Distinct contributions of glutamate and dopamine receptors to temporal aspects of rodent working memory using a clinically relevant task

Rationale: Understanding the mechanistic basis of working memory, the capac ity to hold representation "on line," is important for delineating the proc esses involved in higher cognitive functions and the pathophysiology of tho ught disorders. Objectives: We compared the contribution of glutamate and d opamine receptor subtypes to temporal aspects of working memory using a mod ified rodent spatial working memory task that incorporates important elemen ts of clinical working memory tasks. Methods: A discrete paired-trial varia ble-delay T-maze task was used. Initial characterization studies indicated that performance on this task is stable at seconds-long retention intervals , is sensitive to retention interval and proactive interference, and is dep endent on the integrity of the medial prefrontal cortex. Results: Consisten t with clinical findings, low dose amphetamine (0.25 mg/kg) produced a dela y-dependent improvement in performance, while higher doses impaired perform ance at all retention intervals. D1 receptor blockade produced the predicte d dose- and delay-dependent impairment. D2 receptor blockade had no effect. Activation of metabotropic glutamate 2/3 (mGluR2/3) receptors, which in th e prefrontal cortex inhibits the slow asynchronous phase of glutamate relea se, also produced a delay-dependent impairment. Low doses of an AMPA/kainat e antagonist had effects similar to the mGluR2/3 agonist. In contrast, NMDA receptor antagonist-induced impairment was memory load-insensitive, result ing in chance-level performance at all retention intervals. Conclusions: Th ese findings suggest that activation of NMDA receptors is necessary for the formation of mnemonic encoding while modulatory components involving slow asynchronous release of glutamate and phasic release of dopamine contribute to the active maintenance of information during the delay period.