L 19. Knockout of the Neurokinin 3 receptor enhances cognitive performance and alters behavioral responding to dopaminergic stimulation

Background and aims. The neurokinin 3 (NK sub(3)) receptor is currently under investigation as a target in schizophrenia research, largely because of its influence on dopaminergic transmission. However, investigation of effects of NK sub(3) antagonism in the full profile of behavioral testing has been hindered by species differences between rats, mice and humans. Thus, to explore of the role of the NK sub(3) receptor in animal models designed for mice, we created NK sub(3) receptor knock out mice and tested these animals in schizophrenia-relevant paradigms. Methods. NK sub(3) knock out mice and wild type litter-mates were tested in a neurological assessment battery, models of psychosis (locomotor activity at baseline and response to amphetamine, and prepulse inhibition), and models of cognition (active avoidance, Morris Water Maze and spontaneous alternation). Furthermore, levels of dopamines D sub(1) and D sub(2) receptors as well as the dopamine precursor tyrosine hydroxylase were determined histologically. Results. NK sub(3) knock out mice showed no alteration in physiology or reflexes as tested in a neurological assessment battery, excepting a small but significant decrease in time spent on a rotarod and weight increase in the NK sub(3) knock outs. The knock outs showed hyperlocomotion at baseline and were hyperresponsive to amphetamine when given at an intermediate dose (1 mg/kg) but not at high (3 mg/kg) or low (0.3 mg/kg) doses. There was no genotype effect on prepulse inhibition. The knock out mice acquired both active avoidance and the Morris Water Maze faster than wild types. There was no difference between the genotypes in performance of spontaneous alternation. A small but significant decrease in D sub(1) levels was seen in the dorsal striatum and olfactory tubercle, while no change was seen in D sub(2) or tyrosine hydroxylase levels. Conclusions. The effects observed in the tests for models of psychosis are consistent with the effects of chronic treatment with antipsychotics such as haloperidol and olanzapine. The enhanced cognition observed indicates that the NK sub(3) receptor may have potential to treat cognitive deficits seen in schizophrenics. The small or absent effects on dopamine receptors and tyrosine hydroxlase indicates that NK sub(3)-induced effects may be activity dependent or that other neurotransmitter systems may be at play.