Effects of alcohol detoxification on dopamine D2 receptors in alcoholics: a preliminary study
Introduction
Despite the devastating consequences of alcoholism, the mechanisms leading to addiction are poorly understood. Though multiple neurotransmitters have been implicated in the pharmacological properties of alcohol, there is increasing evidence that ethanol's actions on the dopamine (DA) system are critical in mediating its reinforcing properties (for review, see Samson, 1992) and may participate in addiction.
Of the DA receptor subtypes, the DA D2 receptor appears to be involved in transmitting DA-mediated reinforcing effects of alcohol (Stefanini et al., 1992, Nowak et al., 2000). Evidence for this view includes studies showing that DA D2 receptor antagonists decrease lever pressing for alcohol in rodents (Pfeffer and Samson, 1985, Pfeffer and Samson, 1986) and antagonize alcohol-induced euphoria in humans (Ahlenius et al., 1973). Furthermore, alcohol is less reinforcing in DA D2 receptor knockout mice than in wild-type mice (Phillips et al., 1998, Myers and Robinson, 1999). Genetic–epidemiological studies in humans also implicate DA D2 receptors in alcoholism. Though studies on the association of the DA D2 receptor Taq 1 A1 allele with alcoholism have been inconsistent, with some studies reporting an association (e.g. Blum et al., 1990, Amadeo et al., 1993, Neiswanger et al., 1995, Hietala et al., 1997) and others not (Gelernter et al., 1991, Goldman et al., 1993, Heinz et al., 1996, Goldman et al., 1998, Anghelescu et al., 2001), two meta-analytic studies confirmed a significant association (Cloninger, 1991, Noble, 2000). In addition, postmortem and imaging studies have reported reduced striatal DA D2 receptor levels in the brain of patients with Type II alcohol dependence (Hietala et al., 1994, Volkow et al., 1996, Tupala et al., 2001). However, from these studies it is not possible to determine the extent to which the decreases in DA D2 receptors in alcoholics reflect the consequences of chronic alcohol use and withdrawal, or whether receptor levels recover with detoxification.
The goal of this study was to assess if there are changes in DA D2 receptor availability during alcohol detoxification. For this purpose we used PET with [11C]raclopride (Farde et al., 1986) to measure DA D2 receptors in alcoholics during early (within 1 month) and protracted alcohol detoxification (2–4 months). We evaluated 14 alcoholics and 11 healthy controls using two different PET scanners. The results were separately assessed for the studies with the two instruments, since their different characteristics cause scaling problems in our index of DA D2 receptor availability (Franceschi et al., 1999).
Section snippets
Subjects
Fourteen right-handed alcoholics were recruited from the local outpatient rehabilitation programs in Long Island. Eight of these alcoholics (42±9 years of age; 7 M and 1 F) were tested with the CTI PET scanner and six (39±6 years of age; 6 M) with the HR+ scanner. Alcoholics were tested twice, first within 1 month of last alcohol use (early detoxification) and then retested 1–4 months later (late detoxification) while they were kept alcohol free. All of the alcoholics were in a rehabilitation
Results
For the studies done with the CTI scanner, the comparisons between early (17±10, range 10–41 days off alcohol) and late (68±25, range 49–124 days off alcohol) detoxification showed no significant changes in measures of K1 in caudate, putamen or cerebellum (Table 2). The measures of DA D2 receptor availability (Bmax/Kd) in caudate and in putamen did not differ between early and late detoxification (Fig. 1, Table 2). However, when compared with controls, alcoholics had significantly lower DA D2
Discussion
This study confirms previous findings of significant reductions in DA D2 receptor availability in alcoholics compared with controls (Hietala et al., 1994, Volkow et al., 1996). This study also did not find any significant change in DA D2 receptor availability in alcoholics during detoxification, and further failed to show an association between the DA D2 measures and the days since last alcohol use. Similar findings had been reported by prior PET studies, which showed that the reductions in DA
Acknowledgements
The authors gratefully acknowledge support from the Department of Energy (Office of Biological and Environmental Research) and the National Institute of Alcohol Abuse and Alcoholism (AA 09481). The authors thank David Alexoff, Payton King, Noelwah Netusil, David Schlyer and Donald Warner for advice and assistance.
References (63)
- et al.
D2 dopamine receptor gene and alcoholism
Journal of Psychiatric Research
(1993) - et al.
Receptor subtype-specific dopaminergic agents and conditioned behavior
Neuroscience and Biobehavioral Reviews
(1989) - et al.
Reward deficiency syndrome: genetic aspects of behavioral disorders
Progress in Brain Research
(2000) - et al.
Loss of muscarinic and benzodiazepine neuroreceptors from hippocampus of alcohol abusers
Alcohol
(1989) - et al.
A functionally deficient DRD2 variant [Ser311Cys] is not linked to alcoholism and substance abuse
Alcohol
(1998) - et al.
Neurochemical correlates of alcohol preference in inbred strains of mice
Pharmacology, Biochemistry and Behavior
(1975) - et al.
Densities of dopamine D2 receptors are reduced in CNS regions of alcohol-preferring P rats
Alcohol
(1993) - et al.
Mu and D2 receptor antisense oligonucleotides injected in nucleus accumbens suppress high alcohol intake in genetic drinking HEP rats
Alcohol
(1999) Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: a review
European Psychiatry
(2000)- et al.
Dopamine receptor agonist reduces ethanol self-administration in the ethanol-preferring C57BL/6J inbred mouse
European Journal of Pharmacology
(1994)