Lynn M. Oswald

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.

Opioids and alcoholism.

Although far from conclusive, evidence implicating the endogenous opioid system in the development and maintenance of alcoholism is growing. Currently available data suggest that ethanol increases opioid neurotransmission and that this activation is part of the mechanism responsible for its reinforcing effects. Findings from preclinical research indicate that ethanol consumption and ethanol-induced dopamine (DA) release are both reduced by opioid antagonists. Individual differences in endogenous opioid activity have been linked to inherited risks for alcoholism in studies comparing ethanol-preferring and nonpreferring rats, as well as in studies using targeted gene mutation (knockout) strategies. To a large extent, findings from human studies have paralleled those from the preclinical work. Persons who differ in family history of alcoholism have been shown to also differ in basal beta-endorphin activity, beta-endorphin response to alcohol, and subjective and HPA axis hormonal response to opioid antagonists. Findings from clinical trials indicate that opioid antagonists may reduce ethanol consumption in alcoholics, particularly in persons who have resumed drinking. Nevertheless, many questions remain unanswered about the use of opioid antagonists in alcoholism treatment and about the exact role of the opioid system in ethanol preference and reward. The progression of knowledge in this field suggests that many of these questions are imminently answerable, as our ability to characterize relationships between opioid activity and human behavior continues to develop. This paper summarizes both the progress that has been made and the gaps that remain in our understanding of the interactions between the endogenous opioid system and risk for alcoholism.

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.

Gender differences in hypothalamic–pituitary–adrenal (HPA) axis reactivity

The present study was designed to determine whether there are gender differences in hormonal response patterns to HPA axis activation. To this end, two methods of activating the HPA axis were employed: a standardized psychological stress test and a pharmacological challenge. Healthy subjects (mean age 23.4 years, SD 7.0 years) completed a naloxone challenge and/or the modified Trier Social Stress Test (TSST). For the naloxone challenge, two baseline blood samples were obtained. Placebo was then administered (0 min), followed by increasing doses of intravenous naloxone (50, 100, 200 and 400 microg/kg) at 30-min intervals. Post-placebo blood samples were collected at 15-min intervals for 180 min. The TSST consisted of 5 min of public speaking followed by 5 min of mental arithmetic exercises. Three baseline and five post-TSST blood samples were drawn. Eighty subjects (53 male, 27 female) underwent the TSST. Following the psychological stressor, adrenocorticotropin (ACTH) and cortisol responses were significantly greater in male subjects compared to female subjects (z=-2.34, p=0.019 and z=-2.12, p=0.034, respectively). Seventy-two subjects (52 male, 20 female) underwent HPA axis activation induced by naloxone. In contrast to the TSST, cortisol responses to the naloxone challenge were significantly greater in female subjects compared to male subjects (z=4.11, p<0.001). Forty-one subjects (25 male, 16 female) completed both the TSST and naloxone challenge. In this subset, ACTH and cortisol responses to the TSST did not differ significantly by gender, although the effect size was moderate to large. Adrenocorticotropin and cortisol responses to the naloxone challenge were significantly greater in female subjects compared to male subjects (z=2.29, p=0.022 and z=4.34, p<0.001, respectively). In summary, male subjects had greater HPA axis responses to a psychological stressor than female subjects, and females had greater hormonal reactivity than males to pharmacological stimulation with naloxone. Such differences are of interest as potential contributors to gender differences in health risks.

Relationship between cortisol responses to stress and personality

Although there is growing evidence of links between the cortisol stress response and personality, the nature of the relationships and the underlying mechanisms require further clarification. The purpose of this study was to examine associations between personality traits and cortisol responses to stress using the Revised NEO Personality Inventory five-factor model of personality. In total, 68 healthy adults, aged 18–30 years, completed the personality assessment and underwent a laboratory psychological stress test that consisted of a 5 min speech and 5-min of mental arithmetic. Findings showed that in the sample as a whole, less Openness was associated with lower cortisol responses to the challenge. Cortisol responses also corresponded to certain personality dimensions in a gender-specific manner. Blunted cortisol responses were associated with higher Neuroticism in women and with lower Extraversion in men. These findings suggest that personality traits that have been traditionally associated with greater psychopathology were also associated with blunted HPA axis responses to stress.

The Mu-Opioid Receptor Polymorphism A118G Predicts Cortisol Responses to Naloxone and Stress

A polymorphism in the mu-opioid receptor (MOR) (A118G) has been shown to increase β-endorphin binding affinity, theoretically placing greater inhibitory tone on hypothalamic corticotropin-releasing hormone (CRH) neurons. We hypothesized that the minor allele (G) would predict cortisol responses to both pharmacological (naloxone) and psychological (stress) activation of the hypothalamic–pituitary–adrenal (HPA) axis. Healthy subjects (mean age 25.2 years, SD 9.2 years) completed a naloxone challenge (n=74) and/or the modified Trier Social Stress Test (TSST) (n=86). For the naloxone challenge, two baseline blood samples were obtained. Then, five increasing doses of i.v. naloxone were administered at 30-min intervals and 12 additional blood samples were collected at 15-min intervals. The TSST consisted of 5-min of public speaking and 5-min of mental arithmetic exercises. Three baseline and five post-TSST blood samples were drawn. Both the naloxone and TSST groups had significant adrenocorticotropin (ACTH) and cortisol responses to their respective challenges (P<0.001). There were no differences in baseline ACTH, baseline cortisol, or ACTH response by genotype in either the naloxone or the TSST group. Among subjects expressing a G allele, there was a higher cortisol response to naloxone (P=0.046), but a lower cortisol response to the TSST (P=0.044). In conclusion, the minor allele (G) was associated with a robust cortisol response to naloxone blockade, but a blunted response to psychosocial stress. We speculate that increased opioid avidity of the minor allele receptor contributes to the differential response to naloxone vs stress.

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.

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.

Impulsivity and chronic stress are associated with amphetamine-induced striatal dopamine release

A challenging question that continues to plague the field of addiction is why some individuals are more vulnerable for substance use disorders than others. Several important risk factors for substance abuse have been identified in clinical studies, including trait impulsivity and environmental stress. However, the neurobiological mechanisms that underlie the relationships remain poorly understood. The purpose of this study was to examine associations among impulsivity, stress, and striatal dopamine (DA) responses to amphetamine (AMPH) in humans. Forty healthy M, F adults, ages 18-29 years, completed self-report measures of trait impulsivity, life events stress, and perceived stress. Subjects subsequently underwent two consecutive 90-min positron emission tomography (PET) studies with high specific activity [11C]raclopride. The first scan was preceded by an intravenous injection of saline; the second was preceded by 0.3 mg/kg AMPH. Findings showed that high impulsivity was associated with blunted right ventral striatal DA release. However, effects were modified by a significant interaction with life events stress. Dopamine release was greater in low vs. high impulsivity subjects under conditions of low or moderate stress. Under conditions of high stress, both groups had low DA release. Subjects with high impulsivity reported more pleasant effects with AMPH than subjects with low impulsivity. In contrast, stress was negatively associated with pleasant drug effects. No associations were observed between impulsivity or stress and cortisol responses to AMPH. The findings are consistent with notions that blunted DA responses represent an endophenotype for substance use disorders.

Hormonal Responses to Psychological Stress and Family History of Alcoholism

The present study was designed to determine whether stress hormones and subjective responses to a psychological stressor were different in nonalcoholic offspring from families with a history of alcohol dependence (family history positive, FHP) than in nonalcoholic offspring without a family history of alcohol dependence (family history negative, FHN). Forty-five healthy subjects (17 FHP, 28 FHN), between the ages of 18 and 29 years, completed the Trier Social Stress Test (TSST). The TSST consisted of 5 min of public speaking followed by 5 min of mental arithmetic. Three baseline and five post-TSST blood samples were drawn. Pre- and post-TSST self-report measures of anxiety were obtained. Cortisol, adrenocorticotropin (ACTH), and prolactin significantly increased in response to the TSST in the entire study sample (F(1,187)=70.22, p<0.001, F(1,143)=33, p<0.001, and F(1,134)=14.37, p<0.001, respectively). Cortisol responses were influenced by an interaction between racial composition and family history of alcoholism (F(1,57)=4.50, p=0.038). Among Caucasian subjects, FHP subjects had greater cortisol response to the TSST compared to FHN subjects (F(1,57)=4.45, p=0.039). No family history effect was identified in African-American subjects. Adrenocorticotropin responses did not differ between FHP and FHN subjects. Adrenocorticotropin response was positively associated with baseline ACTH levels in FHN subjects (t=5.02, p=<0.001), but not in FHP subjects. Prolactin responses did not differ between FHP and FHN subjects. Anxiety response scores (post-TSST scores minus pre-TSST scores) were higher in FHP subjects compared with FHN subjects (z=−2.67, p=0.007). In addition, anxiety response scores were positively associated with cortisol response levels to the TSST in FHN subjects (t=4.52, p<0.001). In contrast, anxiety responses were negatively associated with cortisol responses in FHP subjects (t=−2.30, p=0.024). Our findings are consistent with theories that greater reactivity to stress is associated with greater risks for alcoholism. Furthermore, the findings suggest that the association between the hypothalamic–pituitary–adrenal axis hormonal response and the subjective perception of stress might be deranged in offspring of alcoholics.