The researchers noted that people with alcohol use disorder (AUD) had less brain matter than others. The affected brain regions controlled skills like attention, language, memory, and reasoning. Alcohol can, therefore, lead to worse memory and impaired judgments, among other changes. Our findings are the first to identify the dopamine-related functional connections underlying alcohol-related AB in humans. The results point to a significant role of dopamine for both alcohol and non-drug reward AB and indicate that specific dopamine-dependent functional connections between frontal, limbic, striatal, and brainstem regions mediate these behaviors.

Striatal activation to monetary reward is associated with alcohol reward sensitivity

Furthermore, the severe side-effect profiles of many of these compounds may limit their clinical use. Newer dopamine agents, such as partial agonists and dopamine stabilizers, attenuate alcohol‐mediated behaviours in rodents as well as humans. Preclinical as well as clinical studies have shown that substances indirectly targeting the mesolimbic dopamine system may be potential targets for attenuation of alcohol reward. Serotonin also interacts with dopaminergic signal transmission through the 5-HT3 receptor, which helps control dopamine release in the areas reached by VTA neurons, most notably the nucleus accumbens. Serotonin release in these brain regions can stimulate dopamine release, presumably by activating 5-HT3 receptors located on the endings of dopaminergic neurons (Campbell and McBride 1995; Grant 1995).

Reinforcement and Addiction

The axons of the neurons in the raphe nucleus extend, or project, throughout the brain to numerous regions with diverse functions. These brain regions include the amygdala, an area that plays an important role in the control of emotions, and the nucleus accumbens, a brain area involved in controlling the motivation to perform certain behaviors, including the abuse of alcohol and other drugs. In these substance dependence brain regions, the axon endings of the serotonergic neurons secrete serotonin when activated. The neurotransmitter then traverses the small space separating the neurons from each other (i.e., the synaptic cleft) and binds to specialized docking molecules (i.e., receptors) on the recipient cell. Many substances that relay signals among neurons (i.e., neurotransmitters) are affected by alcohol.

Why play? Early games build bonds and brain

Faster dopamine uptake in the female subjects would have the net effect of decreasing the duration of neuromodulation produced by this transmitter. However, the increased uptake rate could be countered by the observed enhanced release, at least in female caudate. Nonetheless, altered dopamine kinetics or release could affect dopamine-dependent synaptic plasticity [42] that might subsequently affect new learning and behavioral flexibility. Indeed, in the multiple abstinence cohort, in which alcohol treated subjects had significantly less dopamine release, a separate study found that alcohol-consuming subjects had poorer cognitive flexibility relative to controls [43, 44]. Alcohol dependence, a chronic relapsing psychiatric disorder, is a major cause of mortality and morbidity. The role of dopamine in alcohol‐induced reward as well in the development of alcohol dependence is reviewed herein.

Together with OSU6162’s favourable side effect profile [198, 197, 199], these results render support for a larger placebo‐controlled efficacy trial in alcohol‐dependent patients to evaluate OSU6162’s effect on drinking outcomes. A recent PET study [118] demonstrated for the first time that, in addition to the ventral striatum, the long‐term consumption of alcohol leads to lowered dopamine levels also in prefrontal cortical structures. These findings support the extensive clinical findings demonstrating that alcohol‐dependent individuals have significant impairments in executive functions such as alcohol effects in the brain working memory, impulsivity and decision‐making; functions governed by the cortical brain structures. The fact that there is also less dopamine in the prefrontal cortex, governing these executive functions, is of significance as it could impair the alcohol‐dependent individual’s capacity to utilize behavioural treatment strategies, which are critical to relapse prevention. The first line of evidence implicating serotonin in the development of alcohol abuse was the discovery of a relationship between alcoholism and the levels of serotonin metabolites in the urine and CSF of human alcoholics.

It was identified serendipitously in the 1950s when Olds and Milner found that rats self‐administer electrical currents into certain specific brain regions [9]. These findings were later corroborated by studies showing that rats favoured electrical stimulation in the same specific brain regions, over natural rewards [10]. The primary neurotransmitter regulating the rewarding sensation was determined to be dopamine [11]. Furthermore, the specific neuronal circuitries were progressively mapped with major projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc, i.e. the ventral striatum), the prefrontal cortex (PFC) and amygdala.

Investigators have postulated that tolerance is regulated by connections between neurons that produce multiple neurotransmitters or neuromodulators (Kalant 1993). For example, evidence indicates that vasopressin (a pituitary hormone with effects on body fluid equilibrium) plays an important role in maintaining tolerance to alcohol (Tabakoff and Hoffman 1996). Remarkably, a single exposure to a vasopressinlike chemical while an animal is under the effects of alcohol is followed by long-lasting tolerance to alcohol (Kalant 1993). The development of this long-lasting tolerance depends not only on vasopressin but also on serotonin, norepinephrine, and dopamine—neurotransmitters with multiple regulatory functions (Tabakoff and Hoffman 1996; Valenzuela and Harris 1997).

In line with the hypothesis that a partial dopamine D2 agonist would block the reinforcing effects of alcohol, aripiprazole attenuates alcohol’s ability to increase the locomotor activity in mice [178, 179](an indirect measure of activation of the mesolimbic dopamine system). On the other hand, aripiprazole did not interfere with the alcohol‐induced impairment in motor balance as measured by rotarod test [179]. Furthermore, repeated systemic aripiprazole administration decreases alcohol intake in alcohol‐preferring rats [180], while single oral administration dose‐dependently decreases alcohol self‐administration in outbred rats [181]. In addition, aripiprazole has been shown to reverse alcohol‐induced place preference and anxiety‐like behaviour in mice [182]. It starts to produce less of the chemical, reduce the number of dopamine receptors in the body and increase dopamine transporters, which ferry away the excess dopamine in the spaces between brain cells. Serotonin may interact with GABA-mediated signal transmission by exciting the neurons that produce and secrete GABA (i.e., GABAergic neurons).

Alcohol interacts with serotonergic synaptic transmission in the brain in several ways. Even single-episode (i.e., acute) alcohol exposure alters various aspects of serotonin’s synaptic functions. In humans, for example, the levels of serotonin metabolites in the urine and blood increase after a single drinking session, indicating increased serotonin release in the nervous system (LeMarquand et al. 1994a). Animal studies also have found that acute alcohol exposure elevates serotonin levels within the brain (LeMarquand et al. 1994b; McBride et al. 1993), suggesting either that more serotonin is released from the serotonergic axons or that the neurotransmitter is cleared more slowly from the synapses. For example, increased serotonin release after acute alcohol exposure has been observed in brain regions that control the consumption or use of numerous substances, including many drugs of abuse (McBride et al. 1993).

1Throughout this article, the term “alcohol abuse” is used to describe any type of alcohol consumption that causes social, psychological, or physical problems for the drinker. Thus, the term encompasses the clinical diagnoses of alcohol abuse and alcohol dependence as defined by the American Psychiatric Association. Researchers are focusing much of their attention on other inhibitory neurotransmitters. Glycine is the major inhibitory neurotransmitter in the spinal cord and brain stem. Alcohol has been shown to increase the function of glycine receptors in laboratory preparations (Valenzuela and Harris 1997).

1. SERT availability was measured in vivo with single photon emission computed tomography and (123) I-labeled 2-((2-((dimethyl-amino) methyl) phenyl) thio)-5-iodophenylamine in the midbrain, thalamus and striatum.
2. Teenagers are likely to engage in high-risk behaviors, such as driving under the influence and using other substances.
3. Fluoxetine reduces alcohol consumption in humans only moderately, however, and does not affect all alcoholics (Litten et al. 1996).
4. Similarly, Kiianmaa and colleagues[28] found no differential increase of extracellular DA concentration in the NAc between AA and ANA rats after microdialysis of ethanol.

As the VTA is a major nucleus of dopamine cell bodies, we explicitly assessed changes in connectivity with the VTA induced by depletion of dopamine precursors. The alcohol-induced stimulation of dopamine release in the NAc may require the activity of another category of neuromodulators, endogenous opioid peptides. (For more information on endogenous opioid peptides, see the article by Froehlich, pp. 132–136.) This hypothesis is supported by observations that chemicals that inhibit the actions of endogenous opioid peptides (i.e., opioid peptide antagonists) prevent alcohol’s effects on dopamine release. Opioid peptide antagonists act primarily on a brain area where dopaminergic neurons that extend to the NAc originate.

As an example, the agent acamprosate modulates glutamate transmission by acting on NMDA and/or metabotropic glutamate receptors.[30] Therefore, by reducing excessive glutamate activity, acamprosate blocks excessive alcohol consumption. The role of dopamine in AUD is complex barbiturates and has been reviewed in detail elsewhere [10,11,12,13]. Briefly, acute alcohol increases dopamine release across the striatum [14] primarily due to increased firing of midbrain dopaminergic neurons, an effect that may underlie the initial reinforcing properties of alcohol.