Protein kinase C interacting protein/histidine triad nucleotide binding protein 1 (PKCI/HINT1) is a member of the histidine triad protein family. Although this protein is widely expressed in the mammalian brain including mesocorticolimbic and mesostriatal regions, its physiological function in CNS remains unknown. Recent microarray studies reported decreased mRNA expression of PKCI/HINT1 in the frontal cortex of individuals with schizophrenia, suggesting the possible involvement of this protein in the pathophysiology of the disease. In view of the documented link between dopamine (DA) transmission and schizophrenia, the present study used behavioral and neurochemical approaches to examine the influence of constitutive PKCI/HINT1 deletion upon: (i) basal and amphetamine (AMPH)-evoked locomotor activity; (ii) DA dynamics in the dorsal striatum, and (iii) postsynaptic DA receptor function. PKCI/HINT1(-/-) (KO) mice displayed lower spontaneous locomotion relative to wild-type (WT) controls. Acute AMPH administration significantly increased locomotor activity in WT mice; nonetheless, the effect was enhanced in KO mice. Quantitative microdialysis studies revealed no alteration in basal DA dynamics in the striatum or nucleus accumbens of KO mice. The ability of acute AMPH to increase DA levels was unaltered indicating that function in presynaptic DA neurotransmission in these regions do not underlie the behavioral phenotype of KO mice. In contrast to WT mice, systemic administration of the direct-acting DA receptor agonist apomorphine (10 mg/kg) significantly increased locomotor activity in KO mice suggesting that postsynaptic DA function is altered in these animals. These results demonstrate an important role of PKCI/HINT1 in modulating the behavioral response to AMPH. Furthermore, they indicate that the absence of this protein may be associated with dysregulation of postsynaptic DA transmission.