Time-dependent changes in brain monoamine oxidase activity and in brain levels of monoamines and amino acids following acute administration of the antidepressant/antipanic drug phenelzine

doi:10.1016/S0006-2952(00)00244-6

Biochemical Pharmacology

Volume 59, Issue 10, 15 May 2000, Pages 1253-1263

https://doi.org/10.1016/S0006-2952(00)00244-6 Get rights and content

Abstract

Phenelzine (PLZ) is a non-selective monoamine oxidase (MAO) inhibitor commonly used to treat depression and panic disorder. Acute administration of PLZ produces several neurochemical changes, including an increase in brain levels of the catecholamines norepinephrine (NE) and dopamine (DA), of 5-hydroxytryptamine (5-HT), and of the amino acids alanine and γ-aminobutyric acid (GABA). The goal of the present series of experiments was to characterize the time course of these PLZ-induced changes. Male Sprague–Dawley rats were sacrificed 6, 24, 48, 96, 168, or 336 hr after acute PLZ administration (15 or 30 mg/kg, i.p., based on free base weight). Whole brain levels of monoamines and amino acids were determined using HPLC, and MAO A and B activities were determined using a radiochemical procedure. The results indicated that PLZ changed amino acid levels 6 and 24 hr after injection, but not 48 hr later. In contrast, the effects of PLZ on MAO activity and monoamines were longer-lasting. For example, PLZ-induced increases in dopamine and 5-HT were observed 1 week after injection, and PLZ-induced inhibition of MAO activity persisted for 2 weeks. Thus, in addition to demonstrating that the effects of PLZ on MAO activity and monoamines were long-lasting, these results indicate that the effects of PLZ on MAO activity and on brain levels of monoamines and amino acids are temporally dissociated. These findings regarding the long-term effects of PLZ on neurochemistry will have considerable critical implications for the design and interpretation of behavioral studies of the acute effects of PLZ.

Section snippets

Materials and methods

All animal procedures were approved by the University of Alberta Health Sciences Animal Welfare Committee and conducted in accordance with the guidelines of the Canadian Council on Animal Care.

MAO activity

Both doses of PLZ inhibited MAO-A and MAO-B activity (MAO-A: F_1,67 = 23.23, P < 0.001; MAO-B: F_1,67 = 36.17, P < 0.001; see Fig. 1). Six hours after PLZ was injected, MAO-A activity was inhibited 95 and 97% by PLZ at the 15 and 30 mg/kg doses, and MAO-B activity was inhibited 73 and 84%. Averaged across all time points, the 30 mg/kg dose of PLZ produced greater inhibition of MAO-A and -B than did the 15 mg/kg dose (P < 0.001). PLZ-induced inhibition of MAO-A and MAO-B activity decreased as the

Discussion

In agreement with previous results, the present findings indicate that acute administration of the antidepressant/antipanic drug PLZ affects brain MAO activity and brain levels of monoamines, their acid metabolites, and amino acids. To our knowledge, the present report is the first to assess these multiple effects of PLZ simultaneously and over such a lengthy (2-week) period. Such a period was chosen for the present study, not only because it covers the period of time in which we have conducted

Acknowledgements

We are grateful for the invaluable technical assistance provided by Gail Rauw and Rick Strel and the statistical advice provided by Dr. Connie Varnhagen. This research was supported by grants from NSERC (OGP0194532 and EGP0195857) to M. B. P. and from the Medical Research Council of Canada (MT-12235) and the George and Dorothy Davey Endowment Fund to G. B. B.

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As illustrated in Fig. 3A, PLZ reduced the number of formalin-evoked Fos+ cells in laminae I–II (Fig. 3B; t-test, t(8) = 2.9533, ∗p ≤ 0.02), but not in the deeper laminae III–VI (Fig. 3C; Mann–Whitney rank sums test used as equal variance requirement was not met, NS, U(5, 5) = 5.000, p ≤ 0.16). PLZ increases the concentration of monoamine neurotransmitters (5-HT, NA, dopamine) in whole spinal cord of naïve and formalin-treated rodents (Griebel et al., 1998; Parent et al., 2000; Musgrave et al., 2011; Mifflin et al., 2016), but these studies did not localize changes to the dorsal and/or ventral horn. PLZ increased 5-HT+ immunoreactivity within the superficial (laminae I–II) SCDH compared to the VEH-treated group (Fig. 4A–C; t-test, t(8) = −2.888, ∗p ≤ 0.02), but had no effect at the ventral horn (Fig. 4D–F; t-test, NS, t(8) = −1.365, p ≤ 0.21)
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This effect in saline-treated rats may be related to the PLZ-produced increases in GABA levels. Biochemical results showed an increase in ALA levels in the hippocampus and a decrease in GLN levels in the frontal cortex following PLZ treatment; this is consistent with past studies (Parent et al., 2000; Paslawski et al., 1995; Todd and Baker, 2008). ALA is an inhibitor of GLN synthetase (Tate and Meister, 1971), an enzyme that is involved in the metabolism of glutamate to glutamine, and it is possible that a buildup of ALA following PLZ treatment underlies the reduction in GLN levels (Paslawski et al., 1995).
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NeuroscienceTime-dependent changes in brain monoamine oxidase activity and in brain levels of monoamines and amino acids following acute administration of the antidepressant/antipanic drug phenelzine

Abstract

Section snippets

Materials and methods

MAO activity

Discussion

Acknowledgements

Neuropharmacology

Prog Neuropsychopharmacol Biol Psychiatry

Prog Neuropsychopharmacol Biol Psychiatry

Brain Res Bull

J Affect Disord

Biochem Pharmacol

Prog Brain Res

J Affect Disord

Biochem Pharmacol

Biochem Pharmacol

Biochem Pharmacol

Biochem Pharmacol

Biochem Pharmacol

Brain Res

Brain Res

Trends Neurosci

J Biol Chem

Life Sci

Neuroscience

Brain Res

Brain Res

Neurosci Res

J Biol Chem

Biol Psychiatry

Pharmacotherapy of the panic disorders

J Clin Psychiatry

MAOIs in panic disorder and agoraphobia

The antidepressant drug phenelzine produces antianxiety effects in the plus-maze and increases in rat brain GABA

Psychopharmacology (Berl)

Neuroscience
Time-dependent changes in brain monoamine oxidase activity and in brain levels of monoamines and amino acids following acute administration of the antidepressant/antipanic drug phenelzine