Reductions in Brain 5-HT1B Receptor Availability in Primarily Cocaine-Dependent Humans

Abstract

Background Preclinical evidence implicates the 5-HT1B receptor in cocaine’s effects. This study explores 5-HT1B in humans by examining receptor availability in vivo with primary cocaine-dependent (CD) subjects using positron emission tomography (PET). Methods Fourteen medically healthy CD subjects (mean age=41±6 yrs) were compared to 14 age-matched healthy control subjects (41±8 yrs) with no past or current history of cocaine or other illicit substance abuse. Participants received an MRI and then a PET scan with the highly selective 5HT1B tracer, [11C]P943, for purposes of quantifying regional binding potential (BPND). Voxel-based morphometry (VBM) and gray matter masking (GMM) were also employed to control for potential partial volume effects. Results [11C]P943 PET imaging data in nine candidate regions (amygdala, anterior cingulate cortex, caudate, frontal cortex, hypothalamus, pallidum, putamen, thalamus and ventral striatum) showed significant or nearly significant reductions of BPND in CD subjects in three regions, including the anterior cingulate (−16%; P<0.01), hypothalamus (−16%, P=0.03) and frontal cortex (−7%, P=0.08). VBM showed significant gray matter reductions in the frontal cortex of CD subjects. After GMM, statistically significant reductions in [11C]P943 BPND were either retained (anterior cingulate, −14%, p=0.01; hypothalamus, −20%, P<0.01) or achieved (frontal cortex, −14%, p<0.01). Whole brain voxel-wise parameter estimation confirmed these results. Secondary analyses were also significant in some regions for years of cocaine and daily tobacco use. Conclusions The reductions found in this study suggest that 5-HT1B receptors may contribute to the etiology and/or expression of cocaine dependence and potentially represent a target for medication development.

Age-related changes in binding of the D2/3 receptor radioligand [11C](+)PHNO in healthy volunteers

“…Slopes were estimated within each region post-hoc and decline per decade was calculated as a percent of the fitted value at age 20. Within-subject correlations were accounted for by fitting three variance-covariance structures to the data (unstructured, compound symmetry, and heterogeneous compound symmetry) and then selecting the best-fitting structure according to the Bayesian Information Criterion (BIC) (Matuskey et al, 2014a; Matuskey et al, 2012). All tests were two-tailed and adjusted for multiple comparisons using the Bonferroni adjustment.…”

OCD is associated with an altered association between sensorimotor gating and cortical and subcortical 5-HT1b receptor binding

“…PET imaging using 11 C-P943 was performed as described in recent studies from our center (72, 78, 83). The antecubital vein was cannulated for radiotracer delivery.…”

Serotonin Transporter and Tryptophan Hydroxylase Gene Variations Mediate Working Memory Deficits of Cocaine Users

“…Positron emission tomography (PET) studies in monkeys showed increased 5-HTT availability in frontal areas after chronic cocaine administration, whereas PET studies in humans revealed that chronic use is associated with reduced 5-HT 1B receptor binding in the PFC (Gould et al, 2011;Matuskey et al, 2013). In addition, studies in rats demonstrated that the TPH2 activity in the raphe nucleus increases after chronic cocaine administration (Vrana et al, 1993).…”