A heuristic model of alcohol dependence

Abstract

Background: Substance dependence poses a critical health problem. Sadly, its neurobiological mechanisms are still unclear, and this lack of real understanding is reflected in insufficient treatment options. It has been hypothesized that alcohol effects are due to an imbalance between neuroexcitatory and neuroinhibitory amino acids. However, glutamate and GABA interact with other neurotransmitters, which form a complicated network whose functioning evades intuition and should be investigated systemically with methods of biomedical systems analysis.

Methods and results: We present a heuristic model of neurotransmitters that combines a neurochemical interaction matrix at the biochemical level with a mobile describing the balances between pairs of neurotransmitters at the physiological and behavioral level. We investigate the effects of alcohol on the integrated neurotransmitter systems at both levels. The model simulation results are consistent with clinical and experimental observations. The model demonstrates that the drug diazepam for symptoms of alcohol withdrawal effectively reduces the imbalances between neurotransmitters. Moreover, the acetylcholine signal is suggested as a novel target for treatment of symptoms associated with alcohol withdrawal.

Conclusions: Efficient means of integrating clinical symptoms across multiple levels are still scarce and difficult to establish. We present a heuristic model of systemic neurotransmitter functionality that permits the assessment of genetic, biochemical, and pharmacological perturbations. The model can serve as a tool to represent clinical and biological observations and explore various scenarios associated with alcohol dependence and its treatments. It also is very well suited for educational purposes.

Figure 1. The neurochemical interaction matrix.

The interactions among six neurotransmitter systems in the human brain form a fully connected network, which may be represented as a matrix. Arrows represent activation; while bar-headed lines represent inhibition. Abbreviation: dopamine (DA), acetylcholine (ACh), serotonin (5-HT), glutamate (Glu), noradrenaline (NA), and gamma-aminobutyric acid (GABA).

Figure 2. The neurochemical mobile as a system of balanced rods with individual neurotransmitters as weights.

The neurochemical mobile represents a hierarchical functional organization of neurotransmitters, along with their relative functional contributions and dynamic imbalances in human brain. The mobile represents synergisms or antagonisms between neurotransmitter systems at the physiological, behavioral, and pathological level, and can be tailored for a specific disease. For illustration, we use a weighting scheme, where the areas of circles are proportional to the relative signal intensities of neurotransmitters 5-HT (100 units), DA (100 units), NA (100 units), ACh (100 units), Glu (200 units), and GABA (150 units). The lengths of the arms of each rod are thus different and reflect corresponding relative signal intensities.

Figure 3. In response to alcohol withdrawal, the mobile system exhibits significant imbalance.

Circles from left to right: 5-HT, DA, NA, ACh, Glu, and GABA. For visibility, the lengths of arms in the mobile are adjusted as described, and neurotransmitter concentrations are transformed into comparable relative signal intensities, so that all neurotransmitters have similar functional weights.

Figure 4. Dynamics of neurotransmitters and rod balances in response to acute alcohol exposure, adaptation, and withdrawal.

Neurotransmitters have similar functional contributions in the mobile system. The three vertical dashed lines represent, from left to right, the beginning of acute alcohol exposure, adaptation, and withdrawal, respectively. A: Dynamic imbalances associated with five rods are represented by rotation angles relative to the horizontal position. B: Dynamics of neurotransmitters. Note that the dynamic responses of DA and NA overlap.

Figure 5. Diazepam reduces imbalances caused by alcohol withdrawal.

The mobile confirms that diazepam reduces imbalances during alcohol withdrawal. Circles from left to right: 5-HT, DA, NA, ACh, Glu, and GABA. For better visibility, the lengths of arms in the mobile are adjusted and do not reflect functional contributions of neurotransmitters.

Figure 6. Diazepam partly restores the balance between excitatory and inhibitory neurotransmitters.

Neurotransmitters have similar functional contributions in the mobile system. The three dashed vertical lines represent, from left to right, the beginning of acute alcohol exposure, adaptation, and withdrawal, respectively. The solid vertical line represents the application of diazepam. A: Dynamic imbalances associated with five rods are represented by rotation angles relative to the horizontal position. B: Dynamics of neurotransmitters. Note that the dynamic responses of DA and NA overlap.