Addiction has for several decades come to be viewed as a disorder of the dopamine neurotransmitter system; however, this view has not led to new treatments. We review the origins of the dopamine theory of addiction and discuss the ability of addictive drugs to elicit the release dopamine in the human striatum. There is robust evidence that stimulants increase striatal dopamine release, some evidence for alcohol, but little if any for cannabis and opiates. Moreover, there is good evidence that striatal dopamine receptor availability and dopamine release are diminished in individuals with stimulant or alcohol dependence but not in individuals with opiate, nicotine or cannabis dependence. These observations have implications for understanding reward and treatment responses in various addictions.
Molecular imaging studies have generated important in vivo insights into the etiology of schizophrenia and treatment response. This article first reviews the PET and SPECT evidence implicating dopaminergic dysfunction, especially presynaptic dysregulation, as a mechanism for psychosis. Second, it summarises the neurochemical imaging studies of antipsychotic action, focussing on D2/3 receptors. These studies show that all currently licensed antipsychotic drugs block striatal D2/3 receptors in vivo- a site downstream of the likely principal dopaminergic pathophysiology in schizophrenia- and that D2/3 occupancy above a threshold is required for antipsychotic treatment response. However, adverse events, such as extra-pyramidal side-effects or hyperprolactinemia, become much more likely at higher occupancy levels, which indicates there is an optimal 'therapeutic window' for D2/3 occupancy, and questions the use of high doses of antipsychotic treatment in clinical practice and trials. Adequate D2/3 blockade by antipsychotic drugs is necessary but not always sufficient for antipsychotic response. Molecular imaging studies of clozapine, the one antipsychotic licensed for treatment resistant schizophrenia, have provided insights into the mechanisms underlying its unique efficacy. To link this pharmacology to the phenomenology of the illness, we discuss the role of dopamine in motivational salience and show how i) psychosis could be viewed as a process of aberrant salience, and ii) antipsychotics might provide symptomatic relief by blocking this aberrant salience. Finally, we discuss the implications of these PET and SPECT findings for new avenues of drug development.
Pathological gambling (PG) is a behavioural addiction associated with elevated impulsivity and suspected dopamine dysregulation. Reduced striatal dopamine D2/D3 receptor availability has been reported in drug addiction, and may constitute a premorbid vulnerability marker for addictive disorders. The aim of the present study was to assess striatal dopamine D2/D3 receptor availability in PG, and its association with trait impulsivity. Males with PG (n = 9) and male healthy controls (n = 9) underwent [11C]-raclopride positron emission tomography imaging and completed the UPPS-P impulsivity scale. There was no significant difference between groups in striatal dopamine D2/D3 receptor availability, in contrast to previous reports in drug addiction. However, mood-related impulsivity (‘Urgency’) was negatively correlated with [11C]-raclopride binding potentials in the PG group. The absence of a group difference in striatal dopamine binding implies a distinction between behavioural addictions and drug addictions. Nevertheless, our data indicate heterogeneity in dopamine receptor availability in disordered gambling, such that individuals with high mood-related impulsivity may show differential benefits from dopamine-based medications.
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