Elevated alcohol consumption in null mutant mice lacking 5–HT1B serotonin receptors

Abstract

Substantial evidence links alcohol drinking and serotonin (5-HT) functioning in animals. Lowered central 5-HT neurotransmission has been found in a subgroup of alcoholics, possibly those with more aggressive, assaultive tendencies. Several rodent studies have also suggested that intact 5-HT systems are important determinants of sensitivity and/or tolerance to ethanol-induced ataxia and hypothermia. Null mutant mice lacking the 5-HT1B receptor gene (5-HT1B-/-) have been developed that display enhanced aggression and altered 5-HT release in slice preparations from some, but not all, brain areas. We characterized these mice for sensitivity to several effects of ethanol. Mutant mice drank twice as much ethanol as wild-type mice, and voluntarily ingested solutions containing up to 20% ethanol in water. Their intake of food and water, and of sucrose, saccharin and quinine solutions, was normal. Mutants were less sensitive than wild-types on a test of ethanol-induced ataxia and, with repeated drug administration, tended to develop tolerance more slowly. In tests of ethanol withdrawal and metabolism, mutants and wild-type mice showed equivalent responses. Our results suggest that the 5-HT1B receptor participates in the regulation of ethanol drinking, and demonstrate that serotonergic manipulations lead to reduced responsiveness to certain ataxic effects of ethanol without affecting dependence.

Relationship of Psychopathology to the Human Serotonin1B Genotype and Receptor Binding Kinetics in Postmortem Brain Tissue

“…We did not examine the globus pallidus of suicides who died by violent means and therefore cannot comment on this result. The absence of altered binding in prefrontal cortex in their study is in agreement with our results.Although 5-HT 1B receptor appears to play a role in the modulation of aggressive behavior and alcohol or cocaine consumption in animal models (Olivier and Most 1990;Saudou et al 1994;Crabbe et al, 1996;Rocha et al, 1998), we found no differences in 5-HT 1B binding kinetics in association with alcoholism or pathological aggression. The mean number of 5-HT 1B receptor binding sites appeared to be about 10% lower in cases who were suicides, or with major depression and alcoholism.…”

“…Genetic factors play a role in alcoholism (Schuckit et al 1985) and major depression (Gershon et al 1989) but their precise nature is unknown. Again, the serotonergic system may play a role.Recently, aggressive behavior as well as increased alcohol and cocaine intake have been reported in 5-HT 1B receptor gene knockout mice (Saudou et al 1994;Ramboz et al 1996;Crabbe et al 1996;Rocha et al 1998). This set of observations raises the possibility that abnormalities in the 5-HT 1B receptor gene may contribute to human psychopathologies such as suicide, aggression, major depression, alcoholism, or substance abuse.…”

Escalated Aggression after Alcohol Drinking in Male Mice: Dorsal Raphé and Prefrontal Cortex Serotonin and 5-HT1B Receptors

“…Chronic Alc self-administration leads to longlasting neuroadaptive changes in multiple neurotransmitter systems and in vivo, ethanol reduces the persistent activity of prefrontal cortical neurons (McBride and Li, 1998;Tu et al, 2007). Some studies have suggested that the 5-HT 1B receptor is involved in regulating Alc self-administration and preference (Crabbe et al, 1996;Hoplight et al, 2006). The currently studied mice self-administered moderate doses of Alc for a minimum of 2 months prior to the microinjection experiments.…”

A Null Mutation of the Serotonin 6 Receptor Alters Acute Responses to Ethanol

“…Some lines of mice carrying a constitutive 5-HT 1B receptor mutation demonstrate increased ethanol consumption compared to wild types (Crabbe et al, 1996;Phillips et al, 1999;however, see Risinger et al, 1999;Bouwknecht et al, 2000;Gorwood et al, 2002 for conflicting reports). Other serotonin receptors, including 5-HT 3 R (Engel et al, 1998;Engel and Allan, 1999;Rodd-Henricks et al, 2003), 5-HT 2A R Maurel et al, 1999;however, see Wilson et al, 2000;Blakley et al, 2001 for conflicting reports), and 5-HT 2C R (Maurel et al, 1999;Tomkins et al, 2002) also modulate ethanol ingestion.…”