Long-term, chronic consumption patterns in socially living macaques: Our laboratory's development of an automated apparatus to dispense fluid and quantify the chronic intake of individual subjects living in large social groups has enabled us to measure alcohol intake in concert with day-to-day stressful events. Substantial variability emerged in day-to-day group averages, but interindividually subjects showed substantial stability. Even in subjects which drink alcohol at high rates, there were days when alcohol consumption did not occur at all. Examination of events surrounding the days when the subjects drank alcohol at high and low levels showed that stressful events in the nearby cage or within the group decreased levels of alcohol consumption. These data are consistent with several comprehensive reviews, which show that home cage alcohol consumption is decreased under stress when a potential danger is present, and that stress only increases alcohol when there is no chance that danger is imminent or when a coping response is not required. MAO as a Marker for Excessive Alcohol Intake and Type 2 Alcoholism: In a collaboration with Drs. Lars Oreland and Claudia Faulke in Sweden, we investigated the relationship between platelet monoamine oxidase (MAO) activity and excessive alcohol consumption in nonhuman primates. We found that as in humans, nonhuman primates with low platelet MAO consume alcohol to excess, have low CSF 5-HIAA concentrations, and are less competent socially, as measured by low social dominance rank. These findings lend further support to the appropriateness of the nonhuman primate to model biochemical and behavioral features of Type 2 alcoholism, and show that the relationship between low MAO activity and alcoholism is not simply an artefact of smoking. Effects of Essential Fatty Acid Diet on Alcohol Consumption: Our collaboration with Drs. Salem and Hibbeln in the LMBB to investigate the role of essential fatty acids in CNS serotonin functioning has continued. Subjects that were fed a diet high in essential fatty acids as infants were shown as adolescents to be less likely to consume alcohol, suggesting long-lasting effects of diets rich in essential fatty acids. These results are preliminary, on a small number of subjects, and will be followed up with investigations of a second cohort this year. Neuroimaging: In a collaboration with Drs. Doris Doudet and Trevor Wheler, we studied the effects of 434 mg of CRF given intracerebroventricularly (ICV) over 40 min in group and individually housed monkeys to examine the role of elevated levels of central CRF on behavior. CRF elicited a wide range of behaviors, which fell into three broad categories: anxiety-like, depressive-like and externally-oriented. Externally-oriented behaviors decreased, and anxiety-like behavior increased regardless of how the animals were housed. Interestingly, increased depressive-like behavior was only observed when the animals were socially housed. In a separate experiment, we examined the effects of the same dose of CRF on the regional cerebral glucose metabolism of lightly anesthetized monkeys using positron emission tomography and [18F]fluorodeoxyglucose. CRF infusion increased glucose metabolism in the pituitary/infundibulum, the amygdala and hippocampus. The fact that ICV CRF elicits signs of depression in socially housed animals and changes activity in limbic brain regions may help explain the behavioral and metabolic alterations seen in humans with affective disorders. In a study with Andreas Heinz, we analyzed data obtained previously using SPECT to measure serotonin transporter availability in rhesus monkeys with low and high CNS serotonin turnover. These same subjects had recently been characterized for alcohol preferences. In a linear multiple regression analysis, the amount of alcohol intake was associated with sero tonin transporter availability. Specifically, higher transporter expression in the raphe nucleus region (10) was associated with greater alcohol intake in a free access paradigm. No significant correlations between b-CIT binding in any other region of interest outside of the raphe nucleus region and behavioral data or CSF 5-HIAA concentrations were found. In a separate collaboration with Carlo Contoreggis in NIDA, we analyzed data collected previously that assessed the relationship between the HPA axis and serotonin using PET. A two-week administration of the CRH-1 antagonist, antalarmin, significantly reduced 5-HT2A binding potential in selected regions of male macaque monkey brains, as measured by [11C]MDL 100907. Areas showing significant decreases in 5-HT2A receptors after chronic antalarmin administration included right medial temporal lobe, thalamus, and right and left striatum. There were non-significant trends towards reduced 5-HT2A binding in the left anterior temporal lobe, right lateral prefrontal cortex and left medial prefrontal. The regions of the brain with significant decreases in 5HT2A receptors are those that have been reported to have high densities of CRH-1 receptors in non-human primates (Sanchez et al., 1999). These regions in the macaque parallel those areas that are functionally abnormal in persons with depression (Galynker et al., 1998; Soares and Mann, 1997), but show normalization of blood flow or glucose metabolic function following successful treatment of depressive symptoms (Martin et al., 2001; Brody et al., 2001a; Brody et al., 2001b), suggesting the potential utility of the macaque as a model to treat depression and antalarmin as a potential treatment. Neurophysiology: One of the primary drawbacks of CSF 5-HIAA as our principal measure of central serotonin functioning is that a metabolite is an estimate and not a direct measure of central serotonin activity. The measurement of cisternal CSF 5-HT levels in the monkey might offer a more direct method of assessing the effects of agents and actions on central 5-HT functioning in the primate brain. In a collaboration with George Anderson at Yale, cisternal CSF 5-HT was for the first time accurately measured in the CSF. This was accomplished by a simple modification of the cisternal puncture technique, and controlling for blood contamination. Good longitudinal stability (variances of 16 and 20%) of CSF 5-HT was demonstrated in two monkeys sampled over a 3-month period. A two-fold increase in CSF 5-HT was seen in seven animals treated with the SSRI. In contrast, levels of 5-HIAA decreased during treatment. Cisternal CSF 5-HT appears to provide a useful index of central 5-HT release. Moreover, initial results tend to support a role for increased extracellular 5-HT in the mechanism of action of chronically administered SSRIs.
Showing the most recent 10 out of 17 publications
