A performance-dependent adjustment of the retention interval in a delayed non-matching-to-position paradigm differentiates effects of amnestic drugs in rats

Operant delayed non-matching-to-position (delayed non-matching-to-position) tasks have been widely used as tests of working memory in rats, but have suffered some loss in sensitivity to differentiating selective mnemonic from non-mnemonic deficits due to floor and ceiling effects. To circumvent this problem, a novel delayed non-matching-to-position was developed in which the retention interval was adjusted on a trial-by-trial basis to hold performance accuracy at an intermediate value. The present study assessed the effects of three amnestic drugs in this delayed non-matching-to-position. Rats were administered (i.p.) NMDA receptor antagonist ((5R,10S)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d,] cyclohepten-5,10-imine (Dizocilpine or MK-801), muscarinic receptor antagonist (-)-scopolamine hydrobromide (scopolamine), or cannabinoid receptor agonist ((R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone) (WIN 55, 212-2). At high doses, both MK-801 (0.12-0.25 mg/kg) and scopolamine (0.25 mg/kg) produced deficits not selective to working memory. At low doses, scopolamine (0.06-0.12 mg/kg) and MK-801 (0.06 mg/kg) produced no deficits in any mnemonic or secondary measures. WIN 55, 212-2 produced deficits at 2.0 mg/kg that were consistent with a specific impairment of working memory. Using this particular delayed non-matching-to-position revealed that consistent changes in performance accuracy at the short retention interval were evident for scopolamine and MK-801, at times in the absence of changes in response tendency, which are consistent with an interpretation that these drugs produce general deficits in reference or procedural memory. In contrast, cannabinoid-induced deficits in choice accuracy support previous reports of delay-dependent deficits. Together, these data suggest that this delayed non-matching-to-position task is able to differentiate deficit patterns of amnestic drugs, and isolate the effects of motivational side effects of drugs from working memory measurement. (C) 2000 Elsevier Science B.V. All rights reserved.