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Disrupted‐in‐Schizophrenia 1 (DISC1) is a susceptibility gene for several psychiatric illnesses. To study the pathogenesis of these disorders, we generated Disc1 mutant mice by introducing the 129S6/SvEv 25‐bp deletion Disc1 variants into the C57BL/6J strain. In this study, we used heterozygous Disc1 mutant (Het) mice to evaluate the DISC1 haploinsufficiency model of schizophrenia. No changes in locomotor behaviors were observed in Het mice; however, after amphetamine injection, greater locomotor activity was observed in Het mice compared with wild‐type (WT) mice. Moreover, amphetamine‐induced elevations of c‐Fos expression and dopamine level in the striatum were greater in Het mice than in WT controls, suggesting an altered dopaminergic regulation in the striatum of Het mice. Compared with those in WTs, the striatal protein levels of dopamine transporter and D2 dopamine receptor were increased in Het mice, while D1 dopamine receptor level was decreased. DISC1 interacting proteins, GSK3α and GSK3β, were downregulated in Het mice, whereas the levels of PDE4B and CREB were not altered. Morphologically, the complexities of striatal median spiny neurons (MSNs), parvalbumin‐positive interneurons and Iba1‐positive microglia were all decreased in Het mice. The density and head diameter of dendritic spines in the MSNs of Het mice were also reduced. Our results indicate that mice lacking one WT Disc1 allele are more sensitive to psychostimulant amphetamine challenge, which might be attributed to the altered structure and function of the striatal dopaminergic system. Here, we demonstrated striatal phenotypes in heterozygous Disc1 mutant mice, which could be a promising model of DISC1 haploinsufficiency.

The combined abuse of recreational drugs such as ketamine (Ket) and amphetamine (Amph) should be seriously considered important social and health issues. Numerous studies have documented the behavioral and neurochemical changes associated with polydrug administration; however, most studies have only examined the acute effects. The consequences following chronic repetitive polydrug use are less studied. In the present study, intraperitoneal injections of saline, Amph (5 mg/kg), low dose Ket (LK, 10 mg/kg), high dose Ket (HK, 50 mg/kg), or Amph plus LK or HK (ALK or AHK) were conducted twice a day for three consecutive days, and one final treatment was administered on day 4. After seven total treatments, animal behaviors, including locomotion, stereotypy and ataxia, were examined in a novel open field. The expression of GAD67 and dopamine (DA) levels were assessed in the striatum and motor-related cortices using immunohistochemistry and high-performance liquid chromatography. Drug-induced hyperactivities and Amph-mediated potentiation of Ket-triggered ataxia manifested after repeated drug treatments. A significant increase in the number of GAD67-positive puncta in the striatum and motor-related cortices was observed, suggesting a neural adaptive change in the GABAergic system. Four hours after the final treatment, while the behavioral hyperactivities had ceased, considerable changes were still evident in the motor-related cortices, suggesting modulation to the DAergic system. Together, our results show the interactive effects of these two drugs in behavioral and neurochemical aspects and neural adaptive changes in the GABAergic and DAergic systems.

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