The aim of this project is to understand inherent differences in serotonin (5-HT) and dopamine (DA) neuronal systems associated with risk for alcoholism. The model to be investigated, the peer-reared rhesus monkey, has significant face validity in terms of clinical correlates of alcoholism: reduced cerobrospinal fluid (CSF) levels of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA), increased consumption of, and tolerance to, ethanol, and increased behavioral impulsivity and aggression. An association of decreased CSF 5-HIAA with impulsivity and high ethanol consumption implicates 5-HT dysfunction, but those functional differences remain unknown. Their impact on ventral striatal DA, also implicated in impulsivity and ethanol reward, are also unknown. The proposed studies will directly examine different aspects of 5-HT and dopaminergic presynaptic function to determine what alterations are associated with reduced CSF 5-HIAA.
The specific aims are: 1) Using in-vivo microdialysis, compare the presynaptic activity of the 5-HT innervation of the forebrain in mother reared vs. peer reared rhesus monkeys. Specific assessments of basal extracellular concentration will be determined using the quantitative no-net-flux method in awake, chaired animals. The functionality of the 5-HT transporter will be assessed in the same studies by determining the in-vivo uptake of 5-HT. 2) Conduct brain imaging of the 5-HT transporter in the forebrain and brainstem of mother reared and peer reared rhesus monkeys. We will employ microPET methods with [11C]DASB, a highly selective 5-HT transporter ligand capable of labeling forebrain sites. The imaging outcome measures will be compared with the functional measures of 5-HT transport determined in the same animals in aim 1.3) Compare the responsiveness of ventral striatal DA and cortical 5-HT to acute ethanol using microdialysis in awake mother reared and peer reared animals. 4) Compare post-mortem whole tissue levels 5-HT, 5-HIAA, the 5-HT transporter, DA (and its metabolites), and monoamine oxidase activity in cingulate cortex and ventral striatum of mother reared and peer reared animals. The values will be compared across individuals with the imaging and microdialysis measures from aims 1, 2 and 3. Unused brain tissue will be banked for future potential uses
|Jedema, Hank P; Carter, Michelle D; Dugan, Brian P et al. (2011) The acute impact of ethanol on cognitive performance in rhesus macaques. Cereb Cortex 21:1783-91|
|Jedema, H P; Gianaros, P J; Greer, P J et al. (2010) Cognitive impact of genetic variation of the serotonin transporter in primates is associated with differences in brain morphology rather than serotonin neurotransmission. Mol Psychiatry 15:512-22, 446|
|Liu, Shijing; Heitz, Richard P; Bradberry, Charles W (2009) A touch screen based Stop Signal Response Task in rhesus monkeys for studying impulsivity associated with chronic cocaine self-administration. J Neurosci Methods 177:67-72|