Update on neuropharmacological treatments for alcoholism: scientific basis and clinical findings

Abstract

The past decade has seen an expansion of research and knowledge on pharmacotherapy for the treatment of alcohol dependence. The Food and Drug Administration (FDA)-approved medications naltrexone and acamprosate have shown mixed results in clinical trials. Oral naltrexone and naltrexone depot formulations have generally demonstrated efficacy at treating alcohol dependence, but their treatment effect size is small, and more research is needed to compare the effects of different doses on drinking outcome. Acamprosate has demonstrated efficacy for treating alcohol dependence in European trials, but with a small effect size. In U.S. trials, acamprosate has not proved to be efficacious. Research continues to explore which types of alcohol-dependent individual would benefit the most from treatment with naltrexone or acamprosate. The combination of the two medications demonstrated efficacy for treating alcohol dependence in one European study but not in a multi-site U.S. study. Another FDA-approved medication, disulfiram, is an aversive agent that does not diminish craving for alcohol. Disulfiram is most effective when given to those who are highly compliant or who are receiving their medication under supervision. Of the non-approved medications, topiramate is among the most promising, with a medium effect size in clinical trials. Another promising medication, baclofen, has shown efficacy in small trials. Serotonergic agents such as selective serotonin reuptake inhibitors and the serotonin-3 receptor antagonist, ondansetron, appear to be efficacious only among certain genetic subtypes of alcoholic. As neuroscientific research progresses, other promising medications, as well as medication combinations, for treating alcohol dependence continue to be explored.

Fig. 1

Schematic representation of opioid interactions with the cortico-mesolimbic dopamine reward pathway. Functional activity of beta-endorphin pathways primarily originating from the nucleus arcuatus can lead to increased dopamine release in the nucleus accumbens via two mechanisms. First, beta-endorphins can disinhibit the tonic inhibition of gamma-aminobutyric acid (GABA) neurons on dopamine cells in the ventral tegmental area [10-12]. Second, beta-endorphins can stimulate dopamine cells in the nucleus accumbens directly. Both mechanisms may be important for alcohol reward. Alcohol stimulates beta-endorphin release in both the nucleus accumbens and ventral tegmental area [13]. Mu receptor antagonists such as naloxone and naltrexone block these central effects of beta-endorphins [9,13]. Embellished from Gianoulakis [13]. Reprinted from Figure 1 in Johnson and Ait-Daoud [14], with the kind permission of Springer Science and Business Media.

Fig. 2

Schematic representation of acamprosate’s effects. Acamprosate has four principal effects: A) reducing post-synaptic excitatory amino acid neurotransmission at N-methyl-D-aspartate (NMDA); B) diminishing Ca²⁺ influx into the cell, which interferes with expression of the immediate early gene c-fos; C) decreasing the sensitivity of voltage-gated calcium channels, and D) modulating metabotropic-5 glutamate receptors (mGluR5). mGluR5 are post-synaptic and are coupled to their associated ion channels by a second messenger cascade system (not shown). Also shown in this representation is synthesis of c-fos and c-jun in the endoplasmic reticulum, which can bind with DNA to alter the transcription of late effector genes. Late effector genes regulate long-term changes in cellular activity such as the function of receptors, enzymes, growth factors, and the production of neurotransmitters. Embellished from Spanagel and Zieglgansberger [103]. Adapted from Figure 2 in Johnson and Ait-Daoud [14], with the kind permission of Springer Science and Business Media.

Fig. 3

Schematic illustration of the hypothesized effects of acute and chronic alcohol, both with and without topiramate, on the cortico-mesolimbic dopamine (DA) reward circuit [127]. (Upper left) Acute alcohol suppresses the firing rate of ventral tegmental area (VTA) gamma-aminobutyric acid (GABA) neurons, which leads to less suppression of VTA DA neuronal activity. This disinhibition leads to VTA DA neuronal firing and DA release in the nucleus accumbens (N Acc.) [127]. (Lower left) With chronic drinking, VTA GABA neurons are hyperexcitable, mainly because of increased glutamatergic input, less GABA tone from the N Acc., and rebound firing of GABA neurons because of their long-term suppression from repeated alcohol ingestion. This leads to VTA DA hypofunction and decreased release (compared with the acute condition) of DA in the N Acc. [127]. (Upper right) During acute drinking, the GABAergic influence of topiramate probably predominates, particularly in the N Acc. This leads to greater inhibition of N Acc. DA neurons, and greater GABA tone from the N Acc. to the VTA suppresses VTA DA cell firing. Topiramate concomitantly inhibits the excitatory effects of glutamatergic neurons on DA neurons in the VTA and N Acc. These combined actions of topiramate should lead to profound suppression of DA neuronal activity and DA release in the N Acc. Hence, topiramate reduces the DA-mediated reinforcing effects of acute alcohol [127]. (Lower right) During chronic drinking, the predominant neuronal activity resides with the hyperexcitable state of VTA GABA neurons. Because of GABA-mediated inhibition and glutamatergic blockade of these neurons, topiramate “normalizes” VTA GABA neuronal activity. Although this would, at first, suggest that DA release in the N Acc. would be enhanced, this does not occur, and DA release in the N Acc. is most likely reduced because these N Acc. terminals are contemporaneously inhibited by GABA inhibition and blockade of glutamate (GLU). In the chronic drinker, the anti-glutamatergic and L-type calcium channel effects of topiramate to block sensitization might predominate. Hence, topiramate would make it easier for a chronic alcoholic to withdraw from alcohol because rebound DA release would not occur (if drinking were ceased abruptly), and topiramate would aid in relapse prevention because alcohol’s reinforcing effects would be decreased [127]. Line weights represent relative strengths of neuronal activity (heavy, medium, and light). The broken line represents decreased tone. VP, ventral pallidum. Reprinted from Figure 1 in Johnson [127], with the permission of Blackwell Publishing, Inc.

Fig. 4

Neuronal pathways involved with the reinforcing effects of alcohol and other abused drugs. Cholinergic inputs that arise from the caudal part of the pedunculopontine tegmental nucleus (PPTg) and laterodorsal tegmental nucleus (LDTg) can stimulate ventral tegmental area (VTA) dopamine neurons. The VTA dopamine neuron projection to the nucleus accumbens (nACC) and cortex, the critical substrate for the reinforcing effects of abused drugs (including alcohol), is modulated by a variety of inhibitory [gamma-aminobutyric acid (GABA) and opioid] and excitatory [nicotinic (NIC-R), glutamate (GLU), and cannabinoid-1 receptor (CB1-R)] inputs. The GLU pathways include those that express alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors. Serotonin-3 receptors (5-HT3-R) also modulate dopamine release in the nACC. Adapted and embellished by Bankole A. Johnson, DSc, MD, PhD, from an original drawing by Dennis Twombly, PhD, at the National Institute on Alcohol Abuse and Alcoholism. Reprinted from the figure in Johnson [267]. Copyright © 2006, American Medical Association. All rights reserved.