Examples of progress made during the prior year are summarized below. 1) We investigated the effects of selective serotonin reuptake inhibitors (SSRIs) on the developing primate brain (Shrestha et al, submitted-a). Our study explored whether long-term, prepubertal fluoxetine treatment had effects on the serotonergic system that were discernible in adulthood;whether these effects varied based on rearing conditions (i.e. whether the monkeys were maternally separated or normally reared);and whether fluoxetine induced any long-lasting behavioral changes into adulthood. The study examined the long-term effects of fluoxetine administered to juvenile rhesus monkeys who, as young adults, were imaged with PET for two serotonergic markers: serotonin transporter (SERT) and serotonin 1A (5-HT1A) receptor. An equal number of monkeys separated from their mothers at birthan animal model of human childhood stresswere also studied. At birth, 32 male rhesus monkeys were randomly assigned to either maternal separation or normal rearing conditions. At age two, half (N = 8) of each group was randomly assigned to fluoxetine (3 mg/kg) or placebo for one year. To eliminate the confounding effects of residual drug in the brain, monkeys were scanned at least 1.5 years after drug washout. Social interactions both during and after drug administration were also assessed. We found that fluoxetine persistently upregulated SERT, but not 5-HT1A receptors, in both neocortex and hippocampus. Whole-brain, voxel-wise analysis found that fluoxetine had a statistically significant effect in lateral temporal and cingulate cortices. In contrast, neither maternal separation by itself nor rearing-by-drug interaction was statistically significant for either markers. Fluoxetine decreased dominance and increased submissive displays into adulthood in both rearing groups. The results suggest that fluoxetine administered to juvenile monkeys upregulates SERT and decreases dominance-like behaviors into young adulthood. Thus, the study showed that in nonhuman primates, administering antidepressants during development had persistent effects into adulthood. While no implications regarding the efficacy or potential adverse effects of SSRIs in humans can be drawn from this study, it is the first study in nonhuman primates to demonstrate that an antidepressant administered during development has long-lasting effects in primate brain. 2) We examined the functional properties and selectivity of the PET radioligand 11CCUMI-101, a putative agonist radioligand for the 5-HT1A receptor in rat brain, both in vitro and in vivo (Shrestha et al, submitted-b). CUMI-101 was previously suggested as a putative agonist radioligand for the 5-HT1A receptor in rat brain. However, a recent study showed that it behaved as a potent 5-HT1A receptor antagonist. CUMI-101 also has moderate affinity (KD = 6.75 nM) for alpha1A (1A) receptors measured in vitro. In this study, the functional assay was performed using 35SGTPS in primate brains. CUMI-101s cross-reactivity with 1A receptors was performed using in vitro radioligand binding studies in rat, monkey, and human brain, as well as in vivo PET imaging in mouse, rat, and monkey brain. We found that CUMI-101 did not stimulate 35SGTPS binding in primate brain, in contrast to 8-OH-DPAT, a potent 5-HT1A receptor agonist. Instead, CUMI-101 behaved as a potent 5-HT1A receptor antagonist by dose-dependently inhibiting 8-OH-DPAT-stimulated 35SGTPS binding. Both in vitro and in vivo studies showed that CUMI-101 had significant 1A receptor cross-reactivity. On average, across all three species examined, cross-reactivity was highest in thalamus (>45%), and lowest in neocortex and cerebellum (<10%). PET imaging further confirmed that only pre-blocking with WAY-100635 plus prazosin decreased 11CCUMI-101 brain uptake to that of self-block. Taken together, the data suggest that CUMI-101 behaves as a 5-HT1A receptor antagonist in primate brain with significant, regional-dependent 1A receptor crossreactivity, which limits its potential use as a PET radioligand in humans. Cited References S. Shrestha, E.E. Nelson, J-S. Liow, R. Gladding, C.H. Lyoo, P.L. Noble, C. Morse, I.D. Henter, J. Kruger, B. Zhang, S.J. Suomi, P. Svenningsson, V.W. Pike, J.T. Winslow, E. Leibenluft, D.S. Pine, and R.B. Innis. Fluoxetine administered to juvenile monkeys: effects on the serotonin transporter and behavior. Am. J Psychiatry, submitted-a. S. Shrestha, J-S. Liow, S. Lu, K. Jenko, R.L. Gladding, P. Svenningsson, C.L. Morse, S.S. Zoghbi, V.W. Pike, and R.B. Innis. 11CCUMI-101, a positron emission tomographic radioligand, behaves as a serotonin 1A receptor antagonist and also binds to alpha1A receptors in brain. J. Nucl. Med., submitted-b.
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