Models Of CNS Functioning: Alcohol Consumption, Impaired

Alcohol Abuse And Alcoholism

Investigators

Linked publications & trials

Abstract

Impulsivity and Alcohol One of the most replicated findings in psychiatry and other research areas is that impaired or low CNS serotonin results in impaired impulse control. Impulsivity and low CNS serotonin is thought to be the basis of Type 2 alcoholism. A standardized test of impulsivity has been developed to quantify impulsiveness in nonhuman primates. This test, known as the intruder challenge, was developed by Lynn Fairbanks and essentially assesses approaches to and interactions with potentially dangerous strangers by individual monkeys. Our results showed that consistent with humans, young animals and adolescents were the most impulsive when using this measure. Interestingly when the parentally-deprived peer-reared (PR) monkeys were compared to the MR monkeys, the PR exhibited the greatest degree of impulsivity, a with levels of impulsivity identical in both males and females. Parentally-deprived surrogate-reared monkeys (SPR), subjects reared in the nursery who, however, have more limited social experience and contact with age-mates than the PR monkeys, exhibited a complex and interesting pattern. For the SPR males, but not the SPR females, levels of impulsivity were similar to the PR monkeys; the females, on the other hand were similar to the MR monkeys in their level of impulsivity. In a preliminary analysis of the data, reduced latency to approach and spontaneous close interactions with the intruder were correlated with high alcohol intake. Further studies of other temperamental styles that are related to excessive alcohol intake using factor analysis enabled us to assess their relationship to different monoamine systems. These analyses indicated that norepinephrine activity, as measured by CSF MHPG concentrations was related to a factor involving activity levels and overall sociality. Dopamine turnover, as measured by CSF HVA was also correlated with the day-to-day activity and sociality factor. Aggressive behavior was correlated with CSF 5-HIAA and MHPG concentrations. Irritability, as measured by stereotypic pacing and ritualized behaviors was correlated with CSF 5HIAA and HVA concentrations. Age at First Exposure to Alcohol Among humans, an early age at first exposure to alcohol is an important risk factor for future alcohol problems. In a study by Dr. Swandt, age at first exposure was examined as a variable affecting alcohol intake in 192 nonhuman primates, varying from 30 months of age (2-Year-Olds) to fully mature young adult 5-year-olds. Subjects were allowed to freely consume alcohol for one hour each day 5-days a week. With cohort and exposure type controlled, two-year-olds consumed significantly more alcohol than the other older age groups. Such data show that early exposure to alcohol is a risk variable for high alcohol intake in nonhuman primates as well as humans. New Psychopharmacology Initiatives In a study by our laboratory that was published in Psychopharmacology, the selective serotonin reuptake inhibitor (SSRI) sertraline (SERT) was shown to decrease alcohol intake in nonhuman primates that engage in high but not modest alcohol consumption. SERT also reduced their rates of aggression. Both effects occurred only after chronic treatment and resulted in decreased CSF 5-HIAA concentrations. SSRIs are known to have a primary site of action at the serotonin transporter. However, it is not clear to what extent serotonin reuptake is inhibited within the primate CNS and whether these effects of SSRIs vary according to the duration of treatment. In what is to our knowledge the first study to simultaneously measure both CSF 5-HIAA concentrations and serotonin during treatment, in a collaboration with George Anderson at Yale, cisternal CSF serotonin and 5-HIAA were measured following SERT administration. Levels of CSF serotonin were significantly increased (290+69%) three hours after the first dose (Day 0). Similar increases in CSF serotonin levels of 436+68%, 260+30%, 407+71%, 340+40% and 360+120%, were seen at Day +3, +7, +14, +21, and +28, respectively. Levels of CSF serotonin returned to baseline levels 7 days after discontinuation (Day 35). CSF levels of the serotonin metabolite 5-HIAA declined to 50% of baseline by Day +3 and remained at similarly reduced levels during the 4-week treatment period. The results indicate that SSRIs in clinically-relevant doses act quickly to increase extracellular fluid serotonin levels, the increase is substantial (approx. 3-fold), the extent of increase is relatively constant during prolonged administration, and values return to baseline levels shortly after discontinuation of active agent. The data suggest that the 2-3 week latency in response reported for SSRIs in depression and in our study of monkeys treated for excessive alcohol intake may not be due to gradually increasing extracellular fluid serotonin levels, and that changes in primate extracellular fluid serotonin levels during SSRI administration are fully reversible.