Higher Binding of the Dopamine D₃Receptor-Preferring Ligand [¹¹C]-(+)-Propyl-Hexahydro-Naphtho-Oxazin in Methamphetamine Polydrug Users: A Positron Emission Tomography Study

Abstract

Positron emission tomography (PET) findings suggesting lower D2-type dopamine receptors and dopamine concentration in brains of stimulant users have prompted speculation that increasing dopamine signaling might help in drug-treatment. However, this strategy needs to consider the possibility, based on animal and postmortem human data, that dopaminergic activity at the related D3 receptor might, in contrast, be elevated, and thereby contribute to drug-taking behavior. We tested the hypothesis that D3 receptor binding is above-normal in methamphetamine (MA) polydrug users, using PET and the D3-preferring ligand [11C]-(+)-PHNO. Sixteen control subjects and 16 polydrug users reporting MA as their primary drug of abuse underwent PET scanning following [11C]-(+)-PHNO. Compared to control subjects, drug users had higher [11C]-(+)-PHNO binding in the D3-rich midbrain substantia nigra (SN, +46%, p<0.02) and in the globus pallidus (+9%, p=0.06) and ventral pallidum (+11%, p=0.1), whereas binding was slightly lower in the D2-rich dorsal striatum (~−4%, NS; −12% in heavy users, p=0.01) and related to drug-use severity. [11C]-(+)-PHNO binding ratio in D3-rich SN vs. D2-rich dorsal striatum was 55% higher in MA users (p=0.004), with heavy but not moderate users having ratios significantly different from controls. [11C]-(+)-PHNO binding in SN was related to self-reported “drug-wanting.” We conclude that the dopamine D3 receptor, unlike the D2 receptor, might be upregulated in brains of MA polydrug users although lower dopamine levels in MA users could have contributed to the finding. Pharmacological studies are needed to establish whether normalization of D3 receptor function could reduce vulnerability to relapse in stimulant abuse.

Further Characterization of Quinpirole-Elicited Yawning as a Model of Dopamine D3 Receptor Activation in Male and Female Monkeys

“…consistent with predominant D2R-mediated signal associated with [ 11 C]PHNO binding potential and pharmacological studies suggesting that the descending limb of the quinpirole-elicited yawning dose-response curve is D2R-mediated (Collins et al, 2005(Collins et al, , 2007. Recent PET studies of chronic cocaine (Payer et al, 2014) and polydrug MA (Boileau et al, 2012) users reported that both drugs were associated with elevated levels of D3R availability in the substantia nigra. Furthermore, the use of cocaine and MA has previously been shown to be associated with decreased D2-like receptor availability (Volkow et al, 1990(Volkow et al, , 2001Nader et al, 2006;Payer et al, 2014).…”

“…In the present study, the highest uptake and binding potentials were in the caudate nucleus, putamen, and ventral striatum. Previous studies in humans found a similar pattern of distribution of PHNO binding, with highest binding potentials in the putamen, globus pallidus, and substantia nigra (Searle et al, 2010;Boileau et al, 2012;Gallezot et al, 2014). Tziortzi and colleagues (2011) …”

“…Changes in sensitivity on the ascending limb of the quinpirole dose-response curve have been hypothesized to be due to upregulation of D3R and/or downregulation of D2R (Collins et al, 2011); PET and receptor autoradiography studies support this mechanism after longterm MA exposure (Kuczenski et al, 2009;Boileau et al, 2012). It also remains possible that changes in DA transporter (DAT) and subsequent changes in extracellular DA may interact with quinpirole's effects at D3R and D2R.…”

“…Postmortem studies indicate higher D3R densities in cocaine overdose victims compared with age-matched controls (Staley and Mash, 1996;Segal et al, 1997), supporting a role for this receptor subtype in drug addiction. Finally, recent brain imaging studies in humans using the positron emission tomography (PET) D3R-preferring ligand [ 11 C]PHNO ([ 11 C]-(+)-propyl-hexahydronaphtho-oxazin) revealed that D3R availability was higher in MA polydrug users (Boileau et al, 2012) and cocaine-dependent individuals (Payer et al, 2014) compared with age-matched controls, an outcome opposite to the decreases in D2-like receptor availability after chronic stimulant exposure (e.g., Volkow et al, 1990Volkow et al, , 2001Nader et al, 2006).…”

Effect of Exercise Training on Striatal Dopamine D2/D3 Receptors in Methamphetamine Users during Behavioral Treatment

“…Moreover, pharmacological treatment with nonselective D2/D3 receptor agonists may have untoward effects by augmenting D3 vs D2 receptor signaling. Notably, stimulant users show greater D3 receptor availability in the limbic striatum compared with healthy control subjects (Boileau et al, 2012). Therefore, nonpharmacologic approaches, such as structured exercise training, that augment dopaminergic signaling in physiologically relevant ways may be useful in treating those with substance use disorders.…”