Striatal presynaptic dopamine function in type 1 alcoholics measured with positron emission tomography

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1 Molecular Psychiatry (1998) 4, Stockton Press All rights reserved /98 $12.00 ORIGINAL RESEARCH ARTICLE Striatal presynaptic dopamine function in type 1 alcoholics measured with positron emission tomography J Tiihonen 1, H Vilkman 2,PRäsänen 3, O-P Ryynänen 4, H Hakko 3, J Bergman 5,THämäläinen 1, A Laakso 2, M Haaparanta-Solin 5, O Solin 5, M Kuoppamäki 2, E Syvälahti 2 and J Hietala 6 1 Department of Forensic Psychiatry, University of Kuopio, Niuvanniemi Hospital, FIN Kuopio; 2 Department of Pharmacology and Clinical Pharmacology, University of Turku, FIN Turku; 3 Department of Psychiatry, University of Oulu, Peltolantie 5, FIN Oulu; 4 Department of Public Health Science and General Practice, University of Kuopio, PO Box 1777, FIN Kuopio; 5 Turku PET Center, Accelerator Laboratory, Medicity PET, FIN Turku; 6 Department of Psychiatry, Turku University Central Hospital, FIN Turku, Finland Recent in vivo studies have shown low dopamine D 2 receptor and dopamine transporter densities among late onset (type 1) alcoholics. We have now studied 6-[ 18 F]-FDOPA (FDOPA) uptake in 10 type 1 alcoholics and eight matched controls to test the hypothesis that striatal presynaptic dopamine function is lower among alcoholics. Markedly low FDOPA uptake (K i ) was observed in the left caudate of two alcoholic patients, but the mean striatal uptake values of the patient group were higher than those of the control group. The greatest difference was observed in the mean FDOPA intake in the left putamen, which was 28% higher in the patient group (t = 3.00, P = 0.008, d.f. = 16, independent samples t-test), and in the right caudate (difference 36%, t = 2.87, P = 0.01). The elevated FDOPA uptake in putamen and caudate correlated with poor Wisconsin Card Sorting Test (WCST) performance (error %) among alcoholics (correlation coefficients from 0.49 to 0.56), which suggests that the magnitude of presynaptic dopamine function alteration correlates with the degree of disability to modify one s behavior. The results do not give support to the hypothesis of generally decreased striatal dopamine turnover in type 1 alcoholism, but on the contrary indicate an increased presynaptic dopamine function. This may represent a compensatory mechanism to low postsynaptic DA function. The low presynaptic DA function observed in the left caudate of two patients suggests that type 1 alcoholism may be a heterogeneous disorder. Keywords: dopamine; alcoholism; striatum; PET Introduction Data obtained from animal studies imply that the development of alcohol dependence is associated with the dopamine (DA) function in the striatum and the limbic system. 1 7 Many genetic studies of humans have suggested that the D 2 receptor gene allele A1 is associated with substance abuse, 8 11 but several other studies have given controversial results Our previous in vivo study with positron emission tomography (PET) showed that striatal D 2 receptor density and affinity were reduced in late-onset, non-violent alcoholic subjects (reminiscent of Cloninger type 1 alcoholics) 19 when compared with healthy controls. 20 Recently we observed that the striatal dopamine re-uptake site densities are markedly lower among non-violent alcoholics than in healthy controls while habitually violent alcoholics (reminiscent of Cloninger type 2) 19 have slightly higher DA transporter densities than con- Correspondence: J Tiihonen, University of Kuopio, Department of Forensic Psychiatry, Niuvanniemi Hospital, FIN-70240, Finland Received 10 July 1997; revised 30 October and 5 December 1997; accepted 5 December 1997 trols. 21 These findings on D 2 receptors and DA transporters have been regarded as the first identification of a specific neuroregulatory deficit in type 1 alcoholism. 22 Results of a recent PET study on alcoholics showed lower D 2 -receptor density, but DA transporter densities were not decreased among five alcoholic patients with a mean alcoholism onset age of 19 years (implying that many of these subjects were possibly type 2 rather than type 1 alcoholics). 23 The aim of this study was to measure the presynaptic dopamine function with PET and 6-[ 18 F]-fluorodopa (FDOPA) uptake to test the hypothesis that overall dopaminergic turnover is lower in the striatum of type 1 19 alcoholics when compared with healthy controls. Material and methods Index subjects and controls The procedure was approved by the local ethical committees (Kuopio University Hospital and Turku University/Turku University Central Hospital) and all subjects gave written informed consent. All 18 subjects were white caucasian Finnish citizens. FDOPA uptake was studied with PET in eight age- and sex-matched

2 healthy control subjects with no neurological or psychiatric disorders nor any kind of medication (all males, aged years, mean 44.2 years, all righthanded), and in 10 non-violent alcoholics (all males, aged years, mean 47.7 years, all right-handed). The background data on controls and patients are shown in Table 1. Three alcoholics were omitted from the original sample of 13 subjects because of non-compliance to study protocol. All subjects were recruited with the help of a local rehabilitation center for alcoholics, where they had obtained non-pharmacological treatment for alcoholism. The subjects were selected from the patient population by a psychiatric nurse who chose those subjects who had little or no psychiatric or somatic co-morbidity and were known not to be using antidepressants, neuroleptics, nor other psychotropic drugs. All patients had had difficulties in their jobs due to their alcoholism, but none of them had committed any criminal offence. All of them fulfilled the criteria for Cloninger type 1 alcoholism. 19 The onset of the dependence was defined as the first time of occurrence of significant difficulties in their job, social relationships or health condition. Their abstinence time prior to PET measurement ranged from 3 days to 42 months (mean ± s.d ± days). All patients were interviewed by a psychologist and completed the structured interview questionnaires of the Michigan Alcoholism Screening Test (MAST), Severity of Alcohol Dependence Questionnaire (SADQ), Zung depression and anxiety scales, and Hopkins Symptom Checklist (90-SCL). All subjects were also studied using the Wechsler Adult Intelligence Scale Revised (WAIS-R) and Wisconsin Card Sorting Test (WCST). PET procedure 6-[ 18 F]-FDOPA preparation and HPLC analysis of unchanged FDOPA and labeled metabolites in arterial plasma were performed as described. 24 The PET experiments were performed using a whole-body PET scanner (ECAT 931/08-12). 25 Radioactivity in the brain was measured for 60 min after giving 4 5 mci 6-[ 18 F]- L-FDOPA intravenously. Karbidopa 100 mg p.o. was given 1.5 h before the study. The head was fixed in a vacuum head holder which was further stabilized with glass fiber tape. The positioning of the head in the gantry was according to the cantho-meatal line. Laser beams in the gantry and ink marks on the head were used to control the position of the head. Region-ofinterest (ROI) definitions were based on MRI images Dopamine function in alcoholism without knowledge of diagnosis. Each patient/control underwent a T1 weighted MRI scan (Siemens) with 1.5- mm slice thickness (3D-MPRAGE sequence, TR 10 ms, TE 4 ms). PET-MRI image alignment was done by using a surface-fitting procedure 26 and subsequent MRI image reslicing to match the two middlemost PET planes transversing the striatum. Occipital cortical ROIs were also defined on these slices. K i values reflecting uptake and decarboxylation of [ 18 F]FDOPA by the dopaminergic nerve terminals were calculated by using a graphical analysis 27 with arterial plasma input and occipital cortex as a dopamine nerve terminal-free reference area. Results The fraction of unchanged 6-[ 18 F]-FDOPA in arterial plasma was slightly lower in patients (Figure 1). Fractions of the 3-O-methyl metabolite were identical in controls and patients. Figure 2 demonstrates the 6[ 18 F]- FDOPA and MRI-scans in an alcoholic subject in two consecutive slices. The ligand uptake is markedly low in the left caudate, but the MRI shows no structural abnormalities in the same region. The average FDOPA K i values in the putamen and caudate among controls and index subjects are shown in Table 2, and the scatter plots of the K i values in the caudate and the putamen among different individuals in Figure 3. The results show that the FDOPA K i values are 39 59% lower in the left caudate of two alcoholic patients when compared with the mean value of controls. The mean striatal FDOPA uptake values were 9 36% higher in the alcoholic group, but the differences between the groups were statistically significant (also with Bonferroni correction) only in the right caudate (t = 2.87, P = 0.01; d.f. = 16, independent samples t-test) and in the left putamen (t = 3.00, P = 0.008). The associations between the clinical variables and the averaged (left + right) FDOPA K i values of the caudate and putamen among index subjects are shown in Table 3. No marked associations ( r 0.50) were found 157 Table 1 Patient/control characteristics Controls Patients Age 44.2 ± ± 6.0 MAST 3.0 ± ± 9.6 Age of alcohol dependence onset ± 8.9 Years of heavy alcohol use ± 9.6 WAIS-R ± ± 12.0 WCST error percentage 23.0 ± ± 14.8 Figure 1 The unchanged fraction of 6-[ 18 F]-L-FDOPA in arterial plasma of controls and alcohol-dependent patients (data from eight patients). The error bars denote s.d.

3 Dopamine function in alcoholism 158 Figure 2 Integrated 6[ 18 F]-L-FDOPA PET image and a corresponding MRI image of an alcohol-dependent patient. Note the low uptake of 6-[ 18 F]-L-FDOPA in the head of left caudate (arrow). The corresponding structure is depicted with an arrow in the MRI image resliced according to the PET image. Table 2 The mean ± s.d. FDOPA K i values among alcoholic patients (n = 10) and matched healthy controls (n = 8). P-values have been obtained with independent t-test, d.f. = 16 Controls (n = 8) Patients (n = 10) t P Putamen (right) ± ± Putamen (left) ± ± Caudate (right) ± ± Caudate (left) ± ± between the clinical variables and the average striatal FDOPA uptake, except between WCST scores and striatal K i values. The correlations between the WCST performance scores and K i values among controls were small ( r 0.35). Those two patients with the lowest K i values in the left caudate had also the longest duration of dependence (30 and 29 years). MRI-scans showed moderate cortical atrophy in two patients and mild cortical atrophy in four patients. Cortical atrophy did not correlate markedly with K i values either in caudate (r = 0.25) or in putamen (r = 0.12). The average IQ of patients in WAIS-R was ± 12.0 points (range ), and ± 6.2 points among controls (difference N.S.). Discussion The FDOPA K i value is an index of presynaptic DA synthetic capacity and as such does not directly tell the intrasynaptic concentrations of dopamine. Recent 6-[ 18 F]-L-FDOPA PET studies on amphetamineinduced changes in primate striatum suggest, however, a good correspondence between directly measured DA levels and FDOPA K i values. 28 The mean FDOPA K i values in the left and the right caudate and in the left and the right putamen were higher among alcoholic patients when compared with matched healthy controls, but the differences were statistically significant only in the right caudate and the left putamen at group level. The results do not give support to the hypothesis of generally decreased striatal dopamine turnover in type 1 alcoholism, but on the contrary indicate an increased dopamine synthesis in the striatum. A markedly low striatal presynaptic dopamine activity was observed in the left caudate in two patients, which implies that type 1 alcoholism is probably a heterogeneous disorder concerning its molecular aetiology. The very low FDOPA activity observed in the left caudate of two patients is of interest as lesions of the left caudate have been observed to be associated with depressive symptoms. 29 However, our patients with low activity in this region clearly did not have more depressive symptoms than other index subjects (scores 31 and 45 points; mean ± s.d ± 7.3). The very low

4 Dopamine function in alcoholism 159 Figure 3 The scatter plots of striatal FDOPA K i values among alcoholic patients and controls. Table 3 The Spearman correlations between the clinical variables and the averaged FDOPA K i values (left + right: 2) of caudate and putamen among index subjects Variable r (Spearman) Putamen Caudate Duration of dependence Duration of abstinence SADQ MAST Zung/anxiety Zung/depression WCST/errors % 0.56 * 0.49 ** WAIS-R * P = 0.09; ** P = dopamine turnover in the left caudate of two patients may be secondary to long-lasting ethanol exposure, or it may reflect an inborn neurobiological variation which results in vulnerability to relatively severe, early-onset alcoholism. The results imply that the dopamine function is not significantly associated with striatal atrophy or with the recent ethanol intake (time of abstinence), or otherwise, the ethanol-induced effect is very long lasting and stable over time. The learning of new rules and the ability to modify one s behavior can be studied with WCST. Clinical data accumulated during the last decades imply that patients with frontal lobe lesions have poor WCST performance. Our results showed an association between the K i values in both caudate and putamen and the WCST scores, although the finding did not reach statistical significance (P-values 0.09 and 0.15) due to the relatively small number of subjects. The observed moderately high negative correlation between the performance in the WCST and the striatal FDOPA uptake among alcoholics is in line with experimental animal studies which imply that impaired dopaminergic function is associated with deficits in cognitive processing, 30 and with the fact that prefrontal cortex and basal ganglia have intense functional interactions. The results in WCST were not explained by poor overall cognitive performance, since mean Wechsler Adult Intelligence Scale Revised (WAIS-R) score of alcoholics was 111 points. The elevated FDOPA uptake (which correlated to poor WCST performance) may be a secondary mechanism to compensate for poor postsynaptic dopamine function in alcoholic subjects. If it is a trait-dependent variable, it may be associated with poor ability to modify one s behavior and with the development of addiction. There may be several different primary pathophysiological mechanisms in alcohol dependence. In vivo PET and single photon emission tomography (SPECT) receptor and transporter studies are not able to provide explicit information on the overall function of the dopaminergic transmission. The low D 2 receptor den-

5 160 Dopamine function in alcoholism sity and affinity measured with [ 11 C] raclopride binding can be explained by the decreased number of receptors per synapse or by decreased number of synapses such as in Parkinson s disease (PD) or, alternatively, by increased endogenous synaptic dopamine activity which competes in D 2 binding with the ligand. In the same way, the low DA transporter density can be explained by the decreased number of synapses as in PD or by the normal number of synapses with decreased number of transporters per synapse. One possibility is that some type 1 alcoholics have disturbed postsynaptic dopamine transmission eg at the level of D 2 receptor binding or due to dysfunction of G-protein second messenger systems. This could lead to a compensatory increase in the presynaptic dopamine synthesis and compensatory decrease in DA reuptake, which would both increase dopamine transmission, but despite this, possibly not achieving the normal level of transmission. The observed great dispersion in striatal dopamine activity in the left caudate among our patients may be associated with the vulnerability to development of addiction, which suggests that drugs stabilizing dopamine transmission such as partial dopamine agonists might be relevant novel candidates for the pharmacological treatment of type 1 alcoholism. This class of drugs such as (+) -UH might be used to dampen the rapid transients in dopamine release during acute ethanol-induced euphoria. A partial agonist would not decrease dopamine transmission in the long run, but would prevent rapid changes in dopamine release which may be associated with the reinforcement and development of addiction. Conclusions The results do not give support to the hypothesis of generally decreased striatal dopamine turnover in type 1 alcoholism but, on the contrary, indicate an increased presynaptic dopamine synthesis. This may represent a compensatory mechanism to low postsynaptic DA function. The low presynaptic DA function observed in the left caudate of two patients suggests that type 1 alcoholism may be a heterogeneous disorder. The observed high correlation between the poor performance in the WCST and the elevated striatal FDOPA uptake is in line with experimental animal studies which imply that impaired dopaminergic function is associated with learning deficits. If the increased presynaptic DA synthesis is a trait-dependent variable, it may be associated with disability to modify one s behavior and with the development of addiction. The observed great dispersion in the striatal dopamine activity in the left caudate among our patients may be associated with the vulnerability to development of addiction, which suggests that drugs stabilizing dopamine transmission such as partial dopamine agonists might be relevant novel candidates for the pharmacological treatment of type 1 alcoholism. References 1 Rossetti ZL, D Aquila PS, Hmaidan Y, Gessa GL, Serra G. Repeated treatment with imipramine potentiates cocaine-induced dopamine release and motor stimulation. Eur J Pharmacol 1991; 201: Sorensen SM, Jumphreys TM, Taylor VL, Schmidt CJ. 5-HT 2 receptor antagonists reverse amphetamine-induced slowing of dopaminergic neurons by interfering with stimulated dopamine synthesis. J Pharm Exp Ther 1992; 260: Spanagel R, Herz A, Bals-Kubik R, Shippenberg TS. -endorphininduced locomotor stimulation and reinforcement are associated with an increase in dopamine release in the nucleus accumbens. Psychopharmacology (Berlin) 1991; 104: Yoshimoto K, McBride WJ, Lumeng L, Li T-K. Alcohol stimulates the release of dopamine and serotonin in the nucleus accumbens. Alcohol 1991; 9: Kaliva PW. Neurotransmitter regulation of dopamine neurons in the ventral tegmental area. Brain Res Revs 1993; 18: Dyr W, McBride WJ, Lumen L, Li T-K, Murphy JM. Effects of D 1 and D 2 dopamine receptor agents on ethanol consumption in the high-alcohol-drinking (HAD) line of rats. Alcohol 1993; 10: Caine SB, Koob GF. Modulation of cocaine self-administration in the rat through D 3 dopamine receptors. Science 1993; 260: Blum K, Noble EP, Sheridan PJ, Montgomery A, Ritchie T, Jagadeeswaran P et al. Allelic association of human dopamine D 2 receptor gene in alcoholism. JAMA 1990; 263: Comings DE, Comings BG, Muhleman D, Dietz G, Shahbahrami B, Tast E et al. The dopamine D 2 receptor locus as a modifying gene in neuropsychiatric disorders. JAMA 1991; 266: Smith SS, O Hara BF, Persico AM, Gorelick DA, Newlin DB, Vlahov D et al. Genetic vulnerability of drug abuse: the D 2 dopamine receptor TagI B1 restriction fragment length polymorphism appears more frequently in polysubstance abusers. Arch Gen Psychiatry 1992; 49: Hietala J, Pohjalainen T, Heikkilä-Kallio U, West C, Salaspuro M, Syvälahti E. Allelic association between D2 but not D1 dopamine receptor gene and alcoholism in Finland. J Psy Gen 1997; in press. 12 Gelernter J, O Malley S, Risch N, Kranzler HR, Krystal J, Merikangas K et al. No association between an allele at the D 2 dopamine receptor gene (DRD2) and alcoholism. JAMA 1991; 266: Goldman D, Dean M, Brown GL, Bolos AM, Tokola R, Virkkunen M et al. D 2 dopamine receptor genotype and cerebrospinal fluid homovanillic acid, 5-hydroxyindoleacetic acid and 3-methoxy-4- hydroxyphenylglycol in alcoholics in Finland and the United States. Acta Psychiatr Scand 1993; 86: Goldman D, Brown GL, Albaugh B et al. D 2 dopamine receptor genotype, linkage disequilibrium and dopamine duction in Finnish, American Indian and US Caucasian alcoholics and the population association approach in psychogenetics. Alcohol Clin Exp Res 1993; 17: Cloninger CR. D 2 dopamine receptor gene is associated but not linked with alcoholism. JAMA 1991; 266: Gelernter J, Goldman D, Risch N. The A1 allele at the D 2 dopamine receptor gene and alcoholism: a reappraisal. JAMA 1993; 269: Uhl G, Blum K, Noble E, Smith S. Substance abuse vulnerability and D 2 receptor genes. Trends Neurosci 1993; 16: Noble EP, Blum K, Ritschie T, Montgomery A, Sheridan PJ. Allelic association of the D 2 dopamine receptor gene with receptor-binding characteristics in alcoholism. Arch Gen Psychiatry 1991; 48: Cloninger CR. Neurogenetic adaptive mechanisms in alcoholism. Science 1987; 236: Hietala J, West C, Syvälahti E, Någren K, Lehikoinen P, Sonninen P et al. Striatal D 2 dopamine receptor binding characteristics in vivo in patients with alcohol dependence. Psychopharmacology 1994; 116: Tiihonen J, Kuikka J, Bergström K, Hakola P, Karhu J, Ryynänen O-P et al. Altered striatal dopamine re-uptake site densities in habitually violent and non-violent alcoholics. Nature Med 1995; 1:

6 22 Cloninger CR. The psychobiological regulation of social cooperation. Nature Med 1995; 1: Volkov ND, Wang G-J, Fowler JS, Logan J, Hitzemann R, Ding Y-S et al. Decreases in dopamine receptors but not in dopamine transporters in alcoholics. Alcohol Clin Exp Res 1996; 20: Bergman J, Haaparanta M, Lehikoinen P, Solin O. Electrophilic synthesis of 6-[ 18 F]-fluoro-L-dopa starting from aqueous [ 18 F]-fluoride. J Label Comp Radipharm 1994; XXXV: Hietala J, Syvälahti E, Vuorio K, Räkköläinen V, Bergman J, Haaparanta M et al. Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients. Lancet 1995; 346: Pellizari CA, Chen GTY, Spelbring DR, Weichselbaum RR, Chen CT. Accurate three dimensional registration of CT, PET and/or MRI images of the brain. J Comp Ass Tomography 1989; 13: Dopamine function in alcoholism 27 Patlak CS, Blasberg RG, Fernstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 1983; 3: Melega WP, Quintana J, Raleigh MJ, Stout DB, Yu DC, Lin KP et al. 6-[ 18 F]fluoro-L-dopa PET studies show partial reversibility of long-term effects of chronic amphetamine in monkeys. Synapse 1996; 22: Starkstein SE, Robinson RG, Price TR. Comparison of cortical and subcortical lesions in the production of poststroke mood disorders. Brain 1987; 110: Goldman-Rakic PS. Regional and cellular fractionation of working memory. Proc Natl Acad Sci USA 1996; 93: Carlsson A. Dopamine autoreceptor agonists in the treatment of schizophrenia. Neuropsychopharmacology 1994; 10(3S): 119S. 161