Central nervous system monoamine metabolite response to alcohol exposure is associated with future alcohol intake in a nonhuman primate model (Macaca mulatta)

Abstract

It is widely held that the central monoamine neurotransmitters modulate alcohol intake. Few studies, however, directly assess the relationship between baseline and alcohol-induced monoamine turnover, as well as the change from baseline, as predictors of alcohol intake. Using a nonhuman primate model, this study investigates baseline, alcohol-induced and alcohol-induced change in monoamine activity and their relationship with alcohol intake. Alcohol-naïve, adolescent rhesus macaques (Macaca mulatta, N = 114) were administered a standardized intravenous bolus of alcohol solution (16.8%, v/v) on two occasions, approximately 1 month apart. One month prior to and 1 h following each alcohol infusion, cisternal cerebrospinal fluid (CSF) was obtained and assayed for monoamine metabolite concentrations. Approximately 6-7 months later, subjects were allowed unfettered access to an aspartame-sweetened alcohol solution (8.4%, v/v) for 1 h/day, 5 days/week, over 5-7 weeks. Results showed strong positive correlations between baseline and post-infusion CSF monoamine metabolite concentrations, indicating a trait-like response. Low baseline and post-infusion serotonin and dopamine metabolite concentrations and a smaller change in serotonin and dopamine metabolites from one infusion to the next were associated with higher alcohol intake. Low baseline and post-infusion norepinephrine metabolite concentrations predicted high alcohol intake, but unlike the other monoamines, a greater change in norepinephrine metabolite concentrations from one infusion to the next was associated with higher alcohol intake. These findings suggest that individual differences in naturally occurring and alcohol-induced monoamine activity, as well as the change between exposures, are important modulators of initial alcohol consumption and may play a role in the risk for excessive alcohol intake.

Keywords: alcohol; dopamine; monoamines; norepinephrine; rhesus monkeys; serotonin.

FIGURE 1

Cerebrospinal fluid (CSF) monoamine metabolite concentrations at Baseline, Time 1 and Time 2. Results from repeated measures analyses of variance (ANOVAs) showed statistically significant concentration increases in each of the monoamine metabolites following each of the alcohol infusions (CSF 5-hydroxyindolecetic acid [5-HIAA]: F[1,113] = 68.56, p < 0.0001; CSF 3-methoxy-4-hydroxyphenylglycol [MHPG]: F[1,113] = 169.65, p < 0.0001); CSF homovanillic acid [HVA]: F[1,113] = 88.81, p < 0.0001). Bars indicate standard error bars

FIGURE 2

Relationship of cerebrospinal fluid (CSF) 5-hydroxyindolecetic acid (5-HIAA) concentrations and oral alcohol intake. Controlling for rearing, results from regressions showed statistically significant negative relationships between Baseline CSF 5-HIAA concentrations (β = −0.24, p = 0.02) and T1 CSF 5-HIAA concentrations (β = −0.20, p = 0.04) and later voluntary alcohol intake. Results also showed that there were negative relationships between the change in CSF 5-HIAA concentrations from Baseline to T1 (β = −0.22, p = 0.04) and from Baseline to T2 (β = −0.29, p = 0.003) and subsequent alcohol intake. The relationship between the change from T1 to T2 and subsequent alcohol intake was also significant (β = −0.36, p = 0.005). The relationship between T2 CSF 5-HIAA concentrations and alcohol intake failed to achieve traditional statistical significance (β = 0.17, p = 0.07)

FIGURE 3

Relationship of cerebrospinal fluid (CSF) 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations and oral alcohol intake. Controlling for rearing, results from the regressions showed statistically significant negative relationships between T1 CSF MHPG concentrations (β = −0.33, p = 0.01) and T2 CSF MHPG concentrations (β = −0.32, p = 0.001) and later voluntary alcohol intake. Results also showed that there were positive relationships between the change in CSF MHPG concentrations from Baseline to T1 (β = 0.33, p = 0.001) and from Baseline to T2 (β = 0.32, p = 0.002) and subsequent alcohol intake. The relationship between the change from T1 to T2 and subsequent alcohol intake was also significant (β = −0.20, p = 0.03). The relationship between Baseline CSF MHPG concentrations and alcohol intake was not statistically significant (β = −0.13, p = 0.21)

FIGURE 4

Relationship of cerebrospinal fluid (CSF) homovanillic acid (HVA) concentrations and oral alcohol intake. Controlling for rearing, results from regressions showed statistically significant negative relationships between Baseline CSF HVA concentrations (β = −0.35, p < 0.0001), as well as T1 CSF HVA concentrations (β = −0.24, p = 0.01) and later voluntary alcohol intake. Results also showed negative relationships between the change in CSF HVA concentrations from Baseline to T1 (β = −0.22, p = 0.03) and from Baseline to T2 (β = −0.40, p < 0.001) and subsequent alcohol intake. The relationship between the change from T1 to T2 and subsequent alcohol intake was also significant (β = −0.33, p < 0.001). The relationship between T2 CSF HVA concentrations and alcohol intake was not statistically significant (β = 0.14, p = 0.17)