In the eight year of this project, we continued to focus on developmental aspects of fear in rodent pups. Previously, we studied the role of opiate benzodiazepine, corticotropin-releasing factor and glutamatergic neural systems in the modulation of the rat pup's response to social isolation. In the past year, we expanded on our earlier clinical and pre-clinical studies of serotonergic compounds as anti-obsessional agents to investigate the possibility that serotonin modulates the rat pup's ultrasonic vocalization (USV) emitted with social isolation. In addition, we investigated the effects of oxytocin on this same behavior, in conjunction with our studies of attachment behavior (see Z01 MH00797-06 LCS). The neurotoxin MDMA selectively reduced serotonin innervation in the pup brain and, in a dose-dependent fashion, reduced the rat pup's vocal response to social isolation without affecting locomotor behavior, thermoregulation, or motor coordination. These behavioral consequences of serotonergic terminal destruction may be a result of the elimination of presynaptic 5-HT1b receptors as 5-HT1b agonists increase while 5-HT1a agonists decrease the production of USV. Results with serotonergic compounds are consistent with earlier findings with benzodiazepines demonstrating that clinical anxiolytics decrease and anxiogenics increase the rate of USV. In this regard, the finding that oxytocin (administered centrally) decreases USV raises the possibility that this peptide may also have anxiolytic efficacy in man. While the rat pup USV is neither equivalent nor homologous to clinical anxiety, the multitude of pharmacologic studies in this project have clearly established this as a simple, reliable animal test for screening novel anxiolytics.
