol administration. The increase in T levels following acute ethanol intake and concomitant gonadotropin stimulation is in contrast to the well-documented effect of chronic ethanol intake on suppression of testosterone synthesis by testicular Leydig cells.
Adult↗
Alcohol and Drug Abuse Research Center Harvard Medical School-McLean Hospital: activities during 1986.
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Academic Medical Centers↗
Alcohol effects on naloxone-stimulated luteinizing hormone, prolactin and estradiol in women.
Plasma luteinizing hormone (LH), estradiol, prolactin and progesterone levels were measured in nine normal adult women prior to and following administration of naloxone and oral ingestion of ethanol or placebo-control solution. Each subject served as her own control in a double-blind study carried out during the midluteal phase of the menstrual cycle. The mean (+/- SD) progesterone level was 13.9 +/- 1.3 during control conditions and 13.9 +/- 1.7 during alcohol conditions. The mean peak blood alcohol level was 100 +/- 13 mg/dl within 45-60 min after initiation of drinking. Under placebo-control conditions, naloxone stimulated a significant increase in plasma LH and prolactin but did not increase estradiol or progesterone. Alcohol did not attenuate the significant naloxone stimulation of LH, and progesterone levels were equivalent under alcohol and control conditions. Alcohol significantly enhanced naloxone stimulation of prolactin and estradiol. Alcohol administration significantly augmented the naloxone-induced increase in plasma prolactin levels. After alcohol administration, naloxone also induced a significant increase in plasma estradiol levels, which was sustained throughout the 180-min sampling period. The mechanisms underlying alcohol's enhancement of naloxone-stimulated prolactin and estradiol remain to be determined. The alcohol-related increase in naloxone-stimulated prolactin secretion may reflect increased hypothalamic and/or pituitary sensitivity to alcohol following endogenous opioid blockade by naloxone or an effect of increased estrogen levels. The significant increase in plasma estradiol levels following concurrent naloxone and alcohol administration may occur as a consequence of alterations in steroid biotransformation associated with intrahepatic ethanol catabolism.
Adult↗