Abstract
Background: Hypofunction of the NMDA receptor has been suggested as a mechanism underlying cognitive deficits experienced by patients with schizophrenia (SZ). Given that cognitive deficits predict functional outcome in SZ, there is an urgent need to develop procognitive therapeutics for this disease. The present study investigated whether acute putative procognitive cholinergic and dopaminergic drugs would attenuate NMDA receptor antagonist-induced working memory (WM) span deficits in mice.
Methods: Male C57BL/6 mice (n = 15) were trained to stability on a 12-arm radial maze paradigm intended to assess working and reference memory (RM). WM arms (8/12) provided a liquid reinforcer (strawberry milkshake) after the first but not on subsequent entries into an arm during a given session. No reinforcer was delivered for any entry into RM arms (4/12; consistent for each subject across sessions). After reaching stability, mice were tested after administration of combinations of the NMDA antagonist MK-801 (vehicle or 0.3 mg/kg) and nonselective nicotinic agonist nicotine (vehicle, 0.03 or 0.30 mg/kg) in a crossover design. After a 1-week washout period, they were then retested with combinations of MK-801 (vehicle or 0.3 mg/kg) and the dopamine D2-family receptor agonist bromocriptine (vehicle, 3 or 10 mg/kg).
Results: Two-way repeated measures analyses of variance confirmed that in both drug trials, MK-801 produced main effects of reducing WM span and increasing both RM and WM error rate (Ps <.05). Nicotine did not attenuate these deficits with the only MK-801/nicotine interaction revealing increased total arms visited, F(2, 28) = 3.68, P < .05), with 0.3 mg/kg increasing arms visited relative to vehicle (P < .01). In contrast, a bromocriptine/MK-801 interaction was observed on WM error rate, F(2, 28) = 3.68, P < .05, with the high dose of bromocriptine significantly decreasing WM error rate relative to vehicle when coadministered with MK-801 (P < .01). Nicotine did not produce any main effects alone (all Ps > .05); however, bromocripitine significantly slowed latency to collect reward (P < .05).
Conclusion: Acute NMDA antagonist administration disrupted radial arm maze performance though, effects were not selective to working memory. Nicotine did not enhance any aspect of performance but rather exacerbated NMDA antagonist-induced impairments in a nonselective manner. Bromocriptine selectively attenuated MK-801-induced WM impairments. Hence, there may be interactions between dopamine D2-family and NMDA receptors underlying WM span performance.
Funding Sources: Supported by VISN 22 MIRECC, and the National Institute of Mental Health (R01-MH071916)