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Behavioral effects of prenatal ketamine exposure in rhesus macaques are dependent on MAOA genotype.

ABSTRACT: Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that is used in anesthetic, abuse, and therapeutic contexts. Recent evidence suggests that ketamine may affect not only glutamate systems, but may also act on receptors in the dopamine and serotonin systems. Because monoamine neurotransmitters play important trophic roles in prenatal development, we hypothesized that the behavioral consequences of prenatal exposure to ketamine may be moderated by genotype of the promoter in the monoamine oxidase-A (MAOA) gene. Eighty-two infant rhesus monkeys were identified that had known dates of conception and exposures to ketamine during gestation. Animals were tested at 3-4 months of age on a battery of tests assessing responsiveness to maternal separation, recognition memory, and contact with novel objects. Animals were classified by putative activity levels for the MAOA genotype. The effects of prenatal ketamine exposure were seen only in the context of MAOA genotype. Greater exposure to ketamine resulted in increased activity, less willingness to perform in the memory task, and reduced emotionality and novel-object contact, but only for individuals with the low-activity genotype. Nearly all effects of ketamine were the result of first- and second-trimester exposure. MAOA genotype moderates the role of prenatal ketamine exposure at time points in gestation earlier than have been shown in past research, and is particularly evident for measures of emotionality. These results support the idea that ketamine's use might be best considered in light of individuals' genetic characteristics.

SUBMITTER: Capitanio JP

PROVIDER: S-EPMC3481859 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Behavioral effects of prenatal ketamine exposure in rhesus macaques are dependent on MAOA genotype.

Capitanio John P JP Del Rosso Laura A LA Calonder Laura A LA Blozis Shelley A SA Penedo M Cecilia T MC

Experimental and clinical psychopharmacology 20120116 3

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that is used in anesthetic, abuse, and therapeutic contexts. Recent evidence suggests that ketamine may affect not only glutamate systems, but may also act on receptors in the dopamine and serotonin systems. Because monoamine neurotransmitters play important trophic roles in prenatal development, we hypothesized that the behavioral consequences of prenatal exposure to ketamine may be moderated by genotype of the promoter in the monoa ...[more]

PMID: 22250657

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Project description:Temperament is a construct whose manifestations are quantifiable from an early age, and whose origins have been proposed as "biological." Our goal was to determine whether maternal rank and infant genotype are associated with five measures of temperament in 3- to 4-month old rhesus monkeys (Macaca mulatta), all of whom were born and reared by their mothers in large, outdoor, half-acre cages. Maternal rank was defined as the proportion of animals outranked by each female, and the two genes of interest to us were monoamine oxidase and serotonin transporter, both of which are polymorphic in their promoter regions (MAOA-LPR and 5-HTTLPR, respectively), with one allele of each gene considered a "plasticity" allele, conferring increased sensitivity to environmental events. Our large sample size (n = 2014-3140) enabled us to examine the effects of individual genotypes rather than combining genotypes as is often done. Rank was positively associated with Confident temperament, but only for animals with the 5-repeat allele for MAOA-LPR. Rank had no other effect on temperament. In contrast, genotype had many different effects, with 5-HTTLPR associated with behavioral inhibition, and MAOA-LPR associated with ratings-based measures of temperament. We also examined the joint effect of the two genotypes and found some evidence for a dose-response: animals with the plasticity alleles for both genes were more likely to be behaviorally inhibited. Our results suggest phenotypic differences between animals possessing alleles for MAOA-LPR that show functional equivalence based on in vitro tests, and our data for 5-HTTLPR revealed differences between short/short homozygotes and long/short heterozygotes, strongly suggesting that combining genotypes for statistical analysis should be avoided if possible. Our analysis also provides evidence of sex differences in temperament, and, to our knowledge, the only evidence of differences in temperament based on specific pathogen-free status. We suggest several directions for future research.

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Behavioral effects of prenatal ketamine exposure in rhesus macaques are dependent on MAOA genotype.

Publications

Behavioral effects of prenatal ketamine exposure in rhesus macaques are dependent on MAOA genotype.

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