THE NITRIC-OXIDE SYNTHASE INHIBITOR, L-NAME, BLOCKS CERTAIN PHENCYCLIDINE-INDUCED BUT NOT AMPHETAMINE-INDUCED EFFECTS ON BEHAVIOR AND BRAINBIOCHEMISTRY IN THE RAT

1. The present experiments examined the effects of the nitric oxide sy nthase (NOS) inhibitor, N-G-nitro-L-arginine methyl ester (L-NAME), on some behavioural and biochemical effects of phencyclidine (PCP) and d -amphetamine (AMPH) in rats. Observation of behaviour was performed us ing a subjective scoring system.2. PCP (4 mg/kg) increased locomotor a ctivity, rearing, sniffing, grooming and stereotyped behaviour, and de creased stillness. PCP also increased forepaw myoclonus, forepaw tread ing, head weaving, licking and chewing behaviour. Most of these behavi ours were significantly suppressed by pretreatment with L-NAME (10 mg/ kg). 3. AMPH (1 mg/kg) exerted different effects on behaviour. It incr eased locomotor activity, rearing, sniffing, and stereotyped behaviour , and decreased stillness and grooming, but failed to affect the other behavioural items observed. Pretreatment with L-NAME did not countera ct these effects. 4. Ex vivo biochemical analysis indicated that PCP i ncreased the tissue concentration of the dopamine (DA) metabolites, di hydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA), in the ventral striatum(i.e., the nucleus accumbens and olfactory tubercles) and frontal cortex but not in the dorsal striatum. DA was not signific antly affected in any of these regions. Furthermore, PCP increased the tissue concentration of the serotonin (5-HT) metabolite, 5-hydroxyind ole acetic acid (5-HIAA), in a similar manner, while 5-HT was not affe cted. These biochemical effects were significantly counteracted by pre treatment with L-NAME. 5. AMPH decreased tissue DOPAC concentration in the dorsal striatum, an effect which was not sensitive to pretreatmen t with L-NAME. However, the combined treatment with L-NAME and AMPH in creased tissue DA concentration in all three regions investigated. 6. The neurochemical and behavioural effects of PCP and AMPH were further investigated in an experimental model which allowed measurement of pr epulse inhibition (PPI) of acoustic startle in parallel with in vivo m icrodialysis sampling of extracellular DA concentration in the brain o f awake, freely moving animals. 7. Both PCP (2 mg/kg) and AMPH (2 mg/k g) caused a significant decrease in PPI of similar magnitude and durat ion. These behavioural effects were accompanied by a significant incre ase in extracellular DA concentration in the nucleus accumbens (PCP: 2 13 +/- 21% of basal concentration; AMPH: 563 +/- 117%). 8. The decreas e in PPI caused by PCP was blocked by pretreatment with L-NAME, but th e change in DA concentration was not. Neither of these measures were s ignificantly affected by L-NAME in AMPH-treated rats. 9. In conclusion , this study shows that several behavioural and biochemical effects of PCP are prevented by pretreatment with the NOS inhibitor, L-NAME, whi le the effects of AMPH are less sensitive to this pretreatment. These observations emphasise the involvement of nitric oxide in the pharmaco logical effects of PCP.