The striatal dopamine dependency of life span in male rats. Longevity study with (-)deprenyl.

The development of monoamine oxidase (MAO) inhibitors has followed a winding path. At the origin was the finding of E. A. Zeller that iproniazid, a hydrazine derivative designed to improve the tuberculostatic action of isoniazid, caused potent inhibition of MAO in vitro and in vivo. The inhibitor also exerted in vivo activity in the brain, subsequent pharmacological research indicating that this inhibition led to changes of cerebral functions [1]. Although the drug had no overt behavioral effects in animals when given alone, it modified the action of reserpine, one of the first modern psychotropic drugs. Thus, administration of iproniazid prior to reserpine unexpectedly antagonized the decreases in locomotor activity and in 5-hydroxy-tryptamine (5 HT) levels induced by reserpine in the brain, the animals sometimes even showing locomotor stimulation [1]. Since one serious side effect of reserpine in man was known to be mental depression, the antagonism of reserpine by iproniazid hinted at the possibility that this drug might be of use in the treatment of mood disorders. However, the actual breakthrough for the development of iproniazid as an antidepressant came from clinical observations. Various investigators had reported psychostimulant side effects of the MAO inhibitor in patients with tuberculosis and other chronic diseases.

The new generation of monoamine oxidase inhibitors.

Monoamine oxidase inhibitors (MAOIs) currently have a "bad rap" and are thus infrequently used in psychopharmacology, even by experienced clinicians. Misinformation about the dietary and drug interactions of MAOIs is widespread, whereas pragmatic tips for utilizing MAOIs to minimize risks and to maximize therapeutic actions are largely lacking in the contemporary literature. While clearly not first-line treatments, MAOIs, in the hands of experienced and well-informed clinicians, can be a powerful therapeutic intervention for patients with depression, panic disorder, and other anxiety disorders who have failed first-line treatments. This article focuses on the pharmacologic mechanisms of MAOIs, since an understanding of these mechanisms may provide a rationale to empower experts to expand their use of these agents. Discussed here are not only the mechanisms of therapeutic action of MAOIs, but also the mechanisms explaining their side effects, including hypertensive interactions with dietary tyramine (so-called "cheese reactions") and drug interactions that can lead to hypertensive reactions with some drugs and serotonin toxicities with others. This article also provides practical tips on how to use MAOIs, including debunking certain myths and giving specific guidance about which foods and drugs to avoid. Those with no previous interest in MAOIs may discover in this article a new "secret weapon" to add to their therapeutic armamentarium for patients who fail to respond to the better-known agents.

Monoamine Oxidase Inhibitors: A Modern Guide to an Unrequited Class of Antidepressants

In vitro rotating disk electrode (RDE) voltammetry and in vivo microdialysis were used to characterize dopamine clearance in the rat medial prefrontal cortex (mPFC). RDE studies indicate that inhibition by cocaine, specific inhibitors of the dopamine transporter (DAT) and norepinephrine transporter (NET), and low Na(+) produced a 50-70% decrease in the velocity of dopamine clearance. Addition of the monoamine (MAO) inhibitors, l-deprenyl, clorgyline, pargyline, or in vivo nialamide produced 30-50% inhibition. Combined effects of uptake inhibitors with l-deprenyl on dopamine clearance were additive (up to 99% inhibition), suggesting that at least two mechanisms may contribute to dopamine clearance. Dopamine measured extracellularly 5 min after exogenous dopamine addition to incubation mixtures revealed that most conditions of DAT/NET inhibition did not produce elevated dopamine levels above controls. Inhibition of MAO produced elevated dopamine levels only after long-term, but not short-term, incubation in vitro. Short-term incubation of l-deprenyl combined with DAT and NET uptake inhibitors increased dopamine above control levels, consistent with more than one mechanism of dopamine clearance. Local infusion of pargyline (100 or 300 microm) into the mPFC or striatum via microdialysis produced more pronounced and immediate increases in mPFC dopamine levels compared with striatum. Furthermore, dopamine elevation in the mPFC was not accompanied by a decrease in the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, as found in the striatum. These findings may have revealed a unique mechanism of mPFC dopamine clearance and therefore contribute to the understanding of multiple behaviors that involve mPFC dopamine transmission, such as schizophrenia, drug abuse, and working memory function.

https://www.jneurosci.org/content/jneuro/21/1/35.full.pdf

Characterization of Extracellular Dopamine Clearance in the Medial Prefrontal Cortex: Role of Monoamine Uptake and Monoamine Oxidase Inhibition

Acute inhibition of monoamine oxidase B (MAO-B) in the rat does not affect striatal dopamine (DA) metabolism, but chronic MAO-B inhibition with deprenyl has been reported to increase the release of striatal DA, as shown using in vitro techniques. To see whether chronic MAO-B inhibition also causes an increase in DA release in vivo, rats were treated for 21 days with either deprenyl (0.25 mg/kg), TVP-1012 [R(+)-N-propargyl-1-aminoindan mesylate; 0.05 mg/kg], an irreversible inhibitor of MAO-B that is not metabolized to amphetamines, clorgyline (0.2 mg/kg), or saline (all doses once daily by subcutaneous injection). Concentric 4-mm-long microdialysis probes were implanted in the left striatum under pentobarbital/chloral hydrate anesthesia on day 21, and microdialysate DA, 3,4, dihydroxyacetic acid (DOPAC), and 4-hydroxy-3-methoxyphenyl acetic acid (HVA) were determined in the conscious animals on day 22. Baseline levels of DA were as follows: control, 0.34 +/- 0.04 (n = 13); deprenyl, 0.88 +/- 0.10 (n = 8, p < 0.01); TVP-1012, 0.94 +/- 0.20 (n = 7, p < 0.01); clorgyline, 0.90 +/- 0.12 (n = 7, p < 0.01) pmol/20 min. Levels of DOPAC and HVA were reduced only in the clorgyline-treated group. The incremental release of DA induced by depolarizing concentration of K+ (100 mM bolus of KCl in perfusate) was significantly greater in clorgyline- and deprenyl-treated rats and elevated (nonsignificantly) in TVP-1012-treated rats. Chronic treatment with the MAO-B inhibitors reduced striatal MAO-B activity by 90%, with 15% (TVP-1012) or 40% (deprenyl) inhibition of MAO-A. Clorgyline inhibited MAO-A by 95%, with 30% inhibition of MAO-B. A single dose of deprenyl (0.25 mg/kg, 24 h before microdialysis) had no significant effect on striatal efflux of DA. The results show that DA metabolism was reduced only by clorgyline, whereas neuronal release of DA was enhanced by both MAO-A and MAO-B inhibitors on chronic administration. The enhanced DA release by chronic MAO-B inhibition does not appear to be dependent on production of amphetamine-like metabolites of the inhibitor. Possible mechanisms for the release-enhancing effect of the MAO-B inhibitors include elevation in levels of endogenous beta-phenylethylamine, or an inhibition of DA reuptake, which develops only on chronic administration, because both deprenyl and TVP-1012 have only very weak effects on amine uptake in acute experiments.

Effect of Long‐Term Treatment with Selective Monoamine Oxidase A and B Inhibitors on Dopamine Release from Rat Striatum In Vivo

The action of clorgyline and (-)deprenyl on the dynamics of dopaminergic and serotonergic transmission in the rat brain was compared. It was found, that daily administration of 0.25 mg/kg sc clorgyline, a specific MAO A inhibitor, reduced the turnover rate of both dopamine and serotonin after two weeks of injections. The treatment for two or four weeks with 0.25 mg/kg sc (-)deprenyl, a specific MAO B inhibitor, enhanced the turnover rate of dopamine and the fractional rate constant of dopamine efflux, reflecting an increased utilization rate of this amine in the striatum. Beside the augmentation of the dopamine turnover rate, the dopaminergic tone was also elevated by the reduction of the dopamine uptake in the striatum. Two week injections with the same dose of (-)deprenyl did not change the dynamics of serotonergic transmission.

G Held

Papers

The effect of repeated doses of (-) deprenyl on the dynamics of monoaminergic transmission. Comparison with clorgyline