What is the role of the D3 receptor in addiction? A mini review of PET studies with [11C]-(+)-PHNO
Introduction
The D3 receptor was discovered in the early 1990s and, based on amino acid sequence and gene organization, was classified as a prototypic D2-like G protein-coupled receptor (Sokoloff et al., 1990). One of the most striking features of this receptor system is its anatomical localization: unlike the D2 receptor, which is highly expressed in the caudate–putamen, the D3 receptor is described as having a complementary distribution restricted to limbic areas, including the ventral striatum (nucleus accumbens shell), Island of Calleja, septum, nucleus basalis, olfactory tubercle, ventral pallidum, lateral substantia nigra pars compacta, medial mammillary nucleus, and dentate gyrus of the hippocampus (Bouthenet et al., 1991, Diaz et al., 2000, Stanwood et al., 2000). The observation that the D3 receptor is mainly distributed on ‘reward’ circuitry led to the suggestion that this receptor preferentially mediates motivational and emotional functions, and by extension may play a role in addiction (Guillin et al., 2003, Le Foll et al., 2005b).
A second key feature of the D3 receptor is that among the five sub-types of dopamine receptors, it has the highest overall affinity for endogenous dopamine (Ki = 30 nM) (Levesque et al., 1992, Sokoloff et al., 1992), making it the most sensitive to basal concentrations. This property suggests that after exposure to dopamine-elevating drugs (including most drugs of abuse), occupancy of the D3 receptor is greater compared to D1 or D2 (estimated 96% vs. 25–27%) (Richtand, 2006), resulting in a rapid saturation of the less numerous D3 receptors. Although the functional consequences of this difference are not yet certain, it is possible that a slight change in dopamine concentration (as occurs with acute and chronic drug exposure) is likely to affect D3 receptor-mediated behaviors before affecting those linked to D1 or D2.
Section snippets
The suspected role of the D3 receptor in motivated behavior and addiction
Although a differential role for D2 and D3 receptors in addiction-related and appetitive behaviors is still controversial, pharmacological studies using D3-selective ligands (reviewed elsewhere (Heidbreder and Newman, 2010)) indicate that this receptor is implicated in motivation to use drugs (but probably not their reinforcing properties per se) (Heidbreder and Newman, 2010, Le Foll et al., 2005b). For instance, unlike most studies using D2-preferring antagonists, D3-selective antagonist
Evidence that the D3 receptor is upregulated in animal models of addiction
Evidence suggesting that the D3 receptor is involved in addiction also comes from reports that dopaminergic stimulation by drugs of abuse or excessive endogenous dopamine elevates D3 mRNA and receptor levels in preclinical models (Le Foll et al., 2005b). This D3 upregulation has been observed after acute, subchronic, and chronic exposure to levodopa (in rats (Bordet et al., 1997) and monkeys (Morissette et al., 1998)), nicotine (Le Foll and Goldberg, 2006), morphine (Spangler et al., 2003),
[11C]-(+)-PHNO: the only available PET probe to investigate D3 receptors in living humans
It has recently become possible to investigate the role of the D3 receptor in addiction in living humans, using brain imaging technology with D3-specific probes. Although commonly used D2/3 PET radioligands such as [11C]raclopride, [11C]FLB-457, [18F]fallypride, and the agonist [11C]-(2)-NPA also bind to D3 receptors, the much greater density of D2 vs. D3 receptors in brain results in a signal that mainly reflects D2. In contrast, [11C]-(+)-PHNO (Wilson et al., 2005) – a recently synthesized
Is the D3 receptor level increased in addiction: evidence from [11C]-(+)-PHNO studies in stimulant users
Positron emission tomography (PET) studies investigating D2/3 receptor levels in addictions (including cocaine, methamphetamine, heroin, nicotine, and alcohol dependence, as well as behavioral addictions such as compulsive eating/obesity) have echoed preclinical data in consistently showing low D2/3 dopamine receptor availability (Fehr et al., 2008, Volkow et al., 2007).1
Translational potential of D3 antagonism and usefulness of [11C]-(+)-PHNO
To date, very few studies have investigated the effects of selective D3 antagonism on clinical outcome (treatment success, quit rate, abstinence, or surrogate markers such as cognitive status) in addicted humans. Among the small number of studies, one promising candidate, the GSK compound GSK598809, was shown to have a 100-fold selectivity for D3 over D2 and a good safety profile, and was therefore deemed a viable candidate for clinical trials in addictions (both substance and behavioral).
Caveats/limitations
To date, [11C]-(+)-PHNO is the only available tool to investigate D3 dopamine receptor levels (and occupancy by candidate drugs) in humans in vivo. Nonetheless, this tool is not without limitations (Shotbolt et al., 2011): For one, although [11C]-(+)-PHNO preferentially binds to D3 receptors, it is non-specific, so that the signal in the substantia nigra (the only region where 100% of signal stems from D3) has to be used to index brain D3 receptor levels; interpretation is therefore
Conclusion
Despite these limitations, neuroimaging with [11C]-(+)-PHNO PET is a valuable new avenue in the field that can not only improve our understanding of the addiction phenotype, but also save resources in the development of D3 pharmacotherapies by providing information that can validate drug targets and guide dose optimization in human clinical trials.
References (74)
- et al.
Localization of dopamine D3 receptor mRNA in the rat brain using in situ hybridization histochemistry: comparison with dopamine D2 receptor mRNA
Brain Res
(1991) - et al.
D(3) dopamine receptors are down-regulated in ampethamine sensitized rats and their putative antagonists modulate the locomotor sensitization to amphetamine
Brain Res
(2003) - et al.
Increased serum brain-derived neurotrophic factor is predictive of cocaine relapse outcomes: a prospective study
Biol Psychiatry
(2011) - et al.
Brain levels of neuropeptides in human chronic methamphetamine users
Neuropharmacology
(2007) - et al.
Striatal and ventral pallidum dynorphin concentrations are markedly increased in human chronic cocaine users
Neuropharmacology
(2008) - et al.
Brain-derived neurotrophic factor controls dopamine D3 receptor expression: therapeutic implications in Parkinson's disease
Eur J Pharmacol
(2003) - et al.
Glutamate transmission in addiction
Neuropharmacology
(2009) - et al.
High concentrations of plasma brain-derived neurotrophic factor in methamphetamine users
Neurosci Lett
(2005) - et al.
Dopamine D3 receptor and drug dependence: effect on reward or beyond?
Neuropharmacology
(2005) - et al.
Blockade of dopamine D(3) receptors in frontal cortex, but not in sub-cortical structures, enhances social recognition in rats: similar actions of D(1) receptor agonists, but not of D(2) antagonists
Eur Neuropsychopharmacol
(2009)