Nonhuman primates offer unique opportunities to study the effects of genes, environments, and their interaction, on physiology and complex behavior. We examined genotype and early environment ...contributions to CNS function in a large sample of rhesus monkeys. In humans, length variation of the serotonin (5-HT) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) that results in allelic variation in 5-HTT expression is associated with decreased serotonergic function and 5-HT-mediated psychopathology. We report that an analogous variation of the gene's regulatory region in monkeys interacts with early experience to affect central 5-HT functioning. Monkeys with deleterious early rearing experiences were differentiated by genotype in cerebrospinal fluid concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid, while monkeys reared normally were not. These findings demonstrate an environment-dependent effect of the rh5-HTTLPR genotype on CNS 5-HT function and suggest nonhuman primates may provide an important avenue for investigating gene/environment interactions using candidate genes for physiological and behavioral traits.
We have used nonhuman primates to examine developmental and behavioral correlates of CNS serotonergic activity, as measured by concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid ...(5-HIAA) in the cerebrospinal fluid (CSF). These studies show that interindividual differences in CNS serotonin turnover rate exhibit traitlike qualities and are stable across time and settings, with interindividual differences in CSF 5-HIAA concentrations showing positive correlations across repeated sampling. Primates with low CNS serotonergic activity exhibit behaviors indicative of impaired impulse control, unrestrained aggression, social isolation, and low social dominance. Maternal and paternal genetic influences play major roles in producing low CNS serotonin functioning, beginning early in life. These genetic influences on serotonin functioning are further influenced by early rearing experiences, particularly parental deprivation.
A human serotonin (5-HT)(2C) receptor gene polymorphism leads to the substitution of cysteine for serine at codon 23 (Cys23Ser); the frequency of the Ser23 allele in unrelated Caucasians is ...approximately 0.13. In the present study, we assessed whether Cys23Ser could affect receptor function. The two alleles were functionally compared following expression in COS-7 cells. The constitutive activity of the receptor in an in situ reconstitution system was also evaluated following expression of each allele in Sf9 cells. Using radioligands, Ser23-expressed membranes showed reduced high-affinity binding to meta-chlorophenylpiperazine (m-CPP) and 5-HT. Although the amplitude of the 5-HT-induced intracellular Ca(2+) peak did not differ between the alleles, Ser23 required higher 5-HT concentrations to elicit the same response. These differences might be due to more extensive desensitization in the Ser23 form. In the in situ reconstitution system, the 5-HT(2C) receptor displayed considerable constitutive activity, with the Ser23 allele being significantly higher in this regard than the Cys23 form. After prolonged serum deprivation in order to resensitize the receptor, four of the 15 cells expressing Ser23 showed abnormally higher m-CPP-induced sensitivity of the Ca(2+) response. These results indicate that the Ser23 allele may be constitutively more active than Cys23. Thus, Ser23 appears to be an abundant candidate allele capable of directly influencing inter-individual variation in behavior, susceptibility to mental disorder, and response to drugs including atypical antipsychotic and some antidepressant drugs that are potent 5-HT(2C) inverse agonists or antagonists.
: Brain serotonin synthesis and metabolism (turnover), as indicated by CSF concentrations of 5‐hydroxyindoleacetic acid (5‐HIAA), may depend on plasma concentrations of the essential amino acid ...L‐tryptophan (TRP). We investigated the biochemical effects of acute plasma TRP depletion (ATD) in normal volunteers undergoing a 36‐h CSF collection via lumbar drain. Six subjects who were in good health were put on a low‐TRP diet (160 mg/day) 24 h before lumbar puncture; this diet was continued for the first 22 h of the CSF collection. At hour 22, subjects ingested a TRP‐deficient 15‐amino acid drink shown previously to deplete plasma TRP. Total plasma TRP, free plasma TRP, and CSF TRP subsequently decreased 86.3, 86.5, and 92.3%, respectively. CSF 5‐HIAA decreased by 32.8%. Plasma total and free TRP concentrations were both decreased at ∼2 h following ingestion of the TRP‐free amino acid drink and were lowest ∼6 h after ATD; CSF TRP and 5‐HIAA were decreased at 2.5 h and ∼4 h after ATD, respectively. CSF TRP was lowest 8.0 h later. CSF 5‐HIAA continued to decrease 14 h after the TRP‐deficient amino acid drink was given.
The mu opioid receptor is implicated in the reward, tolerance and withdrawal effects of alcohol and other drugs of abuse. This hypothesis is supported by the effects of alcohol on beta-endorphin ...release, of mu opioid receptor agonists and antagonists on alcohol consumption, and by the activation of the dopaminergic reward system by both alcohol and opiates. In addition, the murine mu opioid receptor locus, Oprm, is implicated as the major quantitative trait locus (QTL) affecting the different levels of morphine consumption between two inbred mouse strains that also exhibit differences in alcohol and cocaine consumption. Detection of genetic variation affecting OPRM1 expression or mu opioid receptor function would be an important step towards understanding the origins of inter-individual variation in response to mu opioid receptor ligands and in diseases of substance dependence. We directly sequenced the human mu opioid receptor locus, OPRM1, to detect natural variation that might affect function and/or be associated with psychiatric phenotypes related to opioid function. Four DNA sequence variants were found: three non-synonymous substitutions (Ala6Val rare, Asn40Asp, 0.10-0.16, Ser147Cys rare) and one intronic variant (IVS2+691G/C 0.55-0.63). OPRM1 alleles, genotypes and haplotypes from three psychiatrically characterized population samples (US Caucasian USC, n=100, Finnish Caucasian FC, n=324 and Southwestern American Indian SAI, n=367), were used to perform association and sib-pair linkage analyses with alcohol and drug dependence diagnoses. No significant association of OPRM1 genetic variation to phenotype was observed. This analysis has 80% power to detect a small to moderate effect of OPRM1 variation on alcohol dependence and 100% power to detect effects of the magnitude of the ALDH2*2 variant. While these data do not support a role of the mu opioid receptor in susceptibility to alcohol dependence, the potential relationship between OPRM1 genetic variation and response to endogenous opioids and exogenous opiates can now be investigated.
Ebstein and colleagues have recently reported a significant association between the 7-repeat allele of the dopamine D4 receptor (D4DR) 16 amino acid repeat polymorphism and the personality trait of ...Novelty Seeking (NS) in 124 Israeli subjects. This study, and another study conducted in the US (although with a different personality measure) that observed a similar association, have generated wide interest in the identification of the genes involved in personality variation. We have determined D4DR genotypes in two groups of Finnish subjects; 193 psychiatrically screened normal controls and 138 alcoholic offenders and assessed NS with the Tridimensional Personality Questionnaire (TPQ). In normals, we find no significant association between NS and the 7-repeat allele despite similar allele frequencies and the use of the same personality measure as Ebstein et al. The group of alcoholic offenders have significantly higher NS than normals, however we fail to replicate the previous association in this group and, in fact, find a significant association in the opposite direction as previously observed. These data suggest that D4DR may require re-evaluation as a candidate gene for personality variation.
Voluntary ethanol (EtOH) consumption is increased by isolation-rearing in several rat strains. The following experiments examined the effects of isolation-rearing on basal and ethanol-stimulated ...behavior in Fawn Hooded rats, an alcohol-preferring rat strain, compared to Wistar rats. Locomotor activity and anxiety were examined under both conditions. Basal locomotor activity was higher in isolated subjects of both strains in low light conditions, but under bright light conditions, this difference was only observed in Wistar rats. Locomotor stimulant effects of EtOH were only observed in isolation-reared rats. In the elevated plus maze, Fawn Hooded rats were more anxious than Wistar rats under low light conditions, but under bright light conditions, Wistar socials were less anxious than all of the other groups. Administration of 1.5 mg/kg EtOH produced an anxiolytic response in the elevated plus maze under bright light conditions in Fawn Hooded rats, but to a lesser degree Wistar rats, particularly Wistar isolates. In conclusion, although both strain and isolation-rearing had effects on locomotion and anxiety as well as the stimulatory and anxiolytic effects of EtOH, these effects appeared to be independent.
These experiments examined the hypothesis that isolation-rearing and strain influence hedonic mechanisms. In experiment 1, voluntary consumption of ethanol and water was monitored in the home cage of ...Fawn Hooded (FH) and Wistar rats. FH rats were found to consume more ethanol at low concentrations than Wistar rats, independent of rearing condition, and isolation-reared rats were found to consume more of high ethanol concentrations, independent of strain. In experiment 2, isolation-reared rats were found to consume more sucrose, independent of concentration, than socially reared rats. In experiment 3, Fawn Hooded rats were found to be more sensitive to low concentration solutions of saccharin, and to consume less of the high concentration solutions, while isolation-rearing was found to enhance consumption of high concentrations. Thus, hedonic processes are independently modulated by strain and rearing conditions, although the effects of isolation-rearing appear to be exacerbated in Fawn Hooded rats.
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