Ion Channels. The primary mediators of inhibitory neurotransmission in the brain are the ligand-gated γ-aminobutyric acid A (GABAA) receptors, whose function is markedly enhanced by a number of classes of sedative, hypnotic, and anesthetic agents, including barbiturates, benzodiazepines, and volatile anesthetics (Chapter 14). Substantial data implicate the GABAA receptor as an important target for the in vivo actions of ethanol. Stimulation of this multi-subunit, ligand-gated Cl− channel system contributes to feelings of sleepiness, muscle relaxation, and the acute anticonvulsant properties associated with all GABA-boosting drugs (Krystal et al., 2006). Acutely, ethanol results in GABA release; chronic heavy use alters the pattern of expression of genes impacting on GABAA subunits. Intoxication with ethanol can be viewed as a GABA-rich state, and withdrawal phenomena are related in part to GABAA activity deficiencies. Several GABAA receptor gene polymorphisms correlate with a predisposition toward heavy drinking and alcohol use disorders (Dick et al., 2006a,b).
The nicotinic ACh receptor is also sensitive to the effects of ethanol. Drinking acutely increases ACh in the ventral tegmental area, with a subsequent increase in DA in the nucleus accumbens (Joslyn et al., 2008). Varenicline, a partial agonist at the α4β2 subtype of the nicotininc ACh receptor (Chapter 11), decreases ethanol-seeking behavior and ethanol consumption in a rodent model, similar to its actions to effects on nicotine dependence (Steensland et al., 2007). Effects of ethanol on these receptors may be particularly important because there is an association between nicotine exposure (smoking) and alcohol consumption in humans. Furthermore, several studies indicate that nicotine increases alcohol consumption in animal models (Smith et al., 1999).
Excitatory ionotropic glutamate receptors are divided into the N-methyl-D-aspartate (NMDA) and non-NMDA receptor classes, with the latter consisting of kainate- and AMPA-receptor subtypes (see Chapter 14). Ethanol inhibits the function of the NMDA- and kainate-receptor subtypes; AMPA receptors are largely resistant to alcohol (Carta et al., 2003). As with the GABAA receptors, phosphorylation of the glutamate receptor can modulate sensitivity to ethanol.
A number of other types of channels are sensitive to alcohol at concentrations routinely achieved in vivo. Ethanol enhances the activity of large conductance, Ca2+-activated K+ channels in neurohypophyseal terminals (Dopico et al., 1999), perhaps contributing to the reduced release of oxytocin and vasopressin after ethanol consumption. Ethanol inhibits N- and P/Q-type Ca2+ channels in a manner that can be antagonized by channel phosphorylation by PKA (Solem et al., 1997). BK (Maxi-K, slo1) channels also are a target for alcohol action (Davies et al., 2003). G protein-gated inwardly rectifying K+ channels (GIRK or Kir channels) can be activated by the βγ subunits of the Gi/Go family, by PIP2, and, via a different mechanism, by alcohols. Small alcohols bind to a hydrophobic binding pocket on GIRKs, leading to channel activation via stabilization of the open conformation (Aryal et al., 2009).
Other Neurotransmitter Systems. Dopamine-related systems have central importance regarding the feelings of reward and craving associated with all intoxicating substances (Koob and Kreek, 2007). Of special importance are alterations in DA activity in the ventral tegmental and related areas, especially the nucleus accumbens, which are likely to play a major role in feelings of euphoria and reward. Acute alcohol results in an increase in synaptic DA; repeated administration is associated with changes in both D2 and D4 receptors that may be important in the perpetuation of alcohol use as well as in relapse (Voronin et al., 2008).
The impact of ethanol on dopaminergic pathways is closely linked to changes in stress-related systems. These changes are hypothesized to relate to reinforcement from beverage alcohol and other drugs of abuse, as well as withdrawal symptoms and negative moods related to problems with regulation of the DA-rich brain reward systems. Dopaminergic activity in the nucleus accumbens is affected by multiple types of opioid receptors, and acute ethanol causes the release of β endorphins (Job et al., 2007). These actions subsequently activate μ opioid receptors in the ventral tegmentum and nucleus accumbens, with associated release of DA. Thus, many of the effects of alcohol on reward systems, and changes in how the CNS reacts to ethanol (including sensitization), may relate to alterations in opioid systems (Pastor and Aragon, 2006).
The acute administration of ethanol is associated with a significant increase in 5-HT in the synaptic space; continued use of ethanol produces an up-regulation of 5-HT receptors. Lower levels of 5-HT in the synapse, perhaps related to a more rapid reuptake by the 5-HT transporter, is associated with higher levels of alcohol intake and, potentially, lower levels of intensity of reaction to beverage alcohol (Barr et al., 2005). Changes in DA systems are likely to relate to alterations in 5-HT as well.
Cannabinoid receptors, especially CB1 encoded by the gene CNR1, are also affected by ethanol (Hutchinson et al., 2008; Perra et al., 2008). CB1 is a GPCR that is densely represented in the ventral tegmentum, nucleus accumbens, and prefrontal cortex. Activation of CB1 occurs with acute ethanol administration and affects the release of DA, GABA, and glutamate, and reward circuits of the brain. Antagonists of CB1 receptors, such as rimonabant, may block the effect of ethanol on dopaminergic systems.
Protein Kinases and Signaling Enzymes. Knockout mice lacking the γ isoform of PKC display reduced effects of ethanol measured behaviorally and a loss of enhancement by ethanol of GABA's effects measured in vitro (Harris et al., 1995). Intracellular signal-transduction cascades, such as MAPK, tyrosine kinases, and neurotrophic factor receptors, also are thought to be affected by ethanol (Valenzuela and Harris, 1997). Translocation of PKC and PKA between subcellular compartments also is sensitive to alcohol (Constantinescu et al., 1999).
Ethanol enhances the activities of several isoforms of adenylyl cyclase, with AC7 being the most sensitive (Tabakoff and Hoffman, 1998). This promotes increased production of cyclic AMP and thus increased activity of PKA. Ethanol's actions appear to be mediated by activation of Gs and promotion of the interaction between Gs and adenylyl cyclase.
Ethanol Consumption and CNS Function. There are a series of relatively common and temporary effects of ethanol with relatively high prevalence rates reflecting changes in the GABA system that are generally caused by CNS depressants. Large doses of ethanol can interfere with encoding of memories, producing anterograde amnesias, commonly referred to as alcoholic blackouts; affected individuals are unable to recall all or part of experiences during the period of heavy intake. At even 2-3 drinks, ethanol consumption can produce disturbances in sleep architecture, with frequent awakenings and restless sleep; high doses are associated with vivid and disturbing dreams late as a consequence of earlier suppression of night rapid eye movement dream state at higher blood ethanol levels. Perhaps reflecting the effect of ethanol on respirations as well as the muscle-relaxant effects of this drug, heavier drinking can be associated with sleep apnea, especially in older alcohol-dependent subjects (Sakurai et al., 2007). The transient CNS effects of heavy ethanol consumption that produce a hangover—the "next morning" syndrome of headache, thirst, nausea, and cognitive impairment—contribute to much time lost from work and school, and may reflect mechanisms similar to mild alcohol withdrawal, dehydration, and/or mild acidosis (Stephens et al., 2008).
Chronic heavy drinking reportedly increases the probability of developing a more permanent cognitive deficit often referred to as alcoholic dementia. However, the signs of cognitive deficits and brain atrophy observed soon after a heavy drinking period often reverse over the subsequent several weeks to months following abstinence (Bartsch et al., 2007). The thiamine depletion that can accompany heavy ethanol consumption contributes to Wernicke-Korsakoff syndromes; however, the ataxia and ophalmoparesis of Wernicke's, and the severe anterograde and retrograde amnesias of Korsakoff's, are seen in <<1% of chronic alcohol-dependent individuals. Additional severe neurological syndromes associated with chronic heavy use of alcohol include cerebellar degeneration with associated atrophy of the cerebellar vermis (seen in ~1% of alcoholics), and a peripheral neuropathy (observed in ~10% of alcoholics) (Alexander-Kaufman et al., 2007; Peters et al., 2006). The specific mechanisms associated with damage to the cerebellum and peripheral nerves have not been definitively identified.
Heavy doses of ethanol over multiple days or weeks are also associated with several temporary but disturbing "alcohol-induced" psychiatric syndromes (Schuckit, 2006a). As many as 40% of alcohol-dependent humans develop severe alcohol-related depressive symptoms that can include temporary suicidal thoughts and behaviors. Similarly, a range of anxiety conditions, including those characterized by panic attacks and generalized anxiety, are likely in a large minority of alcohol-dependent individuals during the withdrawal syndrome. Perhaps 3% of alcohol-dependent men and women report experiencing temporary auditory hallucinations and paranoid delusions that resemble schizophrenia beginning during periods of heavy intoxication; all of these psychiatric syndromes are likely to markedly improve within several days to a month of abstinence, with residual mild symptoms continuing to diminish thereafter. While no definitive data on the mechanisms for these alcohol-induced psychiatric conditions are available, it is logical to assume that alcohol-related changes in CNS pathways (NE and 5-HT levels, the balance between GABAA and NMDA receptor activity, dopaminergic activity) may operate here in a manner similar to those seen in depression, anxiety, and schizophrenic disorders.