The dopamine, glutamate, and acetylcholine systems in the brain are all affected in mice lacking Fmr1. Dopamine in particular is important for the initiation and reinforcement of motivated behaviors. Mice lacking Fmr1 have increased dopamine turnover but decreased amphetaminestimulated dopamine release in the dorsal striatum, which correlates with decreased sensitivity to amphetamine-induced motor stereotypies; as well as increased dopamine release in the prefrontal cortex. The postsynaptic effects of dopamine D1 receptor activity on AMPA-type glutamate receptor function are also reduced in both prefrontal cortex and striatum. There are relatively fewer behavioral or neurochemical studies on limbic motor system function in Fmr1-null mice than in hippocampus or neocortex. Given the critical involvement of limbic circuitry in motivation and reinforcement, changes in social integrative behavior and motor learning in FXS may be affected by underlying deficits in limbic brain reward circuitry as well as in cortex involved in memory and higher cognitive functions. Although two studies have shown normal acquisition of operant behavior using sucrose or food reinforcement in Fmr1-null mice, the neural mechanisms underlying motivation and reward have not been explored in depth in this model. Imaging studies have identified alterations in both morphology and activation patterns in the 3,4,5-Trimethoxyphenylacetic acid striatum of FXS patients, but the function of dopaminergic projections from the midbrain substantia nigra pars compacta and ventral tegmental area to their forebrain targets in the dorsal striatum and nucleus accumbens have been less extensively investigated than cortical circuits in Fmr1-null mice. Drugs that directly affect the dopamine system, including atypical neuroleptics such as aripiprazole, are of interest for the management of affective and behavioral symptoms in FXS. Cholinergic mechanisms in mesolimbic and nigrostriatal motor function, in which interactions with the dopamine system shape striatal output, are largely unexplored in this model. The goal of the current study was to characterize limbic motor circuitry with behavioral and neurochemical methods in Fmr1-null mice. Intracranial self-stimulation is an operant behavior in which animals perform a task for reinforcement by electrical brain stimulation reward. The predictable effects on BSR of drugs acting through dopamine, glutamate, or acetylcholine receptors can be compared between genotypes, and we have previously used this approach to investigate pharmacological mechanisms in other monogenic neurodevelopmental disorders. We hypothesize that Fmr1-null mice will show increased sensitivity to drugs that enhance the rewarding value of BSR and, conversely, decreased sensitivity to the reward-devaluing effects 
of drugs that diminish BSR. Experiments measuring the effects of the atypical neuroleptic aripiprazole, the mGluR5 antagonist MPEP, and the preferential M1 antagonist trihexyphenidyl on locomotor behavior were also performed to further differentiate drug effects on global motor function from effects specific to operant behavior. To LOUREIRIN-B determine if absence of Fmr1 alters dopaminergic neurons originating in the SNc and VTA, tyrosine hydroxylase immunoreactivity was also quantified by design-based stereology in midbrain histological sections and by western blot in tissue homogenates from dorsal striatum and NAc. We also measured the numbers of neurons expressing tyrosine hydroxylase, the rate-limiting enzyme, in the midbrain, and measured TH expression in forebrain targets of projections from those neurons. Our data suggest that absence of Fmr1 does not affect intrinsic sensitivity of mesolimbic circuits to brain stimulation reward, which we have previously shown to be increased in mice lacking the maternal allele of ubiquitin ligase, a model for Angelman syndrome.