Julia G. Gorey

Genotype Influences In Vivo Dopamine Transporter Availability in Human Striatum

In vivo availability of striatal dopamine transporter (DAT) protein has been reported to be reduced among alcoholics, and allelic variation of the DAT gene (SLC6A3) has been associated with severity of alcohol withdrawal. We examined the VNTR polymorphism of the 3′ untranslated region of SLC6A3 and DAT protein availability in 14 abstinent alcoholics and 11 control subjects. Single photon emission computed tomography (SPECT) and plasma levels of the radioligand [I-123]β-CIT were used to quantify DAT protein availability. Individuals with the 9-repeat/10-repeat genotype had a mean 22% reduction of DAT protein availability in putamen compared with 10-repeat homozygous individuals (t = 2.14, df = 23, p < .05). Consistent with earlier studies, alcoholism, per se, was not significantly associated with either DAT availability or DAT genotype. These findings suggest that the VNTR polymorphism of the DAT gene effects translation of the DAT protein. This effect may explain a variety of clinical associations that have been reported with this polymorphism.

Reduced Central Serotonin Transporters in Alcoholism

OBJECTIVE Dysfunction of monoamine uptake mechanisms has been implicated in the pathogenesis of alcohol dependence. The authors explored whether serotonergic dysfunction is associated with anxiety and depression, which increase the risk of relapse in alcoholics. METHOD The availability of serotonin and dopamine transporters in 22 male alcoholics and 13 healthy male volunteers was measured with the use of [123I] beta-CIT and single photon emission computed tomography, and psychopathological correlates were assessed. RESULTS A significant reduction (a mean of about 30%) in the availability of brainstem serotonin transporters was found in the alcoholics, which was significantly correlated with lifetime alcohol consumption and with ratings of depression and anxiety during withdrawal. CONCLUSIONS The findings support the hypothesis of serotonergic dysfunction in alcoholism and in withdrawal-emergent depressive symptoms.

Tourette Syndrome: Prediction of Phenotypic Variation in Monozygotic Twins by Caudate Nucleus D2 Receptor Binding

Tourette syndrome, a chronic tic disorder with autosomal dominant inheritance, exhibits considerable phenotypic variability even within monozygotic twin pairs. The origins of this variability remain unclear. Recent findings have implicated the caudate nucleus as a locus of pathology, and pharmacological evidence supports dopaminergic involvement. Within monozygotic twins discordant for Tourette syndrome severity, differences in D2 dopamine receptor binding in the head of the caudate nucleus predicted differences in phenotypic severity (r = 0.99); this relation was not observed in putamen. These data may link Tourette syndrome with a spectrum of neuropsychiatric disorders that involve associative striatal circuitry.

Tourette's syndrome [I-123]β-CIT SPECT correlates of vocal tic severity

Objective: To examine in vivo the density of brain monoaminergic transporters in Tourettes syndrome (TS). Background: TS is a heritable neuropsychiatric disorder characterized by chronic vocal and motor tics and is often associated with obsessive-compulsive symptoms. Hyperstimulation of dopamine receptors and dysfunction of serotonergic transmission have been implicated in its pathogenesis, but direct evidence of involvement of these neurochemical systems has been limited. Methods: Symptoms severity and the availability of presynaptic monoaminergic transporters in the basal ganglia, midbrain, and thalamus were measured using SPECT and the radioligand [I-123]2β-carbomethoxy-3β-(4-iodophenyl)tropane ([I-123]β-CIT) in 10 patients with TS and in 10 age-and sex-matched normal volunteers. Results: A significant negative correlation was found between a measure of overall tic severity and β-CIT binding in the midbrain (r = -0.73, p = 0.02) and the thalamus (r = -0.82, p < -0.01). When examined post hoc, these correlations were determined largely by vocal tic severity. No other significant correlations were found between symptom severity and β-CIT binding in the striatum or cortex. Conclusions: These findings indicate that serotonergic neurotransmission in the midbrain and serotonergic or noradrenergic neurotransmission in the thalamus may be important factors in the expression of TS and may suggest novel targets for treatment.

Serotonin transporter availability correlates with alcohol intake in non-human primates

A low level of alcohol intoxication upon initial exposure and impulsive aggressiveness predispose humans to alcoholism. In non-human primates, central serotonin transporter availability and turnover rate were associated with aggressive behavior and a low response to initial alcohol exposure. We assessed the respective effects of these factors on alcohol intake in a free choice paradigm. Serotonin transporter availability in the raphe area, the origin of central serotonergic projections, was measured with single-photon emission computed tomography and the radioligand [123I]β-CIT in 11 rhesus monkeys with low and high central serotonin turnover. The amount of alcohol intake in the 3-month observation period was positively correlated with serotonin transporter availability (R=0.76, P=0.006), but not with aggressiveness (R=0.19, P=0.6) or alcohol response upon first exposure (R=−0.48, P=0.2). In a linear multiple regression analysis with serotonin transporter availability, alcohol response, and aggressiveness as independent variables, 82% of the variance of alcohol intake was explained and serotonin transporter availability emerged as the only statistically significant factor (β=7.81, P=0.006). These observations indicate that there may be a direct relationship between serotonin transporter availability and alcohol intake after controlling for aggression and alcohol response on first exposure.

STRIATAL DOPAMINE RECEPTORS AND TRANSPORTERS IN MONKEYS WITH NEONATAL TEMPORAL LIMBIC DAMAGE

Developmental cortical damage has been implicated in the basic neurobiology of schizophrenia. Adult rhesus monkeys with neonatal temporal limbic damage show a stimulus‐dependent disinhibition of subcortical dopamine (DA) release. We measured dopamine D2 receptors and transporters in vivo in rhesus monkeys with neonatal and adult mesial temporal limbic lesions and control monkeys to explore further the effects of this developmental lesion on striatal DA function. All monkeys were studied with [I‐123]IBZM SPECT to assess the availability of striatal dopamine D2 receptors and with [I‐123]β‐CIT SPECT to measure the availability of dopamine transporters in the striatum. IBZM binding was significantly reduced in monkeys with neonatal limbic lesions. No group difference in β‐CIT binding was found. The reduction in IBZM binding was significantly correlated with subcortical dopamine release after monoaminergic prefrontal stimulation as determinated with in vivo microdialysis. Our findings imply specific interactions between age at lesion and the availability of DA transporter and receptors in non‐human primates, and suggest that stimulus‐dependent DA activity affects the expression of DA receptors. Synapse 31:71–79, 1999. Published 1999 Wiley‐Liss, Inc.

Depletion and restoration of endogenous monoamines affects β-CIT binding to serotonin but not dopamine transporters in non-human primates

The radioligand [123I]beta-CIT binds to dopamine transporters in striatum and to serotonin transporters in brainstem. Endogenous dopamine or serotonin may compete with radioligand binding at monoamine transporters. We used alpha-methyl-p-tyrosine (AMPT) to block dopamine production and measured [123I]beta-CIT binding before and after endogenous dopamine was restored by IV administration of the dopamine precursor L-dihydroxyphenylalanine (L-DOPA) in rhesus monkeys. P-chlorophenylalanine (pCPA) was used to inhibit serotonin production, and [123I]beta-CIT binding was assessed before and after IV administration of the serotonin precursor 5-hydroxy-L-tryptophan (L-5-HTP) restored endogenous serotonin. Pretreatment with benserazide blocked peripheral decarboxylization in both paradigms. Serotonin restoration measurably displaced [123I]beta-CIT binding to brainstem serotonin transporters but not to striatal dopamine transporters. Restoration of dopamine apparently did not affect [123I] beta-CIT binding to striatal dopamine transporters. However, dopamine restoration reduced radioligand binding to brainstem serotonin transporters, most likely due to dopamine release from serotonin neurons following L-DOPA administration. The higher striatal density of dopamine transporters relative to dopamine concentrations may explain why [123I] beta-CIT displacement by endogenous dopamine was not observed. This study indicates that [123I]beta-CIT binding in brainstem (raphe area) is affected by endogenous serotonin release in vivo and that L-DOPA treatment may cause serotonin neurons in the brainstem to corelease dopamine.

Analysis of the metabolites of [I-123]β-CIT in plasma of human and nonhuman primates

[I‐123]β‐CIT is a single photon emission computed tomography (SPECT) radioligand that has been used for in vivo studies of the dopamine and serotonin transporters. Two metabolite peaks of β‐CIT have been observed by high performance liquid chromatography (HPLC), but neither has been chemically identified. One major metabolite is clearly hydrophilic. Previous reports have not agreed on the amount of the second metabolite and the extent to which it may cross the blood‐brain barrier. To clarify this controversy, we have studied β‐CIT metabolites using a protein precipitation method and an organic extraction method followed by HPLC separation. Plasma from both human and nonhuman (rhesus) primates was analyzed. Concentrations of the second metabolite were substantially lower in rhesus than in human for nearly equal parent concentrations. Furthermore, in rhesus the second metabolite is partially soluble in the organic solvent ethyl acetate, whereas in human it is essentially insoluble. These observations account for the contradictions in the literature. The hydrophilic nature of the human metabolite renders it unlikely that it crosses the blood‐brain barrier in sufficient quantities to interfere with the quantitative assessment of dopamine transporter densities. Synapse 25:306–308, 1997.