Altered presynaptic function in monoaminergic neurons of monoamine oxidase-A knockout mice.
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 nm cf. 511 +/- 42 nm; P < 0.001). The NA uptake half time (t(1/2)) 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 nm) 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 alpha 2 agonist dexmedetomidine (10 nm) 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 nm) than C3H mice (157 +/- 16 nm). Moreover, 5-HT uptake t(1/2) 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 nm) 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 microm) 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.
Owesson
Catarina A
CA
Neurotransmission Laboratory, Academic Department of Anaesthesia and Intensive Care, Barts and The London School of Medicine and Dentistry, Alexandra Wing, Royal London Hospital, Whitechapel, London E1 1BB, UK.
Hopwood
Sarah E
SE
Callado
Luis F
LF
Seif
Isabelle
I
McLaughlin
Daniel P
DP
Stamford
Jonathan A
JA
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000201:enzymology*; D018491:Dopamine Agonists / Q000494:pharmacology; D004558:Electric Stimulation; D005110:Extracellular Space / Q000378:metabolism; D008125:Locus Coeruleus / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000172:deficiency* / Q000235:genetics; D017072:Neostriatum / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D009924:Organ Culture Techniques; D017729:Presynaptic Terminals / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure; D011903:Raphe Nuclei / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D012701:Serotonin / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D009435:Synaptic Transmission / Q000235:genetics*
D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D015306:Biogenic Monoamines; D018491:Dopamine Agonists; D008995:Monoamine Oxidase; D009638:Norepinephrine; D012701:Serotonin; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors