Progress in Neuro-Psychopharmacology and Biological Psychiatry
Review articleDopamine and alcoholism: neurobiological basis of ethanol abuse
Introduction
Alcohol abuse is a worldwide problem causing serious medical, economic, and social consequences. The role of the dopamine (DA) system in brain reward mechanisms has been studied for about three decades (Liebman and Butcher, 1973, Yokel and Wise, 1975). This catecholamine has been shown to be relevant not only to drug reward but also to brain stimulation reward, food reward, and the reward inherent in sexual interaction (Koob, 1992, Wise and Rompré, 1989). Brain microdialysis studies have further shown that drugs abused by humans stimulate DA release from the major terminal area of the mesolimbic DA system, nucleus accumbens (NAC). Conversely, withdrawal and drugs with aversive properties reduce DA release in this area. Thus, the DAergic mesolimbic system with NAC as a key mediating structure has been postulated to be one of the main neural networks through which the rewarding or reinforcing effects of drugs of abuse are mediated (Koob and Le Moal, 1997, Robbins and Everitt, 1999, Self and Nestler, 1995, Wise, 1996).
Animal models of alcoholism have pointed to the involvement of DA receptors in ethanol self-administration with animals specially bred for their ethanol preference (Korpi et al., 1987) and with animals trained to prefer ethanol over water (Cohen et al., 1998). Severe chronic alcoholism has also been associated with morphological changes, such as cortical neuronal loss as demonstrated by human neuropathological (Harper and Kril, 1989) and magnetic resonance imaging (MRI) studies (Pfefferbaum et al., 2001). Human in vivo positron emission tomographic (PET) and single-photon emission tomographic (SPET) as well as postmortem autoradiographic studies have shown alterations in DA transporter (DAT) densities (Laine et al., 1999, Repo et al., 1999, Tiihonen et al., 1995, Tupala et al., 2000, Tupala et al., 2001a, Tupala et al., 2001b) and D2 receptor densities in brains of alcoholics (Hietala et al., 1994, Tupala et al., 2001b, Volkow et al., 1996). Furthermore, endocrinological measurements in alcoholics have shown reductions in D2 receptor function (Balldin et al., 1992, Balldin et al., 1993). In the present communication, we review the earlier animal and human studies on DA and alcoholism with some relevant issues relating to those studies.
Section snippets
Mesolimbic dopamine system and connections
There is an abundance of experimental work emphasizing the importance of release of dopamine (DA) in the NAC as a gate, or filter, between brain regions mediating moods and drives on one hand, and brain regions mediating action and motor control on the other (Mogenson et al., 1993). There is an apparent web of neural connections linking the prefrontal and frontal cortices via the NAC to the thalamus and finally to the premotor cortex (Deutch et al., 1993). In addition to the DAergic projection
Direct release of dopamine in the nucleus accumbens
A large number of studies have shown that ethanol given systematically to rats (di Chiara and Imperato, 1985, di Chiara and Imperato, 1988, Heidbreder and De Witte, 1993, Imperato and di Chiara, 1986, Yan, 1999, Yim and Gonzales, 2000, Yim et al., 2000, Yoshimoto et al., 1992a, Yoshimoto et al., 1992b, Yoshimoto et al., 1996) causes a dose-dependent release of DA in the NAC. Ethanol injected locally to the NAC (Wozniak et al., 1991, Yim et al., 1998, Yoshimoto et al., 1992a, Yoshimoto et al.,
Animal studies
The effect of cellular damage to ethanol consumption has been studied by giving intracerebroventricular or local injections of the DA (and noradrenergic) neurotoxin 6-hydroxydopamine (6-OHDA) to laboratory animals. An early study by Myers and Melchior (1975) hinted at a potential role for DA in the mediation of ethanol drinking behaviour by showing that intracerebroventricular injection of 6-OHDA resulted in a decreased preference for ethanol in the rat, a result which was replicated by several
Dopamine receptors
DA is synthesized in the neuron, where it is concentrated in vesicles for its later Ca2+-dependent release into the synaptic cleft and extraneuronal space after a fusion process between the vesicle and the outer cell membrane. The released DA binds to the post- and presynaptic receptors, evoking a series of biological events. The two DA receptor subtypes exhibit different properties in terms of their pharmacological profiles, localization, and mechanisms of action, and the following paragraphs
Cloninger's neurogenetic model of alcoholism
The existence of two subtypes of alcoholism was originally proposed by CR Cloninger based on the studies of Swedish adoptees and families in the United States on the basis of their clinical features and patterns of inheritance (Cloninger et al., 1981). Type 1 alcoholism (∼80% of alcoholics) is characterised by the development of dependence in adulthood on the anxiety-reducing effects of alcohol and is not associated with antisocial behaviour. Type 1 alcoholics are characterised by adult onset
Dopamine binding site studies on alcoholism
Animal and human studies on DA binding sites are summarised inTable 2.
Animal studies
In rats, acute and subchronic exposure to ethanol causes an increase in the firing rate of DAergic neurons in VTA both in vivo and in vitro (Brodie et al., 1990, Diana et al., 1992a, Diana et al., 1993b, Gessa et al., 1985) and in SN in vivo (Mereu et al., 1984), suggesting that the increase in DA neurotransmission in the limbic system participates in the reinforcing effect of ethanol. Conversely, the number of spontaneously active DA neurons in the VTA (Shen and Chiodo, 1993) and their firing
Dopamine D1- and D2-like receptor agents
Although innate strain differences in DA neurotransmission may be predictive of ethanol consumption, and the induction of DA release seems to be a crucial component of ethanol reinforcement, there is some controversy in the studies on the effect of DAergic agents on ethanol consumption. Several studies (Pfeffer and Samson, 1988, Rassnick et al., 1992, Samson et al., 1992, Samson et al., 1993, Slawecki et al., 1997) using operant conditioning procedures have shown both DA agonists and DA
Currently available pharmacological treatments
Although the importance of the neurotransmitter DA in the drug reward has been for long and widely understood and accepted, no DAergic drug has so far proved to be beneficial enough to be accepted to standard clinical practise. In addition to disulfiram, to date there are two drugs which are used more widely in the treatment of alcoholism, namely, naltrexone and acamprosate (Anton, 2001). Naltrexone functions mainly as an opiate antagonist, and one metaanalysis based on eight randomised
Conclusions
It is well established that ethanol enhances the DA function through activation of the mesolimbic DA system, the “reward circuit”. This implies the importance of DA in alcoholism, although also other neurotransmitter systems are involved. Abundance of animal and human studies have demonstrated that manipulation of the DA system with, e.g., DAergic agents results in alterations in ethanol intake, and on the other hand, alterations in DA system, e.g., differences in DA receptors have been
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