Tic disorders produce substantial morbidity, but their pathophysiology remains 
poorly understood. Convergent evidence suggests that dysregulation of the 
cortico-basal ganglia circuitry is central to the pathogenesis of tics. Tourette 
syndrome (TS), the most severe end of the continuum of tic disorders, is 
substantially genetic, but causative mutations have been elusive. We recently 
described a mouse model, the histidine decarboxylase (Hdc) knockout mouse, that 
recapitulates a rare, highly penetrant mutation found in a single family; these 
mice exhibit TS-like phenomenology. These animals have a global deficit in brain 
histamine and a consequent dysregulation of DA in the basal ganglia. Histamine 
modulation of DA effects is increasingly appreciated, but the mechanisms 
underlying this modulation remain unclear; the consequences of modest DA 
elevation in the context of profound HA deficiency are difficult to predict, but 
understanding them in the Hdc knockout mouse may provide generalizable insights 
into the pathophysiology of TS. Here we characterized signaling pathways in 
striatal cells in this model system, at baseline and after amphetamine 
challenge. In vivo microdialysis confirms elevated DA in Hdc-KO mice. We find 
dephosphorylation of Akt and its target GSK3β and activation of the MAPK 
signaling cascade and its target rpS6; these are characteristic of the effects 
of DA on D2- and D1-expressing striatal neurons, respectively. Strikingly, there 
is no alteration in mTOR signaling, which can be regulated by DA in both cell 
types. These cellular effects help elucidate striatal signaling abnormalities in 
a uniquely validated mouse model of TS and move towards the identification of 
new potential therapeutic targets for tic disorders.