| Summary: | 碩士 === 台北醫學院 === 醫學研究所 === 86 === Part 1 :abstract : Long-term neuropsychological abnormality has been documen
ted in child born to morphine addicted mothers, but the mechanism of this phen
omenon until now is not clear. Our previous ligand binding study has shown tha
t combined prenatal and postnatal chronic treatment of morphine could alter th
e ontogenic expression of the NMDA receptor. In that, the density of NMDA rece
ptor of rats born to dam rats received morphine treatment were significantly l
ess than the control rats on postnatal day 14 (PND 14) . It suggested that rat
s born to chronic morphine addicted dam rats could induce the neuronal NMDA re
ceptor downregulation. To further explore what kinds of NMDA receptor subuni
ts are changed, we used western blotting to examine the expression of the NMDA
receptor subunits, namely, (NR1A, NR2A, NR2B) proteins in the brain of rats b
orn to morphine-treated dam rats. In cortex we found that the NR1A of morphine
rats was decreased by 40 % on PND 14 as compare to that of control group. On
the contrary, the NR2A of morphine rats on PND7 was increased 2.8 folds as com
pared to that of control rats. But the NR2B of morphine rats was not different
to that of control rats. In hippocampus, the NR1A and NR2B of morphine rats w
ere not different to that of control rats. However, the NR2A of morphine rats
was decreased by 34 % as compared to that of control rats. These results are i
n consistent with our previous ligand binding assay, suggest that rats born to
chronic morphine addicted dam rats induce cerebral NMDA receptor subunits dow
nregulation, in the cortex that is NR1A and in the hippocampus that is NR2A. P
art 2:abstract: Addition to the psychstimulant drugs, such as amphetamine (A
MPH), is one of the important social and public health problems in Taiwan. Rep
eated administration of amphetamine frequently develop a drug-induced paranoid
psychosis, and the this phenomenon usually dissipates upon the cessation of d
rug use. But there are some long-term sequel associated with amphetamine abuse
, such as, re-exposure to a relatively low dose of amphetamine will often prec
ipitate a psychotic episode in former amphetamine addicts who have been abstin
ent for months to years. The mechanism of amphetamine produces hypersensitivit
y is not clear, however, it may be associated with the change of cerebral exci
tability. Previous investigations of the mechanism by AMPH induced addiction a
nd long-term neurotoxicity is mainly focusing on dopaminergic neuron, however,
recent evidenced have indicated that the N-methyl-D-aspartate receptor (NMDA
receptor), one of the subtype receptor of glutamate receptors, which antagonis
ts significantly attenuated AMPH-induced behavioral sensitization, glutamate r
elease. To explore the amphetamine induced long-term neurotoxicity, we studi
ed the effect of chronic treatment of amphetamine in kainic acid (KA) elicited
seizure activity. Male Sprague-Dawley rats were received daily i.p. injection
of 5 mg/kg amphetamine for 14 days. The animals were received a single dose o
f kainic acid (12 mg/kg) s.c. injection 1, 14 and 28 days after the last injec
tion of amphetamine. We observed the behavior change during the first 3h after
. Control rats were received daily injection of normal-saline before injection
of kainic acid. Furthermore, we used western-blotting to quantify the density
of each NMDA receptor subunits, namely, the NR1A, NR2A, NR2B in the crude mem
brane of cortex and hippocampus tissues prepared from rats received single dos
e of KA after they had received 14 day injection of AMPH (AMPH group) or salin
e (control) group. The results of kainic acid-induced seizure showed that i
n control group rats, the wet-dog shake frequency was significant lower at 1 a
nd 28 days than that of 14 days after the last injection of normal-saline. In
amphetamine-treated group, the wet-dog shake frequency was significant higher
than control group at 1 and 28 days after the last injection of amphetamine. T
he latency of wet-dog shakes onset was later than control group about 31.5 % a
t 14 days after the last injection of amphetamine. The percentage of rats had
motor clonus of amphetamine group is significant higher than that of control g
roup rats at 1 day after the last injection of amphetamine. The results of wes
tern boltting showed a significant decrease in the density of NR1A in the cort
ex of AMPH group one day after last injection of AMPH. However, no significant
difference in the expression of this subunit in other time points or hippocam
pus between control and AMPH group. Furthermore, there is no significant chang
e in the expression of NR2A and NR2B of AMPH group. These results suggested
that chronic administration of amphetamine lead to a transiently enhancing th
e kainic acid-induced neuroexcitation, and demonstrated that chronic treatment
of AMPH with single injection of KA may produce a transient down-regulation o
f one NMDA receptor subunit. This receptor plasticity may be a consequence of
chronic treatment of AMPH which result into an enhanced KA-induced neurotoxici
ty.
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