Models Of CNS Serotonin Functioning: Alcohol Consumption

Alcohol Abuse And Alcoholism

Investigators

Linked publications & trials

Abstract

During the past year, our research included studies that investigated neurobiology and behaviors that are correlated with Type-1 and 2-like excessive alcohol consumption. Development of Type 2-like Behaviors: Our previous studies have shown that nonhuman primates with low serotonin functioning, as measured by low cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentrations, exhibit behaviors that are characteristic of humans with Type 2 alcoholism, such as excessive aggression and unprovoked violence, and incompetent social behavior. Little is known, however, about the development of these deficits in subjects with low CSF 5-HIAA concentrations or the effect of early rearing environments on the development of serotonin-related psychopathology and excessive alcohol consumption. Biochemical Correlates of Developing Type 2 Alcoholism: Dr. Christina Barr found that low CSF 5-HIAA concentrations in infancy, before aggression ever occurs, and high rates of irritability are risk factors for high rates of aggression later in life. High rates of rough-tumble-social play early in life may reduce the probability of aggression later in life; on the other hand, high rates of aggressive social play later in childhood are correlated with high rates of aggression later in life, probably because aggressive play in adolescence sometimes escalates into true aggression in impulsive subjects. Our findings also show that overall sociability and rates of complex social behaviors are positively correlated with CSF 5-HIAA concentrations beginning early in life. Early parental absence, which decreases serotonin functioning, was shown to produce and prolong high rates of infant-like, immature social behaviors, which may result in long-term social deficits and possibly later high rates of aggression. Finally measures of irritable temperament, such as stereotypic pacing, begins early in life and is correlated with low CSF 5-HIAA concentrations. Such results show that low serotonin turnover early in life is a predictive risk factor for excessive aggression, irritable temperament, and high rates of incompetent social functioning. These studies also produced evidence that peer interactions, particularly aggressive play early in life, may function to socialize aggression teaching the developing primate the appropriate use of aggression. As a follow-up of this research, we collaborated with researchers in NIMH, collecting data over three years from 98 infant monkeys to investigate the relationship between monoamine functioning and behavior. Regression analyses indicated relationships between activity levels, sociality, and norepinephrine activity, as measured by CSF MHPG concentrations obtained during baseline and acute separation stress. Dopamine turnover, as measured by CSF HVA obtained during acute separation stress was also correlated with day-to-day activity levels and sociality. Aggressivity was correlated with CSF 5-HIAA and MHPG concentrations. Irritability, as measured by stereotypic pacing and ritualized behaviors was correlated with 5HIAA and HVA concentrations obtained during acute and chronic separation stress. Social Dominance: Alcoholics often show less competent social behavior. In monkeys, one measure of social competence is social dominance ranking. One criticism of our research has centered around the methodology used to study social dominance interactions. Because the frequency of such interactions is limited, one of the methods we have used to increase the rates of dominance competitions is to elicit competition by presenting prized treats as a limited resource. To test whether this produces the same dominance hierarchy as that collected spontaneously, we gathered data from a group of animals during both unprovoked, spontaneous competitions and during elicited social dominance competitions. Data showed that the dominance rank for an individual monkey was essentially identical using either method. Genotypic Variation: During the past year, in a collaboration with Drs. Maribeth Champoux and Steve Suomi, we summarized data obtained over 5 years, from 322 infant macaques, assessing the contribution of genetic and environmental variables on scores obtained during a standardized neonatal examination. Assessments were conducted on postnatal days 14 and 30. Test items were condensed into Orientation, Motor Maturity, Activity, and State Control clusters. Heritability effects were found for State Control and Orientation clusters on Days 14 and 30, and for the Activity cluster on Day 14 only, but not for Motor Maturity. It therefore appears that temperament characteristics reflecting attention and affective intensity are subject to heritable influences in nonhuman primates. To investigate whether genotypic differences in the 5-HTT might contribute to genetic differences in the neonatal assessment of temperament and CNS development, a second study assessed the relationship between genotypic differences in the 5-HTT and the neonatal scales. Findings showed that the 5-HTT genotype, and in some cases the interaction of rearing condition and genotype, were important contributors to infant orienting, attention, and temperament. In general, animals possessing the short allele demonstrated diminished orientation, lower attentional capabilities, and increased affective responding, relative to l/l homozygotes. We investigated whether these early neonatal assessment measures might predict future risk for alcohol consumption. Orientation behaviors and motor maturity scores assessed on Day 14 were highly predictive of later alcohol consumption when the subjects grew to adolescence. Animals with the lowest orientation and attention scores in infancy consumed the most alcohol as young adults. Lower motor maturity scores were also predictive of higher amounts of alcohol consumption. These findings are important because they suggest that to the extent that the monkey data generalize to humans, early behavioral deficits may be predictive of adolescent and young adult alcohol consumption. Corticotrophin Releasing Hormone (CRH): Given our discovery that the strongest predictor of alcohol consumption is plasma cortisol, we continued our studies investigating CRH. In a collaboration with Drs. Phil Gold and Kamal Habib, we found that as in rodents, the selective nonpeptide CRH (type1) antagonist, antalarmin, crossed into the brain, paving the way for studies this year to investigate the role of CRH in alcohol consumption and the potential to treat excessive alcohol intake with antalarmin. Recent studies have shown a role for leptin in the risk for excessive alcohol consumption. In a second study with Drs. Gold and Ayla in NIMH, we investigated the relationship between leptin and the CRH response. To study this association, we sought to investigate the metabolic effects of antalarmin on leptin. Plasma leptin levels were lower during antalarmin administration as compared to placebo administration. Leptin levels during the washout (no drug) period returned to baseline levels. Lower leptin levels cannot be explained by differences in either food consumption or weight gain, as daily behavioral observations revealed no significant differences in feeding patterns and all subjects gained developmentally-expected weight during the study. No significant differences in serum glucose, electrolytes and lipid profile between the groups were observed. This study suggests that pharmacological inhibition of CRH, a potent anorexic substance, with a selective antagonist results in decreases of serum leptin, a peripheral satiety signal to the brain. This observation confirms the existence of a bi-directional loop between CRH and the leptin system.