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Altered presynaptic function in monoaminergic neurons of monoamine oxidase‐A knockout mice
Author(s) -
Owesson Catarina Å.,
Hopwood Sarah E.,
Callado Luis F.,
Seif Isabelle,
McLaughlin Daniel P.,
Stamford Jonathan A.
Publication year - 2002
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.2002.01986.x
Subject(s) - reuptake , monoaminergic , monoamine neurotransmitter , chemistry , endocrinology , medicine , dorsal raphe nucleus , serotonin , desipramine , stimulation , autoreceptor , monoamine oxidase , monoamine oxidase a , locus coeruleus , dopaminergic , knockout mouse , serotonin transporter , dopamine , serotonergic , antidepressant , receptor , biology , central nervous system , biochemistry , hippocampus , enzyme
Monoamine oxidase‐A knockout (MAO‐A KO) mice have elevated brain serotonin (5‐HT) and noradrenaline (NA) levels, and one would therefore anticipate increased monoamine release and compensatory changes in other aspects of presynaptic monoamine function. In this study we used voltammetry in brain slices from the locus coeruleus (LC), dorsal raphe (DRN) and striatum (CPu) in 7‐week‐old MAO‐A KO and C3H control mice to measure stimulated monoamine efflux and its control by amine transporters and autoreceptors. In LC, peak NA efflux on stimulation (99 pulses, 100 Hz) was higher in MAO‐A KO than C3H mice (938 ± 58 n m cf. 511 ± 42 n m ; P < 0.001). The NA uptake half time (t ½ ) was longer in MAO‐A KO than in C3H mice (6.0 ± 0.9 s cf. 1.9 ± 0.3 s; P < 0.001) and the selective NA reuptake inhibitor desipramine (50 n m ) had a smaller effect in MAO‐A KO mice. NA transporter binding was significantly lower in the LC of MAO‐A KO mice compared to C3H controls ( P < 0.01) but not in the DRN. The α 2 agonist dexmedetomidine (10 n m ) decreased stimulated NA efflux more in C3H than in MAO‐A KO mice (73.3% cf. 29.6% inhibition, P < 0.001). In DRN, peak 5‐HT efflux on stimulation (99 pulses, 100 Hz) was greater ( P < 0.01) in MAO‐A KO (262 ± 44 n m ) than C3H mice (157 ± 16 n m ). Moreover, 5‐HT uptake t ½ was longer ( P < 0.05) in MAO‐A KO than in C3H mice (8.8 ± 1.1 s cf. 4.9 ± 0.6 s, P < 0.05) and the effect of citalopram (75 n m ) was attenuated in MAO‐A KOs. Serotonin transporter binding was also lower in both the DRN and LC of MAO‐A KO mice. The 5‐HT 1A agonist 8‐OH‐DPAT (1 µ m ) decreased 5‐HT efflux more in C3H than in MAO‐A KO mice (38.3% inhibition cf. 21.6%, P < 0.001). In contrast, there were no significant differences between MAO‐A KO and C3H mice in CPu dopamine efflux and uptake and the effect of the D 2/3 agonist quinpirole was similar in the two strains. In summary, MAO‐A KO mice show major dysregulation of monoaminergic presynaptic mechanisms such as autoreceptor control and transporter kinetics.