Monoamine oxidase (MAO) catalyzes the deamination of monoamine neurotransmitters within the brain. Inhibition of MAO results in an increase in the amount of neurotransmitter available for release within the presynaptic terminal and also increases the duration of the neurotransmitters' activity within the synaptic cleft.
Monoamine oxidase inhibitors (MAOIs), such as phenelzine and moclobemide, have been found to be therapeutically effective in treating depression and obsessive-compulsive disorder, both of which are believed to be caused by an underactivity of various monoamines within the brain. Consequently, it is thought that MAOIs are effective in treating these disorders due to their ability to increase the activity levels of serotonin, dopamine and norepinephrine within the brain.
However, the pharmacological action of MAOIs within the brain may not be so easily described. The article written by Levant et al. (1996) suggests that MAOIs may also interact within the brain in a manner that is independent of MAO activity.
Using various binding assays, the authors have demonstrated that in vitro, MAOIs inhibit the binding of the dopamine D2 agonist, quinpirole to rat striatal membranes. Furthermore, these binding assays have revealed that the same MAOIs are not able to inhibit the binding of the D2 antagonist spiperone to striatal membranes. These results demonstrate that monoamine oxidase is not the only substrate for MAOI activity and suggests that this groups of drugs may interact with dopamine receptor sites in a unique and previously unknown manner.
All MAOIs tested (see Table 1 of article) exhibited a greater potency for inhibiting quinpirole binding than spiperone binding within striatal membranes, with clorgyline and Ro 41-1049 demonstrating the greatest potency in competition for QNP binding (Ki values of 14 and 27 nM, respectively).
Despite the shared ability of MAOIs to inhibit MAO activity, their affinity for quinpirole binding sites was determined to be independent of MAO activity. It was observed that even compounds which did not have any inhibitory effect on MAO activity but did share a similar chemical structure to that of clorgyline or RO 41-1049, demonstrated a greater affinity for quinpirole binding sites. It was also observed that the rank order of affinity for quinpirole binding sites did not correspond with the MAOIs ability to inhibit the activity of monoamine oxidase.
The regional distribution of MAOI-displaceable binding was examined using Ro 41-1049, and it was observed that the highest density of Ro 40-1049-displaceable quinpirole binding occurred in the caudate putamen. Moderately dense MAOI-displaceable binding was observed in the nucleus accumbens, followed by the substantia nigra/ventral tegmental area. It was also observed that the Ro-1049-displaceable binding was consistent with the distribution of D2-like receptors within the brain, suggesting that the MAOIs were inhibiting quinpirole binding at the D2 receptor site.
It was also demonstrated that binding assay conditions had little effect on the affinity of Ro 40-1049 for quinpirole binding sites within the striatum, indicating that the ability of MAOIs to inhibit quinpirole binding is not dependent on temperature, membrane concentration or buffer composition. Similarly, it was observed that Ro 41-1049 inhibited quinpirole binding at all time points, once again indicating that the inhibition of quinpirole binding is independent of MAO activity, further implicating an interaction at the receptor level.
From these findings the authors have concluded that in addition to their ability to inhibit monoamine oxidase activity, MAOIs are capable of inhibiting quinpirole binding within the striatum. The authors further suggest that this phenomenon may be attributed to an interaction with the MAOI at a novel binding site that is either labelled by quinpirole, or which modulates quinpirole binding at D2-like receptors.
This article has many implications. Firstly, the authors' suggestion of a novel dopamine binding site provides a potential target for agents to modulate dopaminergic activity.
Secondly, the authors note that unlike the binding of the D2 receptor agonist quinpirole, MAOIs do not inhibit the binding of another dopamine receptor agonist, N-propylnorapomorphine. It will be important to determine whether this is a distinct property of quinpirole or whether other dopamine agonists such as bromocriptine also bind to the MAOI-sensitive site.
Thirdly, because this paper reveals that monoamine oxidase is not the only site of action for MAOIs within the brain, it suggests that the therapeutic action, or side effects, of these drugs are not necessarily due to MAO inhibition. Conversely, some of the effects of quinpirole-like dopamine agonists, such as behavioral sensitization, may be due to an action at the MAOI-sensitive site rather than the classic spiperone-labelled D2 binding site. In this context, it would be important to know the characteristics of MAOI-displaceable quinpirole binding following chronic drug adminsitration.
Quinpirole is a dopamine agonist with high affinity for the D2/D3 dopamine receptor subtypes. A variety of drugs, most notably monoamine oxidase inhibitors (MAOIs), inhibit the binding of [3H]quinpirole, but not [3H]spiperone or [3H](-)-N-n-proporamorphine, in rat striatal membranes by a mechanism that does not appear to involve the enzymatic activity of MAO. The study extended the characterization of MAOI-displaceable quinpirole binding in rat brain. Clinically antidepressant MAOIs exhibited selectivity between sites labelled by [3H]quinpirole and [3H]spiperone as did an number of structurally related propargylamines and N-acylthylenediamine derivatives and other drugs such as debrisoquin and phenylbiguanide. The MAOIs clorgyline and Ro 41-1049 were the most potent. Anti-depressant MAOIs inhibited [3H]quinpirole binding with the following rank order of potency: phenelzine > pargyline > tranylcypromine > isocarboxazid > nialamide > moclobemide. In striatal membranes, MAOI Ro 41-1049 inhibited [3H]quinpirole binding with similar potency at a variety of incubation temperatures (4-37C), assay tissue concentrations (5-20 mg original wet weight/ml), and time points (2 min - 4 hr) and in the presence or absence of K+, Mg2+, Ca2+ ions, ascorbate, EDTA and NaCl. The regional distribution of Ro 41-1049-displaceable [3H]quinpirole binding in brain paralleled that of D2-like receptors. These data suggest that MAOIs interact with a novel binding site that is labelled by [3H]quinpirole or that modulates [3H]quinpirole binding. This site may be associated with D2-like dopamine receptors.