Diagnostic evaluation of alcohol and drug abuse problems in women.
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Alcohol-Related Disorders↗
Biomedical subjects
J H Mendelson
Publications and source records attributed to J H Mendelson.
Cocaine's effects on neuroendocrine systems: clinical and preclinical studies.
This review examines the effects of cocaine on the neuroendocrine system and summarizes findings from clinical studies of cocaine abusers and preclinical studies in rodents and rhesus monkeys. The effects of acute and chronic cocaine administration on anterior pituitary, gonadal, and adrenal hormones are described, and the functional consequences of chronic cocaine exposure are discussed. Many of cocaine's acute effects on the endocrine system are consistent with its actions as a monoamine reuptake inhibitor. Acute cocaine administration stimulates release of gonadotropins, ACTH, and cortisol or corticosterone and suppresses prolactin levels. It has been difficult to detect changes in basal levels of most hormones or alterations in hormone responsiveness to a challenge dose of cocaine or other agents after chronic cocaine treatment. Interpretation of clinical data is often complicated by polydrug abuse involving opiates and alcohol as well as cocaine. However, preclinical studies of the effects of chronic cocaine exposure on integrated neuroendocrine function have revealed disruptions of the estrous cycle in rats and the menstrual cycle in rhesus monkeys. Furthermore, the menstrual cycle disorders observed in rhesus monkeys parallel those reported in women who abuse cocaine. Much remains to be learned about cocaine's interactions with the endocrine system and the consequences of cocaine abuse for reproductive function.
Adrenocorticotropic Hormone↗
Dopamine infusion does not alter LH levels before or after chronic cocaine exposure in female rhesus monkeys.
Cocaine stimulates release of luteinizing hormone (LH) in preclinical and clinical studies but the contribution of the indirect dopamine agonist actions of cocaine to its effects on LH are unclear. In the present study, we examined the effects of exogenous dopamine infusions on LH release in drug-naive, normally cycling, female rhesus monkeys. All studies were conducted during the mid-follicular phase (cycle days 6-8). Three successive 80-min dopamine infusions (10 micrograms/kg/min, intravenous) were alternated with 20- or 40-min interruptions of dopamine infusions. There were no significant changes in LH during or following dopamine infusions. Predopamine baseline LH levels averaged 30 +/- 5.4 ng/ml. LH averaged 31.7 +/- 1.3 ng/ml during dopamine infusions and 31.4 +/- 1.3 ng/ml after dopamine infusions stopped. To determine whether chronic cocaine exposure influenced the effect of dopamine on LH, rhesus females were studied after more than 2 years of cocaine self-administration at an average dose of 6.5 +/- 0.2 mg/kg/day. LH averaged 27.3 +/- 3.3 ng/ml during baseline and 26.9 +/- 0.7 ng/ml and 26.1 +/- 0.7 ng/ml during dopamine infusions and interruptions, respectively. Similarly, during withdrawal from cocaine, baseline LH levels averaged 32.1 +/- 4.5 ng/ml, and LH did not change significantly during dopamine infusions (31.2 +/- 1.1 ng/ml) and infusion interruptions (32.1 +/- 1.1 ng/ml). Under the conditions of the present study, dopamine administration did not change LH levels in gonadally intact rhesus monkeys, and these findings are consistent with previous studies in ovariectomized rhesus females. However, these data are not consistent with clinical reports, and some possible implications of this species difference are discussed. Moreover, these data suggest that the stimulation of LH by cocaine may not be explained by its indirect dopamine agonist actions.
Animals↗
Age-related reduction in functional MRI response to photic stimulation.
Many functional imaging studies have demonstrated age-related alterations in cerebral blood flow during the resting state. However, few studies have addressed possible differences in functional response to cerebral activation. We assessed the response of visual cortex to photic stimulation in 9 normal elderly subjects and 17 normal younger subjects with blood oxygenation level dependent functional magnetic resonance imaging. We found that the amplitude of response in elderly subjects was significantly decreased compared to younger subjects (2.5 +/- 1.0% versus 4.0 +/- 1.6%, p = 0.01), suggesting a reduction in functional activation or an age-related alteration in the coupling of blood oxygenation to focal activation.
Adult↗
The effects of chronic cocaine self-administration on the menstrual cycle in rhesus monkeys.
Clinical studies suggest that cocaine disrupts reproductive function, but because cocaine abusers often abuse opiates and alcohol, it has been difficult to determine the contribution of cocaine alone. The effects of chronic cocaine self-administration on menstrual cycle duration and basal levels of progesterone were examined in eight female rhesus monkeys and compared with the effects of occasional administration of single cocaine doses (0.4 or 0.8 mg/kg) in six otherwise drug-free controls. All monkeys had normal ovulatory menstrual cycles before cocaine exposure. Monkeys self-administered cocaine (0.10 mg/kg/injection) and food (1 gm banana pellets) in 4 daily sessions on a second-order schedule (fixed ratio 2 [variable ratio 16:S]). Cocaine intake was limited to 8 mg/kg/day. During the first cocaine exposure (256-776 days), monkeys self-administered 3.51 (+/- 0.77) to 7.41 (+/- 0.27) mg/kg/day. During the second cocaine exposure (103-623 days), monkeys self-administered 6.18 (+/- 0.77) to 7.41 (+/- 0.27) mg/kg/day. In these prospective longitudinal studies, 48% of the menstrual cycles were of abnormal duration in the cocaine self-administration group, whereas only 6% of the menstrual cycles were abnormal in the control group. There were 19 episodes of amenorrhea (61-190 days of no menses). During cocaine self-administration, approximately one-third of the menstrual cycles were anovulatory with low mid-luteal progesterone levels of 2.04 (+/- 0.6) to 4.13 (+/- 0.5) ng/ml. Over 25% of menstrual cycles were anovulatory during cocaine withdrawal with mid-luteal progesterone levels below 5 ng/ml. These data indicate that chronic cocaine exposure can disrupt the menstrual cycle in rhesus monkeys and that menstrual cycle abnormalities often persist during cocaine withdrawal. These data are consistent with clinical studies and reports of cocaine-induced disruption of the estrous cycle in rodents.
Adrenocorticotropic Hormone↗
Effects of alcohol ingestion on estrogens in postmenopausal women.
OBJECTIVE: To determine if moderate alcohol drinking increases circulating estradiol levels in postmenopausal women who are taking estrogen replacement. DESIGN: Randomized, double-blind, placebo-controlled crossover study of the effects of alcohol ingestion on plasma estradiol and estrone. SETTING: Inpatient Clinical Research Center. PARTICIPANTS: Twelve healthy postmenopausal women receiving oral estrogen (estradiol, 1 mg/day) and progestin (medroxyprogesterone acetate) replacement therapy were compared with 12 postmenopausal women who were not using estrogen replacement therapy (ERT). INTERVENTION: Each group drank alcohol (0.7 g/kg) and an isoenergetic (isocaloric) placebo (randomized sequence) on consecutive days. Women who were taking ERT were studied during the estrogen-only portion of their replacement cycle, and estrogen was administered each evening at 2100 hours. MAIN OUTCOME MEASURE: The impact of alcohol ingestion on plasma estradiol and estrone levels. RESULTS: Alcohol ingestion lead to a 3-fold increase in circulating estradiol in women on ERT; however, alcohol did not change estradiol significantly in control women who were not on ERT. In women using ERT, estradiol levels increased from 297 to 973 pmol/L (81 to 265 pg/mL) within 50 minutes (P<.001) during the ascending limb of the blood alcohol curve and remained significantly above baseline for 5 hours (P<.001). No significant increase in circulating estrone was detected in either group. However, estrone levels decreased after alcohol and placebo in women on ERT (P<.05). Blood alcohol levels did not differ significantly in women who used ERT and those who did not. Peak blood alcohol levels of 21 mmol/L were attained in each of the 2 groups within 50 to 60 minutes after drinking began. Changes in estradiol were significantly correlated with changes in blood alcohol levels on both the ascending (P<.001) and descending (P<.001) limb of the blood alcohol curve. CONCLUSIONS: Acute alcohol ingestion may lead to significant and sustained elevations in circulating estradiol to levels 300% higher than those targeted in clinical use of ERT. Potential health risks and benefits of the interactions between acute alcohol ingestion and ERT should be further evaluated.
Alcohol Drinking↗
P300 assessment of opiate and cocaine users: effects of detoxification and buprenorphine treatment.
We assessed cognitive function following heroin and cocaine detoxification and investigated whether buprenorphine treatment improves the disruptive effects of detoxification. Three groups of male volunteers meeting DSM-III-R criteria for concurrent opiate and cocaine dependence were tested using an auditory oddball paradigm before and after detoxification, and again on the 15th day of either buprenorphine or placebo treatment. There were no significant differences in P300 amplitude, latency, or topographic distribution between drug-dependent subjects and controls on admission day. Following detoxification there was a significant decrease in P300 amplitude in the drug-dependent group at a time when self-reported signs of withdrawal were minimal. Buprenorphine treatment significantly reversed the P300 amplitude decrement following detoxification, whereas placebo-treated subjects continued to show depressed P300 amplitudes. These data demonstrate that buprenorphine treatment is effective in eliminating detoxification-induced impairments in one measure of cognitive ability.
Adult↗
Management of cocaine abuse and dependence.
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Antidepressive Agents↗
Brain alcohol detectability increase with repeated administration in humans: a proton spectroscopy study.
Proton MRS was used to detect brain alcohol after repeated alcohol exposure in human subjects. MRS detectability measurements were made after administration of an alcoholic drink (0.6 g/kg alcohol) and after an identical drink administrated 6 h later. Between-drink differences in the methyl proton triplet resonance of ethyl alcohol were assessed at statistically equivalent and near-peak blood alcohol concentrations (reflecting brain alcohol concentrations) and statistically equivalent internal standard N-acetyl resonance areas after Drinks 1 and 2, respectively. Brain alcohol detectability was not altered in TE 30-ms spectra but was increased in all five subjects after Drink 2 by an average of 70% in TE 270-ms spectra (p < 0.01). This was accompanied by significant between-drink differences in subjective ratings of alcohol's effects, suggestive of induction of acute alcohol tolerance. These findings suggest increased brain alcohol detectability in TE 270-ms spectra after repeated alcohol exposure that may reflect acute alcohol tolerance.
Adult↗
Abnormal cerebral metabolism in polydrug abusers during early withdrawal: a 31P MR spectroscopy study.
Phosphorus magnetic resonance spectroscopy (31P MRS) at 1.5 T was performed on nine polysubstance abusing men. All nine patients met DSM-III-R criteria for concurrent cocaine and heroin dependence, were neurologically normal, were negative for the human immunodeficiency virus, and had normal clinical brain MRI scans. Patients were scanned 2-7 days after admission to a drug treatment unit. Eleven age-matched control subjects also were studied. The ISIS localized phosphorus spectra were obtained from a 5-cm thick axial brain slice and a 100-cc white matter volume. In the brain slice, the phosphorus metabolite signal expressed as a percentage of total phosphorus signal was 15% higher for phosphomonoesters, 10% lower for nucleotide triphosphates (beta-NTP), and 7% lower for total nucleotide phosphates in polydrug abusers compared with those in controls. Phosphodiesters, inorganic phosphate, phosphocreatine, total phosphorus, pH, and free magnesium concentration were unchanged. None of these parameters correlated with the methadone dose or the number of days abstinence. Single photon emission computed tomographic imaging of a subgroup of the patients revealed abnormal cerebral perfusion in 80% of the patients scanned. These data suggest that cerebral high energy phosphate and phospholipid metabolite changes result from long term drug abuse and/or withdrawal and that these changes can be detected and studied by 31P MRS.
Adult↗
Sex differences in plasma cocaine levels and subjective effects after acute cocaine administration in human volunteers.
Gender differences after acute cocaine administration have received little attention in spite of the fact that males and females respond differently to many drugs. Seven male and seven female occasional cocaine users received both an intranasal dose of cocaine hydrochloride (0.9 mg/kg) and placebo powder in a randomized order and reported subjective effects via an instrumental joystick device and various questionnaires. Blood samples were withdrawn at 5-min intervals to assess pharmacokinetic differences. Male subjects achieved the highest peak plasma cocaine levels (144.4 +/- 17.5 ng/ml), detected cocaine effects significantly faster than females and also experienced a greater number of episodes of intense good and bad effects. Women studied during the follicular phase of their menstrual cycle had peak plasma cocaine levels of 73.2 +/- 9.9 ng/ml, which was significantly higher than when they were studied during their luteal phase (54.7 +/- 8.7 ng/ml), but there were no differences in their subjective reports of cocaine effects. In spite of the different cocaine blood levels and subjective effects, peak heart rate increases did not differ between males and females suggesting that women may be more sensitive than males to the cardiovascular effects of cocaine. These data suggest that there are significant gender and menstrual cycle differences in the response to acute intranasal cocaine administration and these differences may have implications for the differential abuse of this drug.
Administration, Intranasal↗
Impact of maternal alcoholism on separation of children from their mothers: findings from a sample of incarcerated women.
Patterns of maternal child co-residence among 25 alcoholic women incarcerated for drunk driving are examined. Two-thirds of these mothers reported significant periods of time, not due to incarceration, when minor children did not reside with them. Fewer than half of the placements were mandated by child-protective services. Having two or more children while actively alcoholic or residing with a substance abuser correlated strongly with separate residence.
Adult↗
Effects of cocaine on pulsatile activity of hypothalamic-pituitary-adrenal axis in male rhesus monkeys: neuroendocrine and behavioral correlates.
Cocaine stimulates the hypothalamic-pituitary-adrenal (HPA) axis in rodents and in humans. This study examined the acute effects of cocaine (0.4 and 0.8 mg/kg) and saline placebo on pulsatile adrenocorticotropic hormone (ACTH) and cortisol release in seven male rhesus monkeys. Pulsatile ACTH and cortisol release were evaluated with an intensive (2-min) venous blood sampling procedure and cluster analysis. In addition, the behavioral responses to cocaine were analyzed to assess the relationship between HPA axis activation and behavior. Although analysis of group data revealed significant (P < .05) increases in pulse amplitude and incremental peak height of ACTH and cortisol release after cocaine (0.8 mg/kg) administration, examination of individual data indicated that this effect was not consistent across all monkeys. Cocaine (0.8 mg/kg) increased ACTH plasma levels within 4.7 +/- 1.3 min (P < .05) and amplitude-related characteristics (P < .05) of pulsatile ACTH and cortisol release only in those animals that subsequently showed behavioral stimulation (high responders: n = 3). The frequency of pulsatile ACTH and cortisol remained unchanged by cocaine. Cocaine (0.8 mg/kg) decreased the mean amplitude of ACTH peaks with no changes in pulsatile cortisol release in the four monkeys that showed no behavioral stimulation (low responders). These differences in pulsatile ACTH and cortisol release patterns after cocaine could not explained by different plasma cocaine levels. Peak plasma cocaine levels averaged 63.1 +/- 13.4 and 78.0 +/- 21.4 ng/ml within 2 min after lower dose and 183.3 +/- 52.3 and 204.3 +/- 50.8 ng/ml after higher dose of cocaine in high- and low responder groups, respectively (P > .05; N.S.). Base-line cortisol, but not ACTH, levels were higher (P < .05) in low responders before administration of 0.8 mg/kg of cocaine. Peak and valley characteristics of base-line cortisol release were higher in low responders than in high responders and an inverse relationship was found between basal cortisol levels and postcocaine ACTH release and behavior. In summary, cocaine stimulated the pulsatile ACTH and cortisol release by increasing the amplitude of secretory episodes in behaviorally responsive monkeys.
Adrenocorticotropic Hormone↗
Acute and chronic effects of flupenthixol on the discriminative stimulus and reinforcing effects of cocaine in rhesus monkeys.
It has been proposed that the relatively nonselective dopamine receptor antagonist flupenthixol may be useful in the treatment of cocaine dependence. Drugs used in the treatment of cocaine dependence are administered chronically; however, most preclinical studies have examined only the acute effects of flupenthixol treatment on the effects of cocaine. Consequently, the purpose of the present study was to compare the effects of acute and chronic treatment with flupenthixol (0.0032-0.032 mg/kg) on the discriminative stimulus and reinforcing effects to cocaine in rhesus monkeys. One group of six monkeys was trained to discriminate 0.4 mg/kg cocaine (i.m.) from saline in a two-lever, food-reinforced, drug discrimination procedure. A second group of four monkeys was trained to respond for 0.032 mg/kg/injection cocaine (i.v.) and 1-g banana-flavored food pellets during alternating daily cycles of cocaine and food availability. Neither acute nor chronic treatment with a low dose of flupenthixol (0.0032 mg/kg) significantly altered the discriminative stimulus or reinforcing effects of cocaine. Higher doses of flupenthixol (0.01-0.032 mg/kg) produced a surmountable blockade of both the discriminative stimulus and reinforcing effects of cocaine, shifting the dose-effect curves for both cocaine discrimination and cocaine self-administration up to 0.5 log unit to the right. However, doses of flupenthixol that altered cocaine discrimination also decreased response rates. Similarly, doses of flupenthixol that decreased cocaine self-administration also often decreased rates of food-maintained responding. Consequently, nonselective behavioral effects of flupenthixol may have contributed to its effects on cocaine discrimination and self-administration. Moreover, the effects of flupenthixol on cocaine discrimination and self-administration diminished over time. After only 3 to 5 days of chronic treatment, flupenthixol did not consistently shift the cocaine discrimination dose-effect curve to the right. Similarly, rates of cocaine self-administration that were initially decreased by flupenthixol often recovered partially or completely during a 10-day regimen of chronic flupenthixol treatment. These results suggest that flupenthixol may have limited utility in the long-term treatment of cocaine dependence.
Animals↗
Neuroendocrine function and the relationship to addictions.
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Adrenocorticotropic Hormone↗
Alcohol abuse and HIV.
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AIDS Dementia Complex↗
Sequential dynamic susceptibility contrast MR experiments in human brain: residual contrast agent effect, steady state, and hemodynamic perturbation.
The stability and reproducibility of the dynamic susceptibility contrast (DSC) MRI method for sequential relative cerebral blood volume (relCBV) measurements was evaluated to validate the method for use in quantitative studies of cerebral hemodynamics in humans. A spin echo echo planar imaging protocol was used in conjunction with multiple bolus injections of the susceptibility contrast agent gadoteridol (GD). The effects of variation in interbolus interval (10 min to 4 h), the number of injections (two to four), and the effect of the cerebral vasodilating agent acetazolamide (ACZ) were evaluated in 44 experiments performed with 22 normal subjects. Two fundamental observations were made. First, with multiple injections of GD, the change in MR signal over time was not consistent from first to subsequent boluses. A second bolus administered 10 min to 2 h after an initial bolus resulted in signal change of greater amplitude and duration, resulting in artifactually elevated estimates of relCBV, consistent with a residual effect of GD. Second, a relative steady state could be reached with serial injections of GD, such that the profile of subsequent boluses closely paralleled those of previous ones. This facilitates the reliable measurement of relCBV during activation, as demonstrated by use of ACZ.
Acetazolamide↗
Electroencephalographic correlates of marihuana-induced euphoria.
The present study was conducted to determine if there is a neurophysiological correlate of marihuana-induced good effects or euphoria. Three groups of 6 male occasional marihuana smokers were prepared for electroencephalographic (EEG) recording and smoked either placebo or marihuana cigarettes containing 1.26% or 2.53% delta 9-tetrahydrocannabinol (delta 9-THC) in a controlled laboratory setting. Using a continuously available non-verbal joystick device and a questionnaire, subjects reported changes in their subjective mood state while EEG activity was continuously recorded. Subjects reported multiple episodes of intense good effects or euphoria during the first 15 min after marihuana. These episodes of euphoria occurred while plasma delta 9-THC levels were rapidly rising. EEG alpha power during these discrete episodes of euphoria was significantly higher suggesting that these transient EEG changes may reflect a neurophysiological correlate of the reinforcing effects of marihuana.
Adult↗