Amphetamine-Induced Dopamine Release and Neurocognitive Function in Treatment-Naive Adults with ADHD

Converging evidence from clinical, preclinical, neuroimaging, and genetic research implicates dopamine neurotransmission in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The in vivo neuroreceptor imaging evidence also suggests alterations in the dopamine system in ADHD; however, the nature and behavioral significance of those have not yet been established. Here, we investigated striatal dopaminergic function in ADHD using [¹¹C]raclopride PET with a d-amphetamine challenge. We also examined the relationship of striatal dopamine responses to ADHD symptoms and neurocognitive function. A total of 15 treatment-free, noncomorbid adult males with ADHD (age: 29.87±8.65) and 18 healthy male controls (age: 25.44±6.77) underwent two PET scans: one following a lactose placebo and the other following d-amphetamine (0.3 mg/kg, p.o.), administered double blind and in random order counterbalanced across groups. In a separate session without a drug, participants performed a battery of neurocognitive tests. Relative to the healthy controls, the ADHD patients, as a group, showed greater d-amphetamine-induced decreases in striatal [¹¹C]raclopride binding and performed more poorly on measures of response inhibition. Across groups, a greater magnitude of d-amphetamine-induced change in [¹¹C]raclopride binding potential was associated with poorer performance on measures of response inhibition and ADHD symptoms. Our findings suggest an augmented striatal dopaminergic response in treatment-naive ADHD. Though in contrast to results of a previous study, this finding appears consistent with a model proposing exaggerated phasic dopamine release in ADHD. A susceptibility to increased phasic dopamine responsivity may contribute to such characteristics of ADHD as poor inhibition and impulsivity.     

The Impact of Alexithymia on Desire for Alcohol during a Social Stress Test

Background: Alexithymia is a personality construct comprising difficulty in identifying and describing emotions and externally oriented thinking. Its role in heavy and problematic alcohol consumption is well documented, together with its relationship with social stress. However, little research has examined whether social stress has any effect on desire for alcohol among alexithymic individuals. Objectives: In this experimental study, we explored the relationship between alexithymia and desire for alcohol in response to an experimental social stressor. Methods: One hundred and thirty eight social drinkers completed the Toronto Alexithymia Scale, self-report measures of alcohol consumption and a stress-inducing task. Desire for alcohol was measured at three time points: baseline, stressor and recovery. Results: Correlation analysis demonstrated that alexithymia was associated with significantly higher rates of alcohol consumption and higher levels of desire for alcohol. Mixed measures ANOVA demonstrated a significant main effect of alexithymia and a significant group by time effect of alexithymia on desire for alcohol. Conclusions/Importance: The findings demonstrate increased desire for alcohol before, during and after a social stressor among alexithymic participants. These findings offer an insight into the relationship between alexithymia, social stress and alcohol consumption.     

Evaluation of 5-(Trifluoromethyl)-1,2,4-oxadiazole-Based Class IIa HDAC Inhibitors for Huntington’s Disease

Using an iterative structure–activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC₅₀, using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington’s disease.     

The consequences of risk reducing salpingo-oophorectomy: the case for a coordinated approach to long-term follow up post surgical menopause

Women with germline mutations in BRCA1 and BRCA2 genes have significantly increased lifetime risks of breast and ovarian cancer. To manage both the ovarian and breast cancer risks the current recommendation is undergo a risk reducing salpingo-oophorectomy (RRSO) prior to natural menopause. To date, studies have focussed on quality of life and sexual dysfunction in women who undergo RRSO, but few have reported on the wider physical consequences. We performed a questionnaire study in women with BRCA 1 or 2 gene mutations known to the Peter MacCallum Familial Cancer Centre. We gathered information about ovarian surgery, ongoing follow-up, management of risk factors including osteoporosis, and current severity of menopausal symptoms. Two hundred and nineteen women were surveyed. One hundred and forty-three of 157 responding participants (91?%) reported having RRSO. Sixty one were pre-menopausal at RRSO. Post surgical follow-up rates were generally low, and a minority of women reported recent bone density imaging or pharmaceutical prevention or treatment of osteoporosis. Menopausal symptoms appeared generally mild. No significant differences in symptom severity were observed in women who underwent a pre-menopausal RRSO compared to RRSO after natural menopause. These data indicate that a formalised follow-up protocol is necessary to optimally manage the consequences of a RRSO.