IMPAIRED CNS SEROTONIN ACTIVITY: TOLERANCE, NEUROIMAGING, AND NEUROANATOMY

Alcohol Abuse And Alcoholism

Investigators

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Abstract

During the past year, our research has continued its investigation of central nervous system (CNS) serotonin correlates of low cerebrospinal fluid (CSF) 5-HIAA and tolerance to the intoxicating effects of alcohol.1. To evaluate a new measure of intoxication and to further investigate the relationship between CNS serotonin activity and behavioral tolerance to ethanol, CSF concentrations of 5-HIAA and behavior ratings were obtained from three cohorts of alcohol-naive adolescent rhesus macaque monkeys (N=60, 23 males, 37 females). Subjects were reared in one of three conditions: peer-only-, surrogate peer-, or mother-reared. One month after baseline CSF samples were obtained, subjects were given an IV bolus of 2.1 grams/kg (males) or 2.0 grams/kg (females) ethanol, placed into a clear Plexiglas box suspended from the ceiling in an enclosure, and the latency to escape was recorded. Animals were also rated for degree of intoxication and frequency of aggressive behaviors during a 35 minute observation period. Results showed that following the administration of ethanol, the latency to escape from the box was positively correlated with subjective ratings for intoxication. Baseline CSF 5-HIAA concentrations were also positively correlated with escape latency and another measure of intoxication, the number of times that subjects fell. CSF 5-HIAA was also positively correlated with blood alcohol concentration 5 and10 minutes after the beginning of the infusion. This study shows that in alcohol naive monkeys, objective measures of intoxication are positively correlated with a subjective rating for intoxication, and the degree of intoxication following a standardized alcohol dosage is correlated with CNS serotonin functioning. Our data confirm and extend the finding that low CSF 5-HIAA is predictive of increased intrinsic tolerance to the intoxicating effects of ethanol. These data also suggest that low central serotonin turnover may expedite the metabolism of ethanol in non-human primates.2. In a second series of studies, we analyzed the effect of alcohol on CNS functioning, and the relationship between this effect and future alcohol consumption. Results showed that relative to baseline, concentrations of plasma cortisol and ACTH, and CSF MHPG, HVA, and 5-HIAA (the major metabolites of norepinephrine, dopamine, and serotonin, respectively) were increased by the I.V. alcohol infusion. Baseline 5-HIAA, MHPG, HVA, ACTH, and cortisol, as well as I.V. alcohol-induced MHPG, HVA, and ACTH all predicted future voluntary alcohol consumption. MHPG, HVA, 5-HIAA, ACTH, and cortisol concentrations were highly correlated across baseline and I.V. alcohol conditions, showing that individual differences in neurotransmitter levels were stable and trait-like, and that baseline CSF 5-HIAA concentrations are predictive of monoamine and HPA functioning following alcohol consumption. These findings suggest that alcohol has strong effects on CNS neurotransmission and hormonal functioning and that this response may be important in predicting and possibly mediating alcohol consumption.3. CSF 5-HIAA has been our principle measurement of CNS serotonin functioning. This measurement has been criticized as lacking specificity. To assess the etiology of low CSF 5-HIAA concentrations, we initiated studies using classic neuroanatomical techniques, as well as nuclear medicine studies to assess neuroanatomical correlates of low CSF 5-HIAA concentrations. A collaboration with Drs. Stanley Watson and Juan Lopez at the University of Michigan to quantify neuroanatomical differences in serotonin receptors and mRNA, and glucocorticoid receptors in monkeys with low or high CSF 5-HIAA concentrations was important in this regard. Fourteen monkeys were investigated. NMDA receptor in situ hybridization in prefrontal cortex and hippocampus was performed to assess 5-HT1a, and 5-HT2a receptor mRNA. Analyses were also made to assess NR1, 2a, 2b, 2c, and 2d mRNA as well as binding sites for glutamate, glycine, polymainbes, and pcp/mk801. Dopamine receptor (D1-D5) mRNA were assessed in same regions. Glucocorticoid receptor mRNA and mineralocorticoid receptor mRNA were also assessed. Our initial results show large differences in the distribution of some of these molecules between rat and monkeys, with the distribution of these molecules in monkeys resembling the distribution in humans more than rodents.4. While neuroanatomical studies were being performed, we also initiated studies using PET, SPECT and NMRI technology to longitudinally assess differences in monkeys with low and high CSF 5-HIAA concentrations. PET studies were initiated to investigate corticotrophin releasing hormone differences in subjects with low and high CSF 5-HIAA concentrations. SPECT studies continued to investigate the role of differential serotonin receptors in subjects with low and high CSF 5-HIAA concentrations. PET scans of monkeys with low and high CSF 5-HIAA showed that when using a [C-11] alpha-methyl-L- tryptophan ligand, tryptophan uptake into the brain could be measured, but it bore no relationship to serotonin synthesis. NMRI studies were initiated to investigate the role that early experiences play in normative CNS development.