Low Inherent Sensitivity to the Intoxicating Effects of Ethanol in Rhesus Monkeys with Low CSF Concentrations of the Serotonin Metabolite 5-Hydroxyindoleacetic Acid

Abstract

Background: Type 2 alcoholism is characterized by low serotonin system functioning and has a high degree of heritability, with offspring of alcoholics often showing a reduced response to the intoxicating effects of ethanol (EtOH), which is thought to be marker for future alcohol use disorders (AUDs). As such, an important aim of studies investigating the origins of AUDs is to understand the relationship between serotonin system functioning and level of intoxication. A nonhuman primate model was used to evaluate observational ratings of sensitivity to EtOH and to further investigate the relationship between central serotonin activity and behavioral response to EtOH.

Methods: Cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) were obtained from 4 cohorts of alcohol-naïve, adolescent rhesus macaques (N = 82, 45 females, 37 males). One to 3 months after the CSF sample, subjects were administered a standardized intravenous EtOH bolus (males: 2.1 g/kg body weight, females: 2.0 g/kg body weight), placed into an open-top, clear plexiglass chamber suspended from the ceiling, and their latency to escape was recorded as a measure of the degree of intoxication. Thereafter, subjects were rated using a Likert scale for the degree of intoxication during a 30-minute observation period.

Results: Our results indicate that latency to escape from the chamber was associated with intoxication ratings (p = 0.0009) following the standardized intravenous administration of EtOH. Low CSF 5-HIAA concentrations predicted short escape latency (p = 0.007) and were associated with low intoxication ratings (p = 0.02), indicating that low central nervous system (CNS) serotonin functioning is related to relative insensitivity to the intoxicating effects of alcohol.

Conclusions: Our study shows that, in monkeys exposed to alcohol for the first time, objective measures of intoxication are associated with subjective ratings for intoxication, and both were associated with CSF 5-HIAA concentrations. Our data confirm and extend the finding that low CNS serotonin functioning is predictive of intrinsic low sensitivity to the intoxicating effects of EtOH.

Keywords: Alcohol Sensitivity; Alcohol Use Disorders; Rhesus Macaques; Serotonin; Tolerance.

Figure 1.

Plexiglas™ chamber (height: 184cm; width: 92cm; depth: 60cm) hanging by two chains from the ceiling of the room. To facilitate escape, a plastic chain was suspended from the ceiling extending to the middle of the bottom third of the chamber.

Figure 2.

A between-groups one-way ANOVA comparing intoxication rating across the three intoxication groups showed that subjects rated as highly intoxicated exhibited a significantly longer escape time (M = 177.25±30.12) when compared to subjects rated as medium (M = 57.09±33.55) and subjects rated as low (M = 17.29±31.34); p = 0.0001. The asterisks represent a significant effect at the p < .001 level. The error bars represent standard errors of the mean.

Figure 3.

A linear regression found baseline 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the cerebrospinal fluid (CSF) are significantly predictive of escape latency from the Plexiglas™ chamber (R = .61, F(1,18) = 10.06, p = .007).

Figure 4.

A between-groups one-way ANOVA comparing CSF 5-HIAA concentrations across the intoxication groups when they were collapsed into high (3–5) and low (1–2) groups showed that the subjects given a low intoxication rating exhibiting significantly lower CSF 5-HIAA concentrations (M = 241.46±11.47) than did the subjects given a high intoxication rating (M = 280.01±8.35); p = .02. The asterisk represents a significant effect at the p < .05 level. The error bars represent standard errors of the mean.