Nitric oxide synthase inhibition impairs spatial navigation learning and induces conditioned taste aversion.

The free radical gas nitric oxide (NO) is formed from the amino acid precursor L-arginine in brain regions which are associated with learning and the formation of memory. We have previously reported that administration of the nitric oxide synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-Name) impairs delayed recall in non-human primates but that, at higher doses, impairment is associated with aversive gastrointestinal side effects. The purpose of the present study was to examine the effects of L-Name on learning in a rat spatial navigation task and to assess the ability of L-Name to induce a conditioned taste aversion (CTA) to a novel sucrose solution in a two-bottle choice paradigm. In the Morris water maze. L-Name (5, 20, and 50 mg/kg) markedly impaired cued spatial learning required to locate a hidden platform on three consecutive days of testing, but did not affect general activity levels. These data also demonstrated the ability of L-Name to induce a potent CTA, though only with the 20 and 50 mg/kg doses. Both the impairment of learning and CTA were blocked by administration of a mole equivalent dose of L-arginine, indicating that attenuated NO activity was associated with both behavioral effects. These data demonstrate that inhibition of NO activity by L-Name induces significant and selective impairment of cognitive performance at low pharmacologic doses (< 20 mg/kg). However, with higher doses of NOS inhibitors, impairment may be a secondary effect of drug-induced malaise, possibly related to peristaltic dysregulation of gastrointestinal musculature. Therefore, conclusions as to the mediation of learning and memory processes by CNS NO may be difficult to interpret without the use of selective, centrally-acting compounds.