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Le Foll B.,Campbell Family Mental Health Research Institute | Le Foll B.,Alcohol Research and Treatment Clinic | Le Foll B.,University of Toronto | Collo G.,University of Brescia | And 5 more authors.
Progress in Brain Research | Year: 2014

The dopamine D3 receptor is located in the limbic area and apparently mediates selective effects on motivation to take drugs and drug-seeking behaviors, so that there has been considerable interest on the possible use of D3 receptor ligands to treat drug addiction. However, only recently selective tools allowing studying this receptor have been developed. This chapter presents an overview of findings that were presented at a symposium on the conference Dopamine 2013 in Sardinia in May 2013. Novel neurobiological findings indicate that drugs of abuse can lead to significant structural plasticity in rodent brain and that this is dependent on the availability of functional dopamine D3 autoreceptor, whose activation increased phosphorylation in the ERK pathway and in the Akt/mTORC1 pathway indicating the parallel engagement of a series of intracellular signaling pathways all involved in cell growth and survival. Preclinical findings using animal models of drug-seeking behaviors confirm that D3 antagonists have a promising profile to treat drug addiction across drugs of abuse type. Imaging the D3 is now feasible in human subjects. Notably, the development of (+)-4-propyl-9-hydroxynaphthoxazine ligand used in positron emission tomography (PET) studies in humans allows to measure D3 and D2 receptors based on the area of the brain under study. This PET ligand has been used to confirm up-regulation of D3 sites in psychostimulant users and to reveal that tobacco smoking produces elevation of dopamine at the level of D3 sites. There are now novel antagonists being developed, but also old drugs such as buspirone, that are available to test the D3 hypothesis in humans. The first results of clinical investigations are now being provided. Overall, those recent findings support further exploration of D3 ligands to treat drug addiction. © 2014 Elsevier B.V. Source


Le Foll B.,Campbell Family Mental Health Research Institute | Le Foll B.,Alcohol Research and Treatment Clinic | Le Foll B.,University of Toronto | Wilson A.A.,Campbell Family Mental Health Research Institute | And 10 more authors.
Frontiers in Pharmacology | Year: 2014

There is considerable interest in developing highly selective dopamine (DA) D3 receptor ligands for a variety of mental health disorders. DA D3 receptors have been implicated in Parkinson's disease, schizophrenia, anxiety, depression, and substance use disorders. The most concrete evidence suggests a role for the D3 receptor in drug-seeking behaviors. D3 receptors are a subtype of D2 receptors, and traditionally the functional role of these two receptors has been difficult to differentiate. Over the past 10-15 years a number of compounds selective for D3 over D2 receptors have been developed. However, translating these findings into clinical research has been difficult as many of these compounds cannot be used in humans. Therefore, the functional data involving the D3 receptor in drug addiction mostly comes from pre-clinical studies. Recently, with the advent of [11C]-(+)-PHNO, it has become possible to image D3 receptors in the human brain with increased selectivity and sensitivity. This is a significant innovation over traditional methods such as [11C]-raclopride that cannot differentiate between D2 and D3 receptors. The use of [11C]-(+)-PHNO will allow for further delineation of the role of D3 receptors. Here, we review recent evidence that the role of the D3 receptor has functional importance and is distinct from the role of the D2 receptor. We then introduce the utility of analyzing [11C]-(+)-PHNO binding by region of interest. This novel methodology can be used in pre-clinical and clinical approaches for the measurement of occupancy of both D3 and D2 receptors. Evidence that [11C]-(+)-PHNO can provide insights into the function of D3 receptors in addiction is also presented. © 2014 Le Foll, Wilson, Graff, Boileau and Di Ciano. Source


Le Foll B.,Translational Addiction Research Laboratory | Le Foll B.,Alcohol Research and Treatment Clinic | Le Foll B.,Campbell Family Mental Health Research Institute | Le Foll B.,University of Toronto | And 21 more authors.
Neuropsychopharmacology | Year: 2014

Positron emission tomography (PET) has convincingly provided in vivo evidence that psychoactive drugs increase dopamine (DA) levels in human brain, a feature thought critical to their reinforcing properties. Some controversy still exists concerning the role of DA in reinforcing smoking behavior and no study has explored whether smoking increases DA concentrations at the D3 receptor, speculated to have a role in nicotine's addictive potential. Here, we used PET and 11C-(+)-PHNO (11 C-(+)-4-propyl-3,4,4a,5,6, 10b-hexahydro-2H-naphtho(1,2-b1,4oxazin-9-ol) to test the hypothesis that smoking increases DA release (decreases 11C-(+)-PHNO binding) in D2-rich striatum and D3-rich extra-striatal regions and is related to craving, withdrawal and smoking behavior. Ten participants underwent 11 C-(+)-PHNO scans after overnight abstinence and after smoking a cigarette. Motivation to smoke (smoking topography), mood, and craving were recorded. Smoking significantly decreased self-reported craving, withdrawal, and 11C-(+)-PHNO binding in D2 and D3-rich areas (-12.0 and-15.3%, respectively). We found that motivation to smoke (puff rate) predicted magnitude of DA release in limbic striatum, and the latter was correlated with decreased craving and withdrawal symptoms. This is the first report suggesting that, in humans, DA release is increased in D3-rich areas in response to smoking. Results also support the preferential involvement of the limbic striatum in motivation to smoke, anticipation of pleasure from cigarettes and relief of withdrawal symptoms. We propose that due to the robust effect of smoking on 11 C-(+)-PHNO binding, this radiotracer represents an ideal translational tool to investigate novel therapeutic strategies targeting DA transmission. © 2014 American College of Neuropsychopharmacology. Source


Payer D.,Addiction Imaging Research Group | Payer D.,Campbell Family Mental Health Institute | Payer D.,Research Imaging Center | Payer D.,Center for Addiction and Mental Health | And 7 more authors.
Progress in Neuro-Psychopharmacology and Biological Psychiatry | Year: 2014

The chronic use of drugs, including psychostimulants such as cocaine and amphetamine, has been associated with low D2/3 dopamine receptor availability, which in turn has been linked to poor clinical outcome. In contrast, recent studies focused on the D3 receptor (a member of the D2-like receptor family) suggest that chronic exposure to stimulant drugs can up-regulate this receptor subtype, which, in preclinical models, is linked to dopamine system sensitization - a process hypothesized to contribute to relapse in addiction. In this mini review we present recent human data suggesting that the D3 receptor may contribute to core features of addiction, and discuss the usefulness of the PET imaging probe [11C]-(+)-PHNO in investigating this question. © 2013 Elsevier Inc. Source


Tong J.,Research Imaging Center | Tong J.,Addiction Imaging Research Group | Fitzmaurice P.,ESR Institute of Environmental Science and Research | Furukawa Y.,Juntendo University | And 7 more authors.
Neurobiology of Disease | Year: 2014

Animal data show that high doses of the stimulant drug methamphetamine can damage brain dopamine neurones; however, it is still uncertain whether methamphetamine, at any dose, is neurotoxic to human brain.Since gliosis is typically associated with brain damage and is observed in animal models of methamphetamine exposure, we measured protein levels (intact protein and fragments, if any) of markers of microgliosis (glucose transporter-5, human leukocyte antigens HLA-DRα [TAL.1B5] and HLA-DR/DQ/DPβ [CR3/43]) and astrogliosis (glial fibrillary acidic protein, vimentin, and heat shock protein-27) in homogenates of autopsied brain of chronic methamphetamine users (n. = 20) and matched controls (n. = 23). Intact protein levels of all markers were, as expected, elevated (+. 28%-1270%, P<. 0.05) in putamen of patients with the neurodegenerative disorder multiple system atrophy (as a positive control) as were concentrations of fragments of glial fibrillary acidic protein, vimentin and heat shock protein-27 (+. 170%-4700%, P<. 0.005). In contrast, intact protein concentrations of the markers were normal in dopamine-rich striatum (caudate, putamen) and in the frontal cortex of the drug users. However, striatal levels of cleaved vimentin and heat shock protein-27 were increased (by 98%-211%, P<. 0.05), with positive correlations (r. = 0.41-0.60) observed between concentrations of truncated heat shock protein-27 and extent of dopamine loss (P= 0.006) and levels of lipid peroxidation products 4-hydroxynonenal (P= 0.046) and malondialdehyde (P= 0.11).Our failure to detect increased intact protein levels of commonly used markers of microgliosis and astrogliosis could be explained by exposure to methamphetamine insufficient to cause a toxic process associated with overt gliosis; however, about half of the subjects had died of drug intoxication suggesting that "high" drug doses might have been used. Alternatively, drug tolerance to toxic effects might have occurred in the subjects, who were all chronic methamphetamine users. Nevertheless, the finding of above-normal levels of striatal vimentin and heat shock protein-27 fragments (which constituted 10-28% of the intact protein), for which changes in the latter correlated with those of several markers possibly suggestive of damage, does suggest that some astrocytic "disturbance" had occurred, which might in principle be related to methamphetamine neurotoxicity or to a neuroplastic remodeling process. Taken together, our neurochemical findings do not provide strong evidence for either marked microgliosis or astrogliosis in at least a subgroup of human recreational methamphetamine users who used the drug chronically and shortly before death. However, a logistically more difficult quantitative histopathological study is needed to confirm whether glial changes occur or do not occur in brain of human methamphetamine (and amphetamine) users. © 2014 Elsevier Inc. Source

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