Substantial enantiomer-specific differences in the neurochemical and behavioral actions of the synthetic cathinone mephedrone

Abstract

Aims: Determine whether mu-opioid seeking, stress-related biomarkers, and associative learning are altered by manipulation of noradrenergic and glucocorticoid neurotransmission in heroindependent individuals. Methods: Subjects are being evaluated under buprenorphinemaintained, inpatient conditions using a 3×3 within-subject, randomized crossover, placebo-controlled, double-blind design. In each test session, oral pretreatment doses of the alpha2-adrenergic antagonist yohimbine (YOH 0, 27, 54mg) and glucocorticoid agonist hydrocortisone (CORT 0, 20, 40mg) are administered before a hydromorphone (HYD 1.5mg unit) vs. money ($2 unit) choice, progressive ratio task. Periodic measures include stress biomarkers (blood pressure, saliva cortisol and alpha-amylase), negative mood state, and hippocampal dependent (visual associative) learning measures. Results: In interim analyses (n=6 completers of 15 planned), YOH dose dependently increases HYD breakpoint (lin. F[1,5] = 6.37, p= .053), especially during CORT 40mg (lin. YOH×quadr. CORT F[1,5] = 10.77, p< .03). YOH dose dependently increases systolic and diastolic BP (lin. Fs[1,5] = 41.26 and 31.50, ps < .005); POMS Anxiety (lin. F[2,8]) = 2.71, p= .15; and associative learning rate (lin. F[1,5] = 6.11, p< .06), more so during placebo CORT (lin. YOH×quadratic CORT F[1,5] = 9.31, p< .03). YOH 27mg but not 54mg, relative to placebo, tends to increase cortisol (quadr. F[1,5] = 5.00, p<.08) but not alpha-amylase. CORT dose dependently increases cortisol (lin. F[1,5] = 32.20, p< .002) and decreases learning rate (lin. F[1,5] = 10.42,p< .03), but is not alteringother response measures. Conclusions: YOH-potentiated opioid seeking, blood pressure, and anxiety responses are consistent with Greenwald et al. (2013); emerging effects of YOH on cortisol and learning measures further validate this paradigm and extend findings from animal studies. CORT produces a different profile of effects than YOH (e.g. suppression of learning) and may augment YOH’s effect on opioid reinforcement. Financial support: 2 NIH R01 DA015462 and Joe Young Sr./Helene Lycacki Funds (State of Michigan) support this research.