Laurent Brichard

Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement

Stimulant addiction is often linked to excessive risk taking, sensation seeking, and impulsivity, but in ways that are poorly understood. We report here that a form of impulsivity in rats predicts high rates of intravenous cocaine self-administration and is associated with changes in dopamine (DA) function before drug exposure. Using positron emission tomography, we demonstrated that D2/3 receptor availability is significantly reduced in the nucleus accumbens of impulsive rats that were never exposed to cocaine and that such effects are independent of DA release. These data demonstrate that trait impulsivity predicts cocaine reinforcement and that D2 receptor dysfunction in abstinent cocaine addicts may, in part, be determined by premorbid influences.

A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment

Through the combined use of 18F-fallypride positron emission tomography and magnetic resonance imaging this study examined the neural mechanisms underlying the attentional deficits associated with attention deficit/hyperactivity disorder and their potential reversal with a single therapeutic dose of methylphenidate. Sixteen adult patients with attention deficit/hyperactivity disorder and 16 matched healthy control subjects were positron emission tomography and magnetic resonance imaging scanned and tested on a computerized sustained attention task after oral methylphenidate (0.5 mg/kg) and placebo administration in a within-subject, double-blind, cross-over design. Although patients with attention deficit/hyperactivity disorder as a group showed significant attentional deficits and reduced grey matter volume in fronto-striato-cerebellar and limbic networks, they had equivalent D2/D3 receptor availability and equivalent increases in endogenous dopamine after methylphenidate treatment to that observed in healthy control subjects. However, poor attentional performers drawn from both the attention deficit/hyperactivity disorder and the control groups had significantly reduced left caudate dopamine activity. Methylphenidate significantly increased dopamine levels in all nigro-striatal regions, thereby normalizing dopamine levels in the left caudate in low performers. Behaviourally, methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis. This finding was accompanied by an equally performance-dependent effect of the drug on dopamine release in the midbrain, whereby low performers showed reduced dopamine release in this region. Collectively, these findings support a dimensional model of attentional deficits and underlying nigro-striatal dopaminergic mechanisms of attention deficit/hyperactivity disorder that extends into the healthy population. Moreover, they confer midbrain dopamine autoreceptors a hitherto neglected role in the therapeutic effects of oral methylphenidate in attention deficit/hyperactivity disorder. The absence of significant case–control differences in D2/D3 receptor availability (despite the observed relationships between dopamine activity and attention) suggests that dopamine dysregulation per se is unlikely to be the primary cause underlying attention deficit/hyperactivity disorder pathology in adults. This conclusion is reinforced by evidence of neuroanatomical changes in the same set of patients with attention deficit/hyperactivity disorder.

Direct, nucleophilic radiosynthesis of [18F]trifluoroalkyl tosylates: improved labelling procedures

A rapid and efficient protocol to afford the title compound 2-[(18)F]-fluoro-2,2-difluoroethyl tosylate ([(18)F]7b) is described. Starting from [(18)F]fluoride ion, labelling reagent 7b was obtained in good yields and a high specific radioactivity. Compound ([(18)F]7b) was then used to synthesise a prospective radiotracer for PET-imaging in dementia.

Modelling human drug abuse and addiction with dedicated small animal positron emission tomography

Drug addiction is a chronically relapsing brain disorder, which causes substantial harm to the addicted individual and society as a whole. Despite considerable research we still do not understand why some people appear particularly disposed to drug abuse and addiction, nor do we understand how frequently co-morbid brain disorders such as depression and attention-deficit hyperactivity disorder (ADHD) contribute causally to the emergence of addiction-like behaviour. In recent years positron emission tomography (PET) has come of age as a translational neuroimaging technique in the study of drug addiction, ADHD and other psychopathological states in humans. PET provides unparalleled quantitative assessment of the spatial distribution of radiolabelled molecules in the brain and because it is non-invasive permits longitudinal assessment of physiological parameters such as binding potential in the same subject over extended periods of time. However, whilst there are a burgeoning number of human PET experiments in ADHD and drug addiction there is presently a paucity of PET imaging studies in animals despite enormous advances in our understanding of the neurobiology of these disorders based on sophisticated animal models. This article highlights recent examples of successful cross-species convergence of findings from PET studies in the context of drug addiction and ADHD and identifies how small animal PET can more effectively be used to model complex psychiatric disorders involving at their core impaired behavioural self-control.

Radiosynthesis and characterization of astemizole derivatives as lead compounds toward PET imaging of τ-pathology

Formation of neurofibrillary tangles, comprising of microtubule-associated tau protein, is a hallmark of a group of neurodegenerative diseases, including Alzheimers disease. In consequence, in vivo imaging of neurofibrillary tangles is a current focus of positron emission tomography research. Herein, development of an in vitro radioligand binding assay which uses synthetic aggregates as a model of neurofibrillary tangles is reported, together with evaluation of novel derivatives of the tau protein ligand astemizole.

The role of dopamine in sustained attention: Imaging the effects of methylphenidate in ADHD patients and healthy controls

Attention deficit/hyperactivity disorder (ADHD) is an early-onset neurobehavioural disorder characterised by symptoms of inattention, impulsivity and/or hyperactivity. Methylphenidate (MPH), an effective first-line treatment for ADHD patients, has been found to enhance prefrontal dependent cognition in patients and in healthy volunteers. The mechanisms by which this drug exerts its behavioural effects remain unclear. [18F]fallypride, a high affinity D2/D3 receptor radiotracer, has to date never been shown to be displaced by oral MPH. We used [18F]fallypride in 16 adult ADHD patients and 16 matched controls to investigate (1) D2/D3 availability in striatal sub-regions and substantia nigra (2) relative increases in endogenous DA levels across these regions following 0.5 mg/kg MPH and (3) relationships between (1) and (2) with performance on a sustained attention task. These parameters were assessed in the context of a carefully designed counterbalanced placebo-controlled dual PET scan study. MPH plasma level dependent effects were accounted for. [18F]fallypride binding potential in regions defined on magnetic resonance images was calculated using a reference tissue model. Using rigorous methodology, this study found that inattention, one of the core features of ADHD, was associated with decreased D2/D3 R availability in left caudate across all subjects, regardless of diagnosis. MPH displaced [18F]fallypride preferentially in the sensori-motor striatum, but also in the associative striatum, ventral striatum and substantia nigra (SN). Cognitive effects of the drug on sustained attention were baseline performance dependent, with only low performers showing improvements (all p<0.05). Drug-induced increases in endogenous DA levels in striatum and substantia nigra following MPH had different modulatory effects on cognition (p<0.01). These data provide support for a continuum model of underlying dopaminergic dysregulations in ADHD and implicate, for the first time, a negative nigro-striatal feedback system in the cognitive modulation of oral MPH.