Neuropharmacology of alcohol addiction

Abstract

Despite the generally held view that alcohol is an unspecific pharmacological agent, recent molecular pharmacology studies demonstrated that alcohol has only a few known primary targets. These are the NMDA, GABA A , glycine, 5-hydroxytryptamine 3 (serotonin) and nicotinic ACh receptors as well as L-type Ca 2 þ channels and G-protein-activated inwardly rectifying K þ channels. Following this first hit of alcohol on specific targets in the brain, a second wave of indirect effects on a variety of neurotransmitter/neuropeptide systems is initiated that leads subsequently to the typical acute behavioural effects of alcohol, ranging from disinhibition to sedation and even hypnosis, with increasing concentrations of alcohol. Besides these acute pharmacodynamic aspects of alcohol, we discuss the neurochemical substrates that are involved in the initiation and maintenance phase of an alcohol drinking behaviour. Finally, addictive behaviour towards alcohol as measured by alcoholseeking and relapse behaviour is reviewed in the context of specific neurotransmitter/neuropeptide systems and their signalling pathways. The activity of the mesolimbic dopaminergic system plays a crucial role during the initiation phase of alcohol consumption. Following long-term, chronic alcohol consumption virtually all brain neurotransmission seems to be affected, making it difficult to define which of the systems contributes the most to the transition from controlled to compulsive alcohol use. However, compulsive alcohol drinking is characterized by a decrease in the function of the reward neurocircuitry and a recruitment of antireward/stress mechanisms comes into place, with a hypertrophic corticotropin-releasing factor system and a hyperfunctional glutamatergic system being the most important ones.

Activation of Group II Metabotropic Glutamate Receptors Inhibits the Discriminative Stimulus Effects of Alcohol via Selective Activity Within the Amygdala

“…Interestingly, systemic LY379268 did not reduce alcohol-appropriate responding at a 1.7 g/kg dose of alcohol. Alcohol has actions at multiple cellular and molecular targets (Vengeliene et al, 2008), therefore, it is possible that a higher dose of alcohol may further stimulate other receptor or signaling systems, thereby reducing the efficacy of mGlu2/3 receptor activation in blunting the discriminative stimulus effects of a higher dose of alcohol (Grant, 1999). Further, given that these animals had considerable exposure to the alcohol-training dose (1 g/kg), exposure to higher alcohol doses could produce stronger stimulus effects that are more difficult to alter with pharmacological manipulation.…”

What is in that Drink: The Biological Actions of Ethanol, Acetaldehyde, and Salsolinol

“…Furthermore, manipulation of the DA, serotonin (5-HT), γ-aminobutyric acid (GABA), opioid, and glutamate (GLU) systems within the DA reward pathway, or within structures or areas that project to the DA reward pathway, has been found to effectively alter alcoholrelated behaviors in preclinical research (Vengeliene et al, 2008;Koob et al, 1998).…”

Activation of amylin receptors attenuates alcohol‐mediated behaviours in rodents

“…However, existing pharmacotherapy has shown limited efficacy (Anton et al 2006); therefore, further investigation of possible alcohol neurochemical targets could lead to new pharmacological interventions (Heilig & Egli 2006;Litten et al 2012). Alcohol targets components of the mesolimbic dopamine system (Larsson & Engel 2004;Vengeliene et al 2008;Soderpalm, Lof, & Ericson 2009), which is involved in the expression of its reinforcing properties (Adinoff 2004). Beyond the mesolimbic dopamine system, which includes dopamine projections from the ventral tegmental area (VTA) to nucleus accumbens (NAc) (Koob & Bloom 1988;Kelley & Berridge 2002), recent studies show that alcohol activates the cholinergic inputs from the laterodorsal tegmental nucleus (LDTg) (Larsson et al 2005).…”