Paul Stokes

The dopamine theory of addiction: 40 years of highs and lows

For several decades, addiction has come to be viewed as a disorder of the dopamine neurotransmitter system; however, this view has not led to new treatments. In this Opinion article, we review the origins of the dopamine theory of addiction and discuss the ability of addictive drugs to elicit the release of dopamine in the human striatum. There is robust evidence that stimulants increase striatal dopamine levels and some evidence that alcohol may have such an effect, but little evidence, if any, that cannabis and opiates increase dopamine levels. 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.

Can recreational doses of THC produce significant dopamine release in the human striatum

BACKGROUND Cannabis use in early adolescence may be a risk factor for development of schizophrenia. In animals, Delta9-tetrahydrocannabinol (THC) increases the rate of dopamine neuronal firing and release in the striatum. Thus cannabis use may increase dopamine release in the human striatum leading to vulnerability to psychosis. AIMS To investigate whether THC, the main psychoactive component of cannabis, can produce dopamine release in the human striatum. METHODS Thirteen healthy volunteers, with previous cannabis experience, underwent two [11C]-raclopride positron emission tomography (PET) scans to indirectly measure striatal dopamine levels following either 10 mg THC or placebo. RESULTS Although THC markedly increased psychosis-like symptoms on the Psychotomimetic States Inventory (PSI), there was no significant effect of THC on [11C]-raclopride binding. CONCLUSION In the largest study of its kind so far, we have shown that recreational cannabis users do not release significant amounts of dopamine from an oral THC dose equivalent to a standard cannabis cigarette. This result challenges current models of striatal dopamine release as the mechanism mediating cannabis as risk factor for schizophrenia.

Striatal dopamine D2/D3 receptor binding in pathological gambling is correlated with mood-related impulsivity

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.

Ability of 5‐HT4 receptor ligands to modulate rat striatal dopamine release in vitro and in vivo

1 The ability of 5‐HT4 (5‐hydroxytryptamine4) receptor ligands to modify dopamine release from rat striatal slices in vitro and in the striatum of freely moving rats was assessed by the microdialysis technique. 2 The release of dopamine from slices of rat striatum continually perfused with Krebs buffer was enhanced by 5‐HT4 receptor agonists; 5‐HT (10 μm), 5‐methoxytryptamine (5‐MeOT; 10 μm), renzapride (10 μm) and (S)‐zacopride (10 μm) maximally increased dopamine release by 133 ± 5, 214 ± 25, 232 ± 29 and 264 ± 69%, respectively (mean ± s.e.mean, n = 3–8). The drug‐induced responses were maximal within the first 2 min of drug application, and subsequently declined. The non‐selective 5‐HT3/5‐HT4 receptor antagonist, SDZ205‐557 (10 μm), failed to modify basal dopamine release from striatal slices but completely antagonized the (S)‐zacopride (10 μm)‐induced increase in dopamine release. 3 To allow faster drug application, the modulation of dopamine release from rat striatal slices in a static release preparation was also investigated. The 5‐HT4 receptor agonist, renzapride (10 μm) also enhanced dopamine release in this preparation (maximal increase = 214 ± 35%, mean ± s.e.mean, n = 14), whilst a lower concentration of renzapride (3 μm) was less effective. The renzapride‐induced response was maximal within the first 2 min of drug application, before declining. In this preparation, the stimulation of dopamine release by renzapride (10 μm), was completely antagonized by the selective 5‐HT4 receptor antagonist, GR113808 (100 nM). In addition, both the Na+ channel blocker, tetrodotoxin (100 nM) and the non‐selective protein kinase A inhibitor, H7 (100 nM) completely prevented the stimulation of dopamine release induced by renzapride (10 μm). 4 In vivo microdialysis studies demonstrated that the 5‐HT4 receptor agonists, 5‐MeOT (10 μm), renzapride (100 μm) and (S)‐zacopride (100 μm) maximally elevated extracellular levels of dopamine in the striatum by 220 ± 20, 161 ± 10 and 189 ± 53%, respectively (mean ± s.e.mean, n = 5–9). A lower concentration of renzapride (10 μm) was less effective. The elevation of extracellular striatal dopamine levels induced by either renzapride (100 μm) or (S)‐zacopride (100 μm) were completely antagonized by the non‐selective 5‐HT3/5‐HT4 receptor antagonist, SDZ205‐557 (100 μm). In addition, the elevation of extracellular levels of dopamine induced by either 5‐MeOT (10 μm) or renzapride (100 μm) was completely prevented by the selective 5‐HT4 receptor antagonist, GR113808 (1 μm) and the renzapride (100 μm)‐induced response was also completely prevented by the non‐selective protein kinase A inhibitor, H7 (1 μm). In this in vivo preparation, both GR113808 (1 μm) and H7 (1 μm), when perfused alone, reduced extracellular levels of dopamine. 5 In conclusion, the present study provides evidence that the 5‐HT4 receptor facilitates rat striatal dopamine release in vitro and in vivo.

History of cannabis use is not associated with alterations in striatal dopamine D2/D3 receptor availability

Cannabis use in adolescence is emerging as a risk factor for the development of psychosis. In animal studies, Δ9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, modulates striatal dopaminergic neurotransmission. Alterations in human striatal dopaminergic function have also been reported both in psychosis and in stimulant use. We sought to examine whether striatal dopamine D2/D3 receptor availability was altered in volunteers with a history of cannabis use using a database of previously acquired [11C]-raclopride positron emission tomography (PET) scans. Ten [11C]-raclopride scans from volunteers with a history of cannabis use were compared to ten control scans using a functional striatal subdivision region of interest (ROI) analysis. No significant differences in either overall striatal BPND values or BPND values in any functional striatal subdivision were found between the two groups. There was also no correlation between lifetime frequency of cannabis use and BPND values. Limbic striatal BPND values were ten percent lower in current nicotine cigarette smokers. These findings suggest that, unlike other drugs of abuse, a history of cannabis use is not associated with alterations in striatal dopamine D2/D3 receptor availability.

Classification of schizophrenic patients and healthy controls using [18F] fluorodopa PET imaging

Striatal dopaminergic overactivity has been implicated in the pathophysiology of schizophrenia on the basis of in vivo neuroimaging studies. In particular, elevated striatal dopamine synthesis and storage has been repeatedly demonstrated in schizophrenia using the radiotracer 6-[18F] fluoro-l-DOPA ([18F] DOPA) and positron emission tomography (PET). Conventionally analysed [18F] DOPA PET imaging lacks the sensitivity or specificity to be used diagnostically. The aim of this study was to determine if the application of an Artificial Neural Network (ANN) would improve classification of images, and increase the sensitivity and specificity of [18F] DOPA as a potential diagnostic test for schizophrenia. We tested an ANN model in the discrimination of schizophrenic patients from normal controls using [18F] DOPA rate constants within the anterior-posterior subdivisions of the striatum, and compared the model with a general linear analysis of the same data. Participating in the study were 19 patients diagnosed with paranoid schizophrenia and 31 healthy subjects. Maximum classification was achieved using laterality quotients, - the ANN model correctly identified 94% of the controls and 89% of the patients, equivalent to 89% sensitivity and 94% specificity. Using all bilateral striatal regions correctly categorised 74% of the controls and 84% of the patients, equivalent to 84% sensitivity and 74% specificity. In comparison, the general linear analysis performed poorly, correctly classifying only 58% of the controls and 63% of the patients. Overall, these analyses have shown the potential utility of pattern recognition tools in the classification of psychiatric patients based upon molecular imaging of a single target.

Significant decreases in frontal and temporal [11C]-raclopride binding after THC challenge

Delta9-tetrahydrocannabinol (THC) increases prefrontal cortical dopamine release in animals, but this is yet to be examined in humans. In man, striatal dopamine release can be indexed using [11C]-raclopride positron emission tomography (PET), and recent reports suggest that cortical [11C]-raclopride binding may also be sensitive to dopaminergic challenges. Using an existing dataset we examined whether THC alters [11C]-raclopride binding potential (BP(ND)) in cortical regions. Thirteen healthy volunteers underwent two [11C]-raclopride PET scans following either oral 10 mg THC or placebo. Significant areas of decreased cortical [11C]-raclopride BP(ND) were identified using whole brain voxel-wise analysis and quantified using a region of interest (ROI) ratio analysis. Effect of blood flow on binding was estimated using a simplified reference tissue model analysis. Results were compared to [11C]-raclopride test-retest reliability in the ROIs identified using a separate cohort of volunteers. Voxel-wise analysis identified three significant clusters of decreased [11C]-raclopride BP(ND) after THC in the right middle frontal gyrus, left superior frontal gyrus and left superior temporal gyrus. Decreases in [11C]-raclopride BPND following THC were greater than test-retest variability in these ROIs. R1, an estimate of blood flow, significantly decreased in the left superior frontal gyrus in the THC condition but was unchanged in the other ROIs. Decreased frontal binding significantly correlated to catechol-o-methyl transferase (COMT) val108 status. We have demonstrated for the first time significant decreases in bilateral frontopolar cortical and left superior temporal gyrus [11C]-raclopride binding after THC. The interpretation of these findings in relation to prefrontal dopamine release is discussed.

Striatal dopamine synthesis capacity in twins discordant for schizophrenia

BACKGROUND Elevated striatal dopamine synthesis capacity is thought to be fundamental to the pathophysiology of schizophrenia and has also been reported in people at risk of psychosis. It is therefore unclear if striatal hyperdopaminergia is a vulnerability marker for schizophrenia, or a state feature related to the psychosis itself. Relatives of patients with schizophrenia are themselves at increased risk of developing the condition. In this study we examined striatal dopamine synthesis capacity in both members of twin pairs discordant for schizophrenia. METHOD In vivo striatal dopamine synthesis capacity was examined using fluorine-18-l-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) scans in seven twin pairs discordant for schizophrenia and in a control sample of 10 healthy control twin pairs. RESULTS Striatal 18F-DOPA uptake was not elevated in the unaffected co-twins of patients with schizophrenia (p=0.65) or indeed in the twins with schizophrenia (p=0.89) compared to the control group. Levels of psychotic symptoms were low in the patients with schizophrenia who were in general stable [mean (s.d.) Positive and Negative Syndrome Scale (PANSS) total=56.8 (25.5)] whereas the unaffected co-twins were largely asymptomatic. CONCLUSIONS Striatal dopamine synthesis capacity is not elevated in symptom-free individuals at genetic risk of schizophrenia, or in well-treated stable patients with chronic schizophrenia. These findings suggest that striatal hyperdopaminergia is not a vulnerability marker for schizophrenia.

Acute increases in synaptic GABA detectable in the living human brain: A [11C]Ro15-4513 PET study

The inhibitory γ-aminobutyric acid (GABA) neurotransmitter system is associated with the regulation of normal cognitive functions and dysregulation has been reported in a number of neuropsychiatric disorders including anxiety disorders, schizophrenia and addictions. Investigating the role of GABA in both health and disease has been constrained by difficulties in measuring acute changes in synaptic GABA using neurochemical imaging. The aim of this study was to investigate whether acute increases in synaptic GABA are detectable in the living human brain using the inverse agonist GABA-benzodiazepine receptor (GABA-BZR) positron emission tomography (PET) tracer, [(11)C]Ro15-4513. We examined the effect of 15 mg oral tiagabine, which increases synaptic GABA by inhibiting the GAT1 GABA uptake transporter, on [(11)C]Ro15-4513 binding in 12 male participants using a paired, double blind, placebo-controlled protocol. Spectral analysis was used to examine synaptic α1 and extrasynaptic α5 GABA-BZR subtype availability in brain regions with high levels of [(11)C]Ro15-4513 binding. We also examined the test-retest reliability of α1 and a5-specific [(11)C]Ro15-4513 binding in a separate cohort of 4 participants using the same spectral analysis protocol. Tiagabine administration produced significant reductions in hippocampal, parahippocampal, amygdala and anterior cingulate synaptic α1 [(11)C]Ro15-4513 binding, and a trend significance reduction in the nucleus accumbens. These reductions were greater than test-retest reliability, indicating that they are not the result of chance observations. Our results suggest that acute increases in endogenous synaptic GABA are detectable in the living human brain using [(11)C]Ro15-4513 PET. These findings have potentially major implications for the investigation of GABA function in brain disorders and in the development of new treatments targeting this neurotransmitter system.

Decreased regional gray matter volume in S allele carriers of the 5-HTTLPR triallelic polymorphism

Decreased regional gray matter volume in S’ allele carriers of the 5-HTTLPR triallelic polymorphism