PET imaging of the effects of age and cocaine on the norepinephrine transporter in the human brain using (S,S)-[¹¹C]O-methylreboxetine and HRRT

Abstract

Objectives The role of the norepinephrine transporter (NET) in cocaine dependence has never been demonstrated via in vivo imaging due to the lack of suitable NET radioligands. Here we report our preliminary studies evaluting the NET in individuals with cocaine dependence (COC) in comparison to healthy controls (HC) using (S,S)-[11C]methylreboxetine ([11C]MRB), the most promising C-11 labeled positron-emission tomography (PET) radioligand for NET developed to date. Methods Twenty two human volunteers (10 COC and 12 HC) underwent dynamic 11C-MRB-PET acquisition using a High Resolution Research Tomograph (HRRT). Binding potential (BPND) parametric images were computed using the simplified reference tissue model (SRTM2) with occipital cortex as reference region. BPND values were compared between the two groups. Results Locus coeruleus (LC), hypothalamus, and pulvinar showed a significant inverse correlation with age among HC (age range = 25–54 years; p = 0.04, 0.009, 0.03 respectively). The BPND was significantly increased in thalamus (27%; p < 0.02) and dorsomedial thalamic nuclei (30%; p < 0.03) in COC as compared to HC. Upon age normalization, the upregulation of NET in COC also reached significance in LC (63%, p < 0.01) and pulvinar (55%, p < 0.02) regions. Conclusion Our results suggest that (a) brain NET concentration declines with age in HC, and (b) there is a significant upregulation of NET in thalamus and dorsomedial thalamic nucleus in COC as compared to HC. Our results also suggest that the use of [11C]MRB and HRRT provides an effective strategy for studying alterations of the NET system in humans.

Increased Sensorimotor Gating in Recreational and Dependent Cocaine Users Is Modulated by Craving and Attention-Deficit/Hyperactivity Disorder Symptoms

“…2) An increase of thalamic NE transporter density has been reported in DCU (16) and growing evidence suggests an involvement thalamocortical and ventral forebrain NE transmission in the regulation of PPI (25-28,64). Therefore, also dysregulation of NE transmission in CDU as well as RCU might contribute to the current results (17).…”

“…Thus, dysregulated DA functioning in DCU has been associated with widespread consequences including craving, impulsive behavior, loss of control over drug intake, and relapse (12,13,15). Recently, also upregulation of thalamic NE transporters has been reported in DCU (16) and NE seems to play an important role in craving, withdrawal-related anxiety, and relapse in cocaine addiction (17,18). While most studies investigated dependent users, little is known about the effects of occasional and recreational cocaine use.…”

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

“…Cocaine is known to up-regulate both NET and DAT (1,(71)(72)(73). Although the signals or the mechanisms involved in DAT up-regulation have not been identified, our earlier study demonstratedthatcocaine-activatedp38MAPKandThr 30 phosphorylation play a role in cocaine-mediated NET up-regulation (1).…”

Differential Internalization Rates and Postendocytic Sorting of the Norepinephrine and Dopamine Transporters Are Controlled by Structural Elements in the N Termini

“…It will also be interesting to clarify the precise biological significance of the distinct trafficking itineraries for NET and DAT, and whether or not these can be related to neuropsychiatric disease or chronic drug use. For example, differential up-and down-regulation of brain NET and DAT, respectively, was reported upon chronic cocaine or methamphetamine exposure in humans (47,78). For homologous receptors, distinct sorting mechanisms are believed to enable differential physiological adaptation to agonist exposure (48,74,75).…”