Mary E. McCaul

Sex Differences in Striatal Dopamine Release in Healthy Adults

BACKGROUND Sex differences in addictive disorders have been described. Preclinical studies have implicated the striatal dopamine system in these differences, but human studies have yet to substantiate these findings. METHODS Using positron emission tomography (PET) scans with high-specific-activity [11C] raclopride and a reference tissue approach, we compared baseline striatal dopamine binding potential (BP) and dopamine release in men and women following amphetamine and placebo challenges. Subjective drug effects and plasma cortisol and growth hormone responses were also examined. RESULTS Although there was no sex difference in baseline BP, men had markedly greater dopamine release than women in the ventral striatum. Secondary analyses indicated that men also had greater dopamine release in three of four additional striatal regions. Paralleling the PET findings, mens ratings of the positive effects of amphetamine were greater than womens. We found no sex difference in neuroendocrine hormone responses. CONCLUSIONS We report for the first time a sex difference in dopamine release in humans. The robust dopamine release in men could account for increased vulnerability to stimulant use disorders and methamphetamine toxicity. Our findings indicate that future studies should control for sex and may have implications for the interpretation of sex differences in other illnesses involving the striatum.

The Mu-Opioid Receptor Gene Polymorphism (A118G) Alters HPA Axis Activation Induced by Opioid Receptor Blockade

An A118G nucleotide exchange in exon 1 of the mu-opioid receptor causes an Asn40Asp substitution polymorphism in the receptors extracellular domain. In vitro studies show that the Asp40 variant of the mu-opioid receptor binds β-endorphin three times more avidly than the more common Asn40 variant. Paraventricular corticotropin releasing hormone neurons, which activate the HPA axis, express mu-opioid receptors and are modulated by β-endorphin neurons. This preliminary study was designed to test the hypothesis that the Asn40Asp substitution polymorphism in the mu-opioid receptor influences HPA axis activation induced by opioid receptor blockade. Thirty-nine healthy men were genotyped (A vs. G) and then underwent opioid receptor blockade with Naloxone. Subjects expressing the A118G receptor variant had greater cortisol responses to opioid receptor blockade. Also, a significant difference in the rate of increase of ACTH (slope) between A/A and A/G was observed between 30–90 minutes as well as a significant difference in the rate of decrease after 90 minutes. Moreover, subjects expressing the variant polymorphism had lower scores on the Conscientiousness Factor and associated subscales of NEO Personality Inventory compared to subjects expressing the common receptor. Because serotonin also modulates the CRF neuron, subjects were genotyped for a functional polymorphism within the serotonin transporter gene. We did not see differences in hormone responses resulting from expression of this functional polymorphism. It is plausible that persons expressing the mu-opioid receptor variant have altered HPA axis dynamics and altered responses to other physiological processes regulated through activation of the mu-opioid receptor.

Relationships Among Ventral Striatal Dopamine Release, Cortisol Secretion, and Subjective Responses to Amphetamine

There is evidence that stress and glucocorticoids alter drug self-administration and mesolimbic dopamine (DA) activity in preclinical models. The primary purpose of this study was to test the hypothesis that glucocorticoids are associated with psychostimulant reinforcement and DA release in humans. In total, 16 healthy adults, ages 18–27 years, underwent two consecutive 90-min PET studies with high specific activity [11C]raclopride. The first scan was preceded by intravenous saline, and the second by intravenous amphetamine (AMPH 0.3 mg/kg). DA release was defined as the percent change in raclopride binding between the placebo and AMPH scans. Measures of subjective drug effects, plasma cortisol, and growth hormone (GH) were obtained. Findings showed that cortisol levels were positively associated with AMPH-induced DA release in the left ventral striatum (LVS) and the dorsal putamen. Subjects with higher cortisol responses to AMPH also reported more positive subjective drug effects than subjects with lower cortisol responses; no association was observed between cortisol levels and negative drug effects. Higher ratings of positive drug effects were also associated with greater DA release in the LVS, dorsal putamen, and dorsal caudate. A general lack of relationship was observed between GH responses to AMPH and DA release or subjective drug responses. Our findings provide evidence of interrelationships between glucocorticoid levels, subjective responses to IV AMPH, and brain DA release in humans. The results are consistent with those of preclinical studies, suggesting that individual differences in HPA axis function may influence vulnerability to alcohol and drug dependence in humans.

Directly Administered Antiretroviral Therapy in Methadone Clinics Is Associated with Improved HIV Treatment Outcomes, Compared with Outcomes among Concurrent Comparison Groups

BACKGROUND Directly administered antiretroviral therapy (DAART) in methadone clinics has the potential to improve treatment outcomes for human immunodeficiency virus (HIV)-infected injection drug users (IDUs). METHODS DAART was provided at 3 urban methadone clinics. Eighty-two participants who were initiating or reinitiating highly active antiretroviral therapy (HAART) received supervised doses of therapy at the clinic on the mornings on which they received methadone. Treatment outcomes in the DAART group were compared with outcomes in 3 groups of concurrent comparison patients, who were drawn from the Johns Hopkins HIV Cohort. The concurrent comparison patients were taking HAART on a self-administered basis. The 3 groups of concurrent comparison patients were as follows: patients with a history of IDU who were receiving methadone at the time HAART was used (the IDU-methadone group; 75 patients), patients with a history of IDU who were not receiving methadone at the time that HAART was used (the IDU-nonmethadone group; 244 patients), and patients with no history of IDU (the non-IDU group; 490 patients). RESULTS At 12 months, 56% of DAART participants achieved an HIV type 1 RNA level <400 copies/mL, compared with 32% of participants in the IDU-methadone group (P=.009), 33% of those in the IDU-nonmethadone group (P=.001), and 44% of those in the non-IDU group (P=.077). The DAART group experienced a median increase in the CD4 cell count of 74 cells/mm3, compared with 21 cells/mm3 in the IDU-methadone group (P=.04), 33 cells/mm3 in the IDU-nonmethadone group (P=.09), and 84 cells/mm3 in the non-IDU group (P=.98). After adjustment for other covariates in a logistic regression model, DAART participants were significantly more likely to achieve viral suppression than were patients in each of the 3 comparison groups. CONCLUSIONS These results suggest that methadone clinic-based DAART has the potential to provide substantial clinical benefit for HIV-infected IDUs.

Naltrexone alters subjective and psychomotor responses to alcohol in heavy drinking subjects.

Preclinical studies support endogenous opioid system involvement in alcohol reinforcement and consumption; however, recent clinical trials and human laboratory studies have provided mixed findings of the effects of naltrexone (a non-selective opioid antagonist) on alcohol responses. This study used a within-subject design (n = 23) to investigate naltrexone effects (0, 50 and 100 mg qd) on subjective and psychomotor responses to alcohol (none, moderate, high) in heavy drinkers. Before alcohol administration, subjects reported decreased desire to drink alcohol when maintained on 50 mg compared with placebo naltrexone. Following alcohol administration, active naltrexone significantly increased subjective ratings of sedative, and unpleasant/sick effects and decreased ratings of liking, best effects and desire to drink. Naltrexone generally did not alter subjective or objective indicators of drunkenness. Finally, high doses of naltrexone and alcohol interacted to produce the greatest decreases in liking and best effects. Findings support the role of endogenous opioids as determinants of alcohols effects and suggest that naltrexone may be particularly clinically useful in those treatment patients who continue to drink heavily.

A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence

Abstract: The opiate antagonist nalmefene has been shown in 2 single-site studies to reduce alcohol consumption and relapse drinking in alcohol-dependent individuals. This safety and preliminary multisite efficacy study evaluated 3 doses of nalmefene (5, 20, or 40 mg) in a double-blind comparison to placebo over a 12-week treatment period in 270 recently abstinent outpatient alcohol-dependent individuals. Participants concomitantly received 4 sessions of a motivational enhancement therapy (with a medication compliance component) delivered from trained counselors. Although more subjects in the active medication groups terminated the study early secondary to adverse events, the rates did not differ significantly from that of placebo. The 20-mg/d group experienced more insomnia, dizziness, and confusion, while the 5-mg group also had more dizziness and the 40-mg group had more nausea than the placebo group. Most of these symptoms were mild and improved over time. Although all subjects had a reduction in heavy drinking days, craving, γ-glutamyl transferase, and carbohydrate-deficient transferrin concentrations over the course of the study, there was no difference between the active medication and placebo groups on these measures. The time to first heavy drinking day was also not significantly different between the placebo and the active treatment groups. This relatively small multisite trial showed that nalmefene was reasonably well tolerated in recently abstinent alcoholics. However, possibly because of variation among the sites or the comparatively small sample size, there was no evidence of superior efficacy outcomes with nalmefene treatment.

Association of Amphetamine-Induced Striatal Dopamine Release and Cortisol Responses to Psychological Stress

Preclinical studies have shown that stress and glucocorticoids increase mesolimbic dopamine (DA) and thereby facilitate psychostimulant self-administration. The relationship between stress-induced cortisol and mesolimbic DA responses to psychostimulants has not been studied in humans. To test the hypotheses that glucocorticoid responses to psychological stress are correlated with DA and subjective responses to psychostimulants in humans, 25 healthy adults (18–29 years) completed the Trier Social Stress Test (TSST) and two positron emission tomography (PET) scans with high-specific [11C]raclopride. The first scan was preceded by intravenous saline and the second by amphetamine (AMPH). Findings showed that stress-induced cortisol levels were positively associated with AMPH-induced DA release in the ventral striatum and other striatal regions. Subjects with higher cortisol responses to stress also reported more positive subjective drug effects with AMPH than subjects with lower responses. The results are consistent with preclinical findings showing an interrelationship between glucocorticoids and mesolimbic DA dynamics, which may influence psychostimulant self-administration in humans.

The Relationship Between Recent Alcohol Use and Sexual Behaviors: Gender Differences Among Sexually Transmitted Disease Clinic Patients

BACKGROUND Binge drinking is associated with risky sexual behaviors and sexually transmitted diseases (STDs). Few studies have investigated this by gender or in an STD clinic. This cross-sectional study examined the association between binge drinking and risky sexual behaviors/STDs among patients attending an urban STD clinic. METHOD A total of 671 STD clinic patients were tested for STDs, and queried about recent alcohol/drug use and risky sexual behaviors using audio computer-assisted-self-interview. The association between binge drinking and sexual behaviors/STDs was analyzed using logistic regression adjusting for age, employment, and drug use. RESULTS Binge drinking was reported by 30% of women and 42% of men. Gender differences were found in rates of receptive anal sex which increased linearly with increased alcohol use among women but did not differ among men. Within gender analyses showed that women binge drinkers engaged in anal sex at more than twice the rate of women who drank alcohol without binges (33.3% vs. 15.9%; p < 0.05) and 3 times the rate of women who abstained from alcohol (11.1%; p < 0.05). Having multiple sex partners was more than twice as common among women binge drinkers than women abstainers (40.5% vs. 16.8%; p < 0.05). Gonorrhea was nearly 5 times higher among women binge drinkers compared to women abstainers (10.6% vs. 2.2%; p < 0.05). The association between binge drinking and sexual behaviors/gonorrhea remained after controlling for drug use. Among men, rates of risky sexual behaviors/STDs were high, but did not differ by alcohol use. CONCLUSION Rates of binge drinking among STD clinic patients were high. Among women, binge drinking was uniquely associated with risky sexual behaviors and an STD diagnosis. Our findings support the need to routinely screen for binge drinking as part of clinical care in STD clinics. Women binge drinkers, in particular, may benefit from interventions that jointly address binge drinking and risky sexual behaviors. Developing gender-specific interventions could improve overall health outcomes in this population.

GABRA6 gene polymorphism and an attenuated stress response

The glucocorticoid component of the stress response has been the subject of intense scientific scrutiny because of the wide ranging pathological consequences resulting from excess glucocorticoid exposure, including mood and anxiety disorders, and cognitive impairment. Exposure to stress activates the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic adrenomedullary system, which are regulated by neuronal pathways, including the inhibitory GABAergic (γ-aminobutyric acid) system. Approximately 60% of the variance in glucocorticod levels may be attributable to genetic individual differences. In the present study, 56 healthy subjects underwent genotyping to determine the influence of the T1521C single nucleotide polymorphism (SNP) in the GABAAα6 receptor subunit gene (GABRA6) on the hormonal and autonomic responses to psychological stress induced by the Trier Social Stress Test (TSST). Adrenocorticotropin (ACTH), cortisol, diastolic blood pressure, and mean blood pressure responses to the TSST were significantly greater in subjects homozygous for the T allele or heterozygous compared to subjects homozygous for the C allele. Behavioral data was collected employing the Revised NEO Personality Inventory (NEO PI-R); subjects homozygous for the C allele scored significantly lower on the Extraversion factor compared to subjects homozygous for the T allele or heterozygous. These results suggest that the T1521C polymorphism in the GABRA6 gene is associated with specific personality characteristics as well as a marked attenuation in hormonal and blood pressure responses to psychological stress.

COST-EFFECTIVENESS OF TREATMENT FOR DRUG-ABUSING PREGNANT WOMEN

Neonatal intensive care unit (NICU) and drug treatment costs were compared in two groups of pregnant drug abusing women: 100 admissions to a multidisciplinary treatment program and active in care at the time of delivery and 46 controls not entering drug treatment. Clinical measures included urine toxicology at delivery, infant birthweight. Apgar scores and need for and duration of NICU services. Cost measures included drug treatment and NICU costs. Treatment patients showed better clinical outcome at delivery, with less drug use and higher infant estimated gestational age, birthweight and Apgar scores. Infants of treatment patients were also less likely to require NICU services and, for those that did, had a shorter stay. When total cost was examined (including drug treatment), mean net savings for treatment subjects was