The dopamine system and alcohol dependence PMC

This section summarizes PET studies that investigate the key neurotransmitter systems and review the evidence in case-control studies (summarized in Table 1). The dopamine, GABA and opioid systems are by far the most researched using PET and SPECT imaging techniques to measure neurochemical dysfunction in alcohol dependence, due to the availability of selective radiolabeled tracers for the targets of DRD2/3, GABA-A and MOR receptors, respectively. Well validated tracers for other targets such as those in the serotonergic system do exist, but their use in alcohol dependent individuals is not well characterized. Studies using novel radioligands to assess other receptor targets and neurochemical systems including the endocannabinoid and glutamatergic systems is less advanced, but a few selective tracers do exist. It must be acknowledged that PET/SPECT is somewhat limited as a technique because of its radioactivity meaning that young people and repeat scanning cannot be carried out.

Altered emotional processing has been found both during alcohol intoxication and dependence and appears to worsen as consumption increases. Alcohol works on the brain to produce its desired effects, e.g., sociability and intoxication, and hence the brain is an important organ for exploring subsequent harms. On top of that are peripheral factors that compound brain damage such as poor diet, vitamin deficiencies leading to Wernicke-Korsakoff syndrome.

Gene variants related to DA systems and alcohol dependence

Pavlovian conditioned responses to alcohol cues in rodents provide a model of alcohol AB that allows direct measurements and mechanistic manipulations of the neural circuitry underlying AB [20,21,22]. Taken together, preclinical evidence indicates a key role for dopaminergic pathways in mediating responses to alcohol-related cues [23,24,25]. Moreover, work in non-human primates highlights a role for the prefrontal cortex in reward signaling [26], and human fMRI studies show that prefrontal cortex drives phasic cue responses in the VTA [27, 28]. However, the dopaminergic circuitry mediating AB to alcohol cues in humans––and the extent to which this circuitry overlaps with the circuitry mediating conditioned responses to non-drug rewards––remains unclear.

Less is known about the dose-response mechanism, though it has been suggested moderate drinking lies somewhere intermediate [52,53]. This would again imply that the impact of alcohol consumption on brain structure is not limited to heavy alcohol consumption. However, it has been noted there are differences in brain structure that predate alcohol initiation and may predispose individuals to heavy alcohol use. Structural precursors have mostly been found in the prefrontal cortex and fronto-limbic white matter and show considerable overlap with structural differences found in individuals with a family history of alcohol dependence [54].

Distinct sub-second dopamine signaling in dorsolateral striatum measured by a genetically-encoded fluorescent sensor

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. To modulate the responsiveness of neighboring neurons to glutamate, dopamine modifies the function of ion channels in the membrane of the signal-receiving (i.e., postsynaptic) neuron. The activity of some of these ion channels (i.e., whether they are open or closed) depends on the voltage difference, or potential, between the inside and the outside of the cell membrane adjacent to these channels. Through its effects on G proteins, dopamine indirectly modifies the sensitivity with which voltage-dependent channels respond to changes in the membrane potential that occur when glutamate binds to its receptors, which also act as ion channels (i.e., receptor-operated channels). A one-factor ANOVA with Tukey’s post hoc test was used to compare the average lifetime alcohol intake between cohorts. Two-factor ANOVAs (stimulation intensity and treatment group) were used for the input–output curve experiments examining dopamine release.

Several longitudinal studies have probed response inhibition in adolescent drinkers. Such studies have found that adolescents who later transitioned into heavy drinking had lower BOLD activation at baseline and increased activation in frontal regions when subsequently drinking heavily compared with continuous non-drinkers [110,111]. This supports the role of impaired response inhibition as a risk factor rather than a consequence of alcohol consumption. The compensatory changes previously alcohol and dopamine described might be involved in the development of alcohol-related behavior. An example of such behavior is tolerance (i.e., a person must drink progressively more alcohol to obtain a given effect on brain function). For example, in animals exposed for several days to alcohol, many neurotransmitter receptors appear resistant to the short-term actions of alcohol on glutamate and GABAA receptors compared with animals that have not been exposed to alcohol (Valenzuela and Harris 1997).