No abstract

Cognitive deficits in schizophrenia, which include impairments in working memory and attention, represent some of the most disabling symptoms of this complex psychiatric condition, and lack effective treatments. NMDA receptor (NMDAr) hypofunction is a strong candidate mechanism underlying schizophrenia pathophysiology, and has been modeled preclinically using acute administration of NMDAr antagonists to rodents to investigate biological mechanisms underpinning cognitive dysfunction. However, whether and how NMDAr hypofunction specifically influences all affected cognitive domains is unclear. Here we studied the effects of the NMDAr antagonist MK-801 (dizocilpine) on tasks of attention and working memory in rats using automated touchscreen chambers. Adult male Wistar rats were trained to perform the trial-unique nonmatching to location (TUNL) task of spatial working memory, or the 5-choice serial reaction time task (5CSRTT) of attention. Once trained, rats received injection of vehicle (saline) or low-dose MK-801 (0.06 mg/kg sc) 10 min prior to commencing test sessions. MK-801 significantly impaired working memory, as evidenced by reduced performance accuracy on the TUNL task (p < .0001), compared with vehicle. However, we found no significant effects on attentional processing or perseveration on the 5CSRTT. Additional measures indicated that MK-801 impaired behavioral flexibility in the TUNL task, and decreased response inhibition in both tasks. Using the automated touchscreen system to measure different cognitive functions under the same testing environment, we demonstrate that spatial working memory, response inhibition, and behavioral flexibility are more vulnerable to NMDAr hypofunction than attentional processing. This may have implications for the NMDAr hypofunction hypothesis of schizophrenia.

Sensory gating deficits have been demonstrated in schizophrenia, but the mechanisms involved remain unclear. In the present study, we used disruption of paired-pulse gating of evoked potentials in rats by the administration of (±)-3,4-methylene-dioxymethamphetamine (MDMA) to study serotonergic and dopaminergic mechanisms involved in auditory sensory gating deficits. Male Sprague-Dawley rats were instrumented with cortical surface electrodes to record evoked potential changes in response to pairs of 85dB tones (S1 and S2), 500msec apart. Administration of MDMA eliminated the normal reduction in the amplitude of S2 compared to S1, representing disruption of auditory sensory gating. Pretreatment of the animals with the dopamine D1 receptor antagonist, SCH23390, the dopamine D2 receptor antagonist, haloperidol, the serotonin (5-HT)1A receptor antagonist, WAY100635, or the 5-HT2A receptor antagonist, ketanserin, all blocked the effect of MDMA, although the drugs differentially affected the individual S1 and S2 amplitudes. These data show involvement of both dopaminergic and serotonergic mechanisms in disruption of auditory sensory gating by MDMA. These and previous results suggest that MDMA targets serotonergic pathways, involving both 5-HT1A and 5-HT2A receptors, leading to dopaminergic activation, involving both D1 and D2 receptors, and ultimately sensory gating deficits. It is speculated that similar interactive mechanisms are affected in schizophrenia.