| pA2
online © Copyright 2003 The British Pharmacological Society |
045P
University
of Manchester Autumn Meeting September 2003 |
|
Amphetamine-induced
elevation of thalamic/hypothalamic tryptophan concentrations
|
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We have
used a genetically manipulated mouse strain to un-ravel the role of the
alpha-2A-adrenoceptor subtype. Mice lacking this receptor (
2A-ko)
do not show the normal responses when challenged with non-subtype specific
agonists (dexmedetomidine, DEX) or antagonists (atipamezole, ATI). We
observed a role for the 2A-receptor
in modulating the actions of amphetamine (AMPH). We now describe other
effects of AMPH on brain neurochemistry in 2A-ko
mice.
Male
2-ko mice were used
(n=52). An equivalent number of age and sex-matched C57BI/6J mice were
used as wild type (wt) controls. The mice in each strain were divided
into six groups; 1= saline; 2 = DEX 3 µg/kg, s.c.; 3 = ATI 1 mg/kg
s.c.; 4 = AMPH 10 mg/kg i.p.; 5= DEX 3 µg/kg + AMPH 10 mg/kg; 6=
ATI 1 mg/kg +AMPH 10 mg/kg. Where only one drug was given, the mice were
given saline at the same time as those receiving a second active drug.
Fifty min after the first injection and forty min after AMPH, the rectal
temperature of the mice was measured, then thalamus/hypothalamus dissected
and assayed for tryptophan (TRP) by HPLC-EC. Statistical analysis was
ANOVA followed by Dunnett's test against the strain control with P<0.05
statistically significant.
AMPH
caused a major elevation in the thalamic/hypothalamic TRP concentration
in both strains, but the AMPH-induced increase was much greater in the
2A-ko mice (table
1). In the wt mice, the AMPH-induced increase was reduced by DEX;ATI had
no significant effect. In 2A-ko
mice, neither DEX nor ATI was able to modify the AMPH-induced elevation.
There
was a tendency for AMPH to elevate the rectal temperature in wt type,
DEX reduced this effect, but this did not reach statistical significance.
In the 2A-ko mice,
AMPH caused an elevation in temperature; neither DEX nor ATI could prevent
this effect.
Table
1:Thalamic/hypothalamic tryptophan concentrations and rectal temperature
after drug administration in 2A-ko
mice.
|
Thalamic/hypothalamic
TRP (nmol/g ) |
Rectal
temperature( oC)
|
|||
| Drug (n) |
wt
|
2A-ko |
wt
|
2A-ko |
| Control (10) |
20.8
±1.3
|
17.7
±0.7
|
38.9
±0.2
|
38.7
±0.1
|
| DEX (8) |
19.6
±1.3
|
16.7
±1.2
|
38.6
±0.1
|
38.8 ±0.2
|
| ATI (8) |
19.9
±1.6
|
19.7
±1.8
|
38.2
±0.3
|
39.1
±0.1
|
| AMPH (10) |
27.0
±1.9*
|
33.5 ±3.8**
|
39.1
±0.2 *
|
39.7
±0.3
|
| AMPH+DEX (8) |
23.7
±1.6
|
36.0
±1.8**
|
38.4
±0.3
|
39.6
±0.2*
|
| AMPH+ATI (8) |
28.2
±1.8*
|
32.8
±2.0*
|
38.7
±0.4
|
39.2
±0.3
|
| F / p |
5.2/
0.007
|
12.1 / 0.0001
|
1.3
/ 0.3
|
4.1
/ 0.004
|
Results
are means (± s.e. mean) * P < 0.05; ** P < 0.01 compared
with Dunnett's test to control mice from same strain.It is concluded that
the ability of AMPH to elevate TRP is partly prevented by 2A-adrenoceptor
activation though other effects of AMPH e.g. hyperthermia (Fernando &
Curzon 1978) as well as AMPH-induced release of NA and b-receptor activation
(Lenard et al. 2003) may be involved.
Fernando
J.C. & Curzon G. (1978) Eur. J. Pharmacol. 49; 339-349.
Lenard N.R.
et al. (2003) J. Pharmacol. Exp. Ther. 305, 653-659.