These results should rekindle interest in the study of how brain hyposerotonemia can contribute to ASDs. It is certainly not the case that individuals with ASDs have a total lack of brain 5HT, but the consequences of a dysfunction in 5HT neurochemistry during critical periods of CNS development could be revealed in the complex, heterogeneous behavioral phenotype of this disorder. A large body of evidence has accumulated in support of an extremely important role for 5HT in the development of the brain. For instance, 5HT signaling is thought to direct such diverse processes as neurogenesis, synaptogenesis, corticogenesis, neuronal migration and maturation, and axonal network formation. The expression patterns of selected 5HT receptors during development overlap with receptors involved in axonal guidance and 5HT signaling determines the specific trajectory of thalamocortical pathways via its influence on axonal responses to the axon guidance molecule netrin-1. The developing forebrain may also depend on an exogenous source of 5HT. At early stages of brain development prior to the time when 5HT is supplied to the forebrain endogenously by emerging projections from the 5HT neurons of the dorsal raphe, 5HT can be supplied by the placenta. The fact that an extraneous source of 5HT can influence the developing fetal brain serves as further testament to the importance of this monoamine in neurodevelopment and establishes the possibility that disruptions in 5HT function at the level of the placenta or within the CNS can have enduring behavioral consequences. It is also well established that maternal 5HT is essential for murine morphogenesis and embryonic development. Thus, while ASDs are being viewed increasingly as disorders of the synapse or misconnection syndromes resulting from altered gene expression, the possibility remains that early disruptions in 5HT function during critical CNS development periods could alter brain wiring resulting in persistent effects on postnatal behaviors. For these reasons, the TPH22/2 mouse model constitutes a valuable Cinoxacin resource for investigating how brain network formation and synaptic gene expression are influenced by a lack of endogenous 5HT during development, particularly as it relates to ASDs. Mice treated with these low doses of nicotine also buried fewer marbles compared to when they were treated with Chlorhexidine hydrochloride saline in an ethological marble burying task, and previous studies show that similarly low doses of nicotine decrease anxiety-like behavior as measured by increases in open arm activity in an elevated plus maze. These divergent behavior-stimulating and behavior-inhibiting measures indicate that these observations were not due to nonselective effects of DHbE or nicotine on activity. Neither effective doses of nicotine nor DHbE showed any change in beam break activity during a locomotor task. Together these findings suggest that low dose nicotine and DHbE attenuate negative affective and anxiety-like behavior. This is in contrast to the current studies which show that systemic administration of DHbE promotes lever pressing maintained by saccharin during presentation of a stressful cue. The current studies also showed that subthreshold doses for nicotine conditioned place preference, but not a reward-like dose, were capable of increasing suppression ratios during the CER operant task. The non-selective nAChR antagonist mecamylamine has been shown to have anxiolytic efficacy in the elevated plus maze, social interaction and marble burying tasks. Low dose nicotine had similar effects as DHbE to decrease negative affective behavior.