MDMA or 'ecstasy' (3,4-methylenedioxymethamphetamine) is a commonly used psychoactive drug that has unusual and distinctive behavioral effects in both humans and animals. In rodents, MDMA administration produces a unique locomotor activity pattern, with high activity characterized by smooth locomotor paths and perseverative thigmotaxis. Although considerable evidence supports a major role for serotonin release in MDMA-induced locomotor activity, dopamine (DA) receptor antagonists have recently been shown to attenuate these effects. Here, we tested the hypothesis that DA D 1 , D 2 , and D 3 receptors contribute to MDMA-induced alterations in locomotor activity and motor patterns. DA D 1 , D 2 , or D 3 receptor knockout (KO) and wild-type (WT) mice received vehicle or ( + /À)-MDMA and were tested for 60 min in the behavioral pattern monitor (BPM). D 1 KO mice exhibited significant increases in MDMA-induced hyperactivity in the late testing phase as well as an overall increase in straight path movements. In contrast, D 2 KO mice exhibited reductions in MDMA-induced hyperactivity in the late testing phase, and exhibited significantly less sensitivity to MDMA-induced perseverative thigmotaxis. At baseline, D 2 KO mice also exhibited reduced activity and more circumscribed movements compared to WT mice. Female D 3 KO mice showed a slight reduction in MDMA-induced hyperactivity. These results confirm differential modulatory roles for D 1 and D 2 and perhaps D 3 receptors in MDMA-induced hyperactivity. More specifically, D 1 receptor activation appears to modify the type of activity (linear vs circumscribed), whereas D 2 receptor activation appears to contribute to the repetitive circling behavior produced by MDMA.

The α7-nicotinic acetylcholine receptor (nAChR) has long been a procognitive therapeutic target to treat schizophrenia. Evidence on the role of this receptor in cognition has been lacking, however, in part due to the limited availability of suitable ligands. The behavior of α7-nAChR knockout (KO) mice has been examined previously, but cognitive assessments using tests with cross-species translatability have been limited to date. Here, we assessed the cognitive performance of α7-nAChR KO and wild-type (WT) littermate mice in the attentional set-shifting task of executive functioning, the radial arm maze test of spatial working memory span capacity and the novel object recognition test of short-term memory. The reward motivation of these mutants was assessed using the progressive ratio breakpoint test. In addition, we assessed the exploratory behavior and sensorimotor gating using the behavioral pattern monitor and prepulse inhibition, respectively. α7-nAChR KO mice exhibited normal set-shifting, but impaired procedural learning (rule acquisition) in multiple paradigms. Spatial span capacity, short-term memory, motivation for food, exploration and sensorimotor gating were all comparable to WT littermates. The data presented here support the notion that this receptor is important for such procedural learning, when patterns in the environment become clear and a rule is learned. In combination with the impaired attention observed previously in these mice, this finding suggests that agonist treatments should be examined in clinical studies of attention and procedural learning, perhaps in combination with cognitive behavioral therapy.

It has been well established that schizophrenia patients display impaired NMDA receptor (NMDAR) functions as well as exacerbation of symptoms in response to NMDAR antagonists. Abnormal NMDAR signaling presumably contributes to cognitive deficits which substantially contribute to functional disability in schizophrenia. Establishing a mouse genetic model will help investigate molecular mechanisms of hypoglutmatergic neurotransmission in schizophrenia. Here, we examined the responses of Sp4 hypomorphic mice to NMDAR antagonists in electroencephalography and various behavioral paradigms. Sp4 hypomorphic mice, previously reported to have reduced NMDAR1 expression and LTP deficit in hippocampal CA1, displayed increased sensitivity and prolonged responses to NMDAR antagonists. Molecular studies demonstrated reduced expression of glutamic acid decarboxylase 67 (GAD67) in both cortex and hippocampus, consistent with abnormal gamma oscillations in Sp4 hypomorphic mice. On the other hand, human SP4 gene was reported to be deleted in schizophrenia. Several human genetic studies suggested the association of SP4 gene with schizophrenia and other psychiatric disorders. Therefore, elucidation of the Sp4 molecular pathway in Sp4 hypomorphic mice may provide novel insights to our understanding of abnormal NMDAR signaling in schizophrenia.

Corticotropin-releasing factor (CRF), a neuropeptide released during stress, has been reported to modulate startle behavior, including reducing the threshold for acoustic startle responding and reducing prepulse inhibition (PPI). The central mechanisms mediating CRF system regulation of startle and PPI are still unclear. Some antipsychotic drugs attenuate CRF-induced deficits in PPI in rats and mice. Here we tested the hypothesis that indirect activation of DA 1 -receptors (D 1 ) and DA 2 -receptors (D 2 ) contributes to the effects of CRF on PPI. We compared the effect of central administration of h/r-CRF (0.2-0.6 nmol) on PPI in mice with either a D 1 or D 2 receptor null mutation (knockout, KO) or in mice pretreated with D 1 or D 2 receptor antagonists SCH23390 (1 mg/kg) or haloperidol (1 mg/kg). D 1 and D 2 KO mice exhibited no significant differences in their sensitivity to CRF-induced disruptions of PPI. Similarly, neither SCH23390 nor haloperidol pretreatment altered the CRF-induced disruption in PPI, although both increased PPI at baseline. CRF-induced increases in startle also remained unchanged by any of the DA receptor manipulations. These results indicate that neither D 1 -nor D 2 -receptor activation is necessary for CRF to exert its effects on acoustic startle and PPI in mice.