Molecular Genetics of Alcoholism
The precise molecular genetic basis for the hereditability of alcoholism is largely unknown, but several lines of evidence have provided some insights into possible genetic factors. Early studies on alcoholism found that individuals with alcoholism or certain subgroups of individuals with alcoholism have reduced cerebrospinal fluid levels of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of the neurotransmitter serotonin. A series of studies highlighted the role of serotonin in impulse control, and low cerebrospinal 5-HIAA levels were associated with increased irritability and impaired impulse control in violent individuals with alcoholism with antisocial personality disorder. These characteristics are hallmarks of the young male with alcoholism. Studies of the association between single-nucleotide polymorphisms and alcohol dependence have revealed some possible polymorphisms in the genes that encode GABA, dopamine, opioid peptides, serotonin, and CRF. One of the associations is with a specific subunit of the GABAA receptor (the α2 subunit; for further reading, see Palmer et al., 2012).
Alcohol reinforcement has long been associated with the activation of opioid peptides. In animal studies, opioid receptor antagonists blocked alcohol self-administration, and opioid receptor antagonists have also been shown to have efficacy in treating alcoholism in humans. Some human genetic studies have identified an association between a functional polymorphism of the μ opioid receptor gene (A118G single-nucleotide polymorphism) and the therapeutic response to naltrexone in the treatment of alcoholism. Such studies point to a polymorphism that may contribute to the genetic vulnerability to alcoholism.
A parallel approach to the study of the neuropharmacological basis of excessive drinking involves the selective breeding of rodents for high alcohol consumption. Investigators capitalized on well-known within-species preference for alcohol drinking to develop lines of rats that voluntarily consume large amounts of alcohol. Extensive innate differences exist in the neurochemical systems implicated in the reinforcing effects of alcohol between selectively bred high- and low-drinking rodents. Alcohol-preferring rats have lower levels of serotonin and dopamine function, upregulation of the GABA system, and downregulation of the neuropeptide Y system (for further reading, see Murphy et al., 2002).
Figure 6.21 Increased GABA release in the central nucleus of the amygdala in ethanol-dependent rats. (Top) Chronic alcohol treatment increased the mean frequency and amplitude of spontaneous mini inhibitory postsynaptic currents (mIPSCs). The average frequency of mIPSCs in the central nucleus of the amygdala neurons in naive rats (n = 9) and chronic alcohol-treated rats (n = 15) is shown on the left (*p < 0.001). The same group of neurons showed an increase in the mean amplitude of mIPSCs in chronic alcohol-treated rats (*p < 0.05). (Bottom) Acute and chronic alcohol increased dialysate levels of GABA in the central nucleus of the amygdala. In both the naive and chronic alcohol-treated rats, alcohol administration into the central nucleus of the amygdala significantly (*p < 0.05) and dose-dependently increased mean dialysate GABA levels. The mean baseline dialysate GABA level was significantly (#p < 0.001) increased in chronic alcohol-treated rats compared with naive rats. These data provide electrophysiological and neurochemical evidence of an increase in GABA release in the central nucleus of the amygdala in alcohol-dependent rats. Increases in the mean frequency and amplitude of spontaneous mini inhibitory postsynaptic currents (mIPSCs) indicate the presynaptic release of GABA. The microdialysis results provide neurochemical confirmation. The hypothesized change in GABA release in the central nucleus of the amygdala is driven by CRF and parallels the development of dependence in rats. [Taken with permission from Roberto M, Madamba SG, Stouffer DG, Parsons LH, Siggins GR. Increased GABA release in the central amygdala of ethanol-dependent rats. Journal of Neuroscience, 2004, (24), 10159–10166.]
Figure 6.22 Effect of restraint stress on exploratory behavior in rats in the elevated plus maze 6 weeks after exposure to an alcohol liquid diet over a 3 week period. Control rats received a sucrose-containing liquid diet. The rats were injected intracerebroventricularly with 10 μg of the corticotropin-releasing factor antagonist D-Phe-CRF12–41 (n = 8–11/group) or vehicle (n = 7–8/group) and subsequently placed in restraint tubes or returned to their home cages for 15 min. The mean percentage of time spent in the open arms of the elevated plus maze was measured. ∗p < 0.05, compared with all other groups. These data show that rats with a history of dependence present no overt anxiety-like effects during protracted abstinence but present an exaggerated stress response when challenged with mild restraint stress. The exaggerated stress response in the animals with a history of dependence is blocked by intracerebroventricular administration of a peptide CRF1/CRF2 receptor antagonist. These results suggest residual long-term “sensitization”of the extrahypothalamic CRF systems in animals with a history of alcohol dependence. [Taken with permission from Valdez GR, Zorrilla EP, Roberts AJ, Koob GF. Antagonism of corticotropin-releasing factor attenuates the enhanced responsiveness to stress observed during protracted ethanol abstinence. Alcohol, 2003, (29), 55–60.]
Effects of Drugs on Animal Models of Cue- and Stress-Induced Reinstatement of Alcohol Drinking
Given that alcoholism is heritable, genetic differences may also be relevant to the role of brain stress systems in driving compulsive alcohol seeking. Animal models support the hypothesis that gene variants of CRF system molecules may promote compulsive-like alcohol intake. For example, many msP alcohol-preferring rats carry two G-to-A polymorphisms in allelic identity with one another in the distal promoter region of the CRF1 receptor Crhr1 gene. These mutations are not seen in other alcohol-preferring lines or outbred rats. This msP line exhibits increased CRF1 receptor expression in several stress-related brain regions, increased anxiety-like behavior, and increased sensitivity to the ability of CRF1 receptor antagonists to reduce alcohol self-administration and stress-induced reinstatement of alcohol seeking. Similarly, rhesus monkeys that carry a C-to-T single-nucleotide polymorphism in the promoter region of the Crh gene (the gene for CRF) do not show normal glucocorticoid feedback inhibition of CRF peptide expression, and this gene variant is associated with two-fold greater alcohol consumption in monkeys exposed to early life stress, without altering the basal drinking of unstressed monkeys. Several polymorphisms in human CRF system molecules have also been associated with alcohol use phenotypes, often in an interaction with stress history. Crhr1 single-nucleotide polymorphisms predicted greater alcohol consumption in already-dependent individuals and interacted with stress history. Converging evidence suggests that some individuals may be more vulnerable to the transition to dependence via negative reinforcement mechanisms that involve the activation of brain stress systems.