Y. Noda et al., ROLE OF NITRIC-OXIDE IN THE DEVELOPMENT OF TOLERANCE AND SENSITIZATION TO BEHAVIORAL-EFFECTS OF PHENCYCLIDINE IN MICE, British Journal of Pharmacology, 117(7), 1996, pp. 1579-1585
1 To determine whether nitric oxide (NO) was involved in tolerance and
sensitization to the effects of phencyclidine (PCP), we examined NO s
ynthase activity and the number of NADPH-diaphorase (NADPH-d)-positive
cells in discrete brain regions of saline-, acute PCP- and repeated P
CP-treated mice. We also investigated the effects of a NO synthase inh
ibitor, N-G-nitro-L-arginine methyl ester (L-NAME), on the behavioural
changes induced by repeated PCP treatment in mice. 2 Acute PCP (1, 3,
and 10 mg kg(-1), s.c.) treatment induced dose-dependent hyperlocomot
ion, motor incoordination and stereotyped behaviours, consisting of sn
iffing, head movement and ataxia in mice. 3 In mice treated repeatedly
with PCP (1, 3, and 10 mg kg(-1) day(-1)), s.c., once a dal for 14 da
ys), the sniffing, head movement. ataxia and motor incoordination indu
ced by PCP were attenuated (indicating the development of tolerance to
these behaviours), whereas the hyperlocomotion induced by PCP was pot
entiated (indicating the development of sensitization to hyperlocomoti
on). The development of tolerance and sensitization to PCP-induced beh
aviours in the repeated PCP-treated mice was more marked at the dose o
f 10 mg kg(-1) day(-1)) than at other doses. 4 NO synthase activity in
the cerebral cortex and cerebellum, but not in the striatum and hippo
campus, was significantly decreased by acute PCP (10 mg kg(-1)) treatm
ent in comparison with saline treatment, and such changes in activity
in the cerebral cortex and cerebellum were reversed by repeated PCP tr
eatment (10 mg kg(-1) day(-1)). 5 The number of neurones containing NA
DPH-d reactivity in the cerebral cortex, nucleus accumbens, and striat
um of acute and repealed PCP-treated mice showed no change in comparis
on with saline treated mice. 6 Tolerance to PCP (10 mg kg(-1) day(-1))
-induced ataxia and motor incoordination was significantly attenuated
by combined treatment with L-NAME (50 mg kg(-1) day(-1) i.p.). 7 Sensi
tization to PCP-induced hyperlocomotion was further enhanced by combin
ed treatment with L-NAME (50 mg kg(-1) day(-1)). However, N-G-nitro-D-
arginine methyl ester (D-NAME. 50 mg kg(-1) day(-1), i.p.), a less act
ive enantiomer of L-NAME, had no effect, suggesting a stereospecific m
echanism. 8 The PCP-induced behaviours in animals that had exhibited t
olerance and sensitization to PCP (10 mg kg(-1) day(-1)) were not infl
uenced by acute L-NAME (5 and 50 mg kg(-1), i.p.) or D-NAME (50 mg kg(
-1), i.p.) treatment. 9 These results suggest that NO may play an impo
rtant role in the development, but nor in the maintenance, of toleranc
e and sensitization to the effects of PCP in mice.