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© Copyright 2004 The British Pharmacological Society

101P University of Bath
Summer Meeting July 2004

Homovanillic acid levels in thalamus/hypothalamus of mice treated with amphetamine and/or atipamezole mirror changes in the noradrenaline metabolite, MHPG

Ewen MacDonald,1. Janne Lähdesmäki, 2 Jukka Sallinen, 3& Mika Scheinin. 2 1 Depts. Pharmacol. & Tox. University of. Kuopio; 2Pharmacol. & Clin. Pharmacol. University of Turku, 3Orion-Pharma Ltd. Turku, Finland

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MacDonald E
Lähdesmäki J
Sallinen J
Scheinin M

Over the past few years we have been using genetically-manipulated mice to explore the roles of 2-adrenoceptor sub-types. One focus has been on 2-receptor modulation of dopamine (DA) release, since there is evidence that 2-adrenoceptor antagonists have a role to play in the treatment of parkinsonism. One way to assess DA release has been to measure levels of its metabolites, homovanillic acid (HVA) and dihydroxphenylacetic acid (DOPAC) in response to drugs.

Male C57BL/6J alpha-2A knockout (KO) mice (25-35 g) (Altman et al. 1999) were used with age and sex-matched mice as wild-type controls (WT) received either the 2-adreno-ceptor antagonist, atipamezole (ATI) (1 mg/kg, s.c.), amphetamine AMP (10 mg kg-1, i.p.) or a combination of these drugs. Mice were sacrificed 1 hr after ATI (and 50 min after AMP). Brain regions were dissected and biogenic amines and metabolites assayed by HPLC-EC. Comparison between the groups was ANOVA and Dunnett’s t-test (P<0.05 considered significant). Correlations between different neurochemical para-meters were performed by simple regression analysis, separately for WT and KO mice.

In WT mice, ATI caused an increase in the levels of the noradrenaline (NA) metabolite 3-methoxy-4-hydroxyphenyl glycol (MHPG). Though AMP did not change MPHG levels in WT mice; it caused a major increase in the KO mice. In thalamus/hypothala-mus, the drug-induced changes in MHPG were mirrored in HVA not in DOPAC levels.

Table 1: Concentrations of MHPG and HVA after atipamezole and/or amphetamine

Thalamic/hypothalamic concentrations (nmol g-1± s.e. mean)

Drug (no. of mice)

MHPG

HVA

WT

2A-KO

WT

2A-KO

Saline (10)

0.16±0.03

0.32±0.05

1.22±0.04

1.23±0.05

ATI 1 mg/kg (8)

0.33±0.05*

0.42±0.04

1.26±0.04

1.29±0.07

AMP 10 mg/kg (10)

0.12±0.04

0.49±0.05*

1.34±0.04

1.50±0.09*

ATI + AMP (8)

0.54±0.04*

0.60±0.04*

1.72±0.04*

1.62±0.07*

*P < 0.05 at least compared to saline mice from the same strain (Dunnett’s t-test)

There were better correlations between HVA and MHPG levels in hypothalamus (r2 values of 0.42 in KO mice, and 0.61 in WT mice, P<0.05) than between HVA and other DA parameters (r2 values < 0.2, NS). This was not apparent in the striatum. In contrast, DOPAC correlated with DA (r2 values 0.44 in KO mice, and 0.65 in WT, P<0.05 at least), not with HVA or MHPG (all r2 values < 0.20).

We conclude that in brain regions like thalamus/hypothalamus which have extensive NA innervations, HVA may be a marker for NA rather than DA release. This is in agreement with the theory proposed by Scheinin (1986) who came to the same conclusion after assaying HVA concentrations in cerebrospinal fluid in rats treated with 2-adrenoceptor modulating drugs.

Altman J.D. et al. Mol. Pharmacol.(1999), 56, 154-161
Scheinin H. J Neurochem. (1986), 47, 665-7