Role of catecholamines and cyclic AMP systems in phencyclidine and
morphine dependence. Study of mutant mice*
Toshitaka Nabeshima**, Takayoshi Mamiya, and Yukihiro Noda
Department of Neuropsychopharmacology and Hospital
Pharmacy, Nagoya University Graduate School of Medicine, 65, Tsuruma-cho,
Showa-ku, Nagoya 466-8560, Japan
Abstract: To investigate an involvement of catecholamines
and/or the cyclic adenosine monophosphate (cAMP) systems in the development
of drug dependence, we examined whether phencyclidine (PCP) and morphine
dependence were developed in tyrosine hydroxylase (TH) heterozygous
(TH+/-) and cAMP response element binding protein (CREB)
binding protein (CBP) heterozygous (CBP+/-) mice. PCP (8
mg/kg) induced place preference in wild-type mice pretreated with PCP
(10 mg/kg/day for 28 days) and increased the level of cAMP in the striatum,
but not in the thalamus/hypothalamus. In TH+/- and CBP+/-
mice, however, we could not find PCP-induced place preference.
The increased level of cAMP in the striatum was observed in CBP+/-,
but not TH+/- mice. When wild-type mice pretreated with morphine
(10 mg/kg) twice a day for 5 days were challenged with naloxone (5 mg/kg),
they showed increased jumping, rearing, and forepaw tremor counts as
a sign of withdrawal and an increased level of cAMP in the thalamus/hypothalamus,
but not in the striatum. In TH+/- and CBP+/- mice,
however, jumping and forepaw tremor counts were decreased compared to
in wild-type mice. An increase in the level of cAMP in the thalamus/hypothalamus
in CBP+/-, but not in TH+/- mice was observed.
These results suggest that catecholamines and CBP are involved in the
development of PCP and morphine dependence, and that changes in catecholaminergic
and/or cAMP systems induced by repeated PCP and morphine treatments
play an important role in the addiction to PCP and morphine.
*Lectures presented
at the 4th Congress of Toxicology in Developing Countries (4th CTOX-DC),
Antalya, Turkey, 6-10 November 1999
**Corresponding author
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