Novel drug interactions at D2 dopamine receptors: Modulation of [3H]quinpirole binding by monoamine oxidase inhibitors

Life Sciences 71 (2002) 2691 – 2700 www.elsevier.com/locate/lifescie

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Novel drug interactions at D2 dopamine receptors: Modulation of [3H]quinpirole binding by monoamine oxidase inhibitors Beth Levant * Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7417, USA Received 8 May 2002; accepted 11 June 2002

Abstract D2 dopamine receptors are the principal target of drugs used to treat schizophrenia and Parkinson’s disease. Recent findings suggest novel drug interactions at D2 receptors, specifically interactions of monoamine oxidase inhibitors (MAOIs) at a novel binding site that modulates the binding of [3H]quinpirole to the D2 receptor. That MAOIs inhibit [3H]quinpirole binding challenges the traditional understanding of ligand interactions at dopamine receptors and may shed light on the mechanism of behavioral sensitization to psychostimulants and the pharmacology and toxicity of MAOIs. D 2002 Elsevier Science Inc. All rights reserved. Keywords: D2 dopamine receptor; Quinpirole; Monoamine oxidase inhibitor

Introduction D2 dopamine receptors are the principal targets of drugs used to treat schizophrenia and Parkinson’s disease. Recent findings suggest novel drug interactions at D2 receptors. Specifically, a variety of nondopaminergic compounds, most notably monoamine oxidase inhibitors (MAOIs), modulate the binding of [3H]quinpirole to the D2 receptor. Evidence supporting this observation, which challenges the traditional understanding of ligand binding at dopamine receptors, is reviewed followed by a discussion of the potential functional consequences and therapeutic relevance of this surprising interaction.

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Tel.: +1-913-588-7527; fax: +1-913-588-7501. E-mail address: [email protected] (B. Levant). 0024-3205/02/$ - see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 0 0 2 4 - 3 2 0 5 ( 0 2 ) 0 2 1 0 9 - 4

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The D2 dopamine receptor The D2 dopamine receptor is the principal member of the family of D2-like dopamine receptors, which includes the D2, D3 and D4 receptors. Because of the structural similarity of these receptors and the limited ability of drugs to discriminate between the subtypes (for review see: [1]), this group of receptors will be referred to as ‘‘D2-like’’. D2-like receptors are of great interest as they are the primary targets of antipsychotic drugs [2]. D2-like receptors also appear to be of major importance in the treatment of Parkinson’s disease [3]. A variety of D2-like receptor agonists and antagonists have been identified and used to study the pharmacology, localization, and function of the D2-like receptors in detail. Briefly, D2-like receptors are located both pre- and post-synaptically and are distributed heterogeneously throughout the central nervous system with highest densities in the striatum, nucleus accumbens, olfactory tubercles, and substantia nigra pars compacta (for review see: [6]). The receptors signal through Gi/Go to inhibit adenylyl cyclase and also influence other second messenger systems such as the phosphoinositide cascade (for review see: [4]). In addition, the receptors exist in high and low affinity states for dopamine agonists that are regulated by sodium ions and guanyl nucleotides [5].

Quinpirole Quinpirole, or LY-171555, is a tricyclic ergoline agonist selective for D2-like receptors [7,8]. In vivo, quinpirole, like other D2-like receptor agonists, produces a variety of behavioral effects in animals. These behavioral effects include increased motor activity including locomotion and rearing [9–11], decreased stress-induced immobility, inhibited grooming [10,12], altered learning [13,14], analgesia [15], and facilitation of male sexual performance [16]. In addition, intermittent, repeated injection of quinpirole, as with many other dopaminergic psychostimulants, induces an enhanced locomotor response to the drug [17–20], a phenomenon known as behavioral sensitization (for review see: [21]). In order to elucidate the pharmacology and binding characteristics of quinpirole, the compound was radiolabeled and compared to other radiolabeled dopaminergic compounds. In the early 1990s, several laboratories demonstrated specific, saturable, high affinity in vitro binding of [3H]quinpirole in rat striatal membranes and in autoradiographic studies. These studies revealed that although the binding profile was not strictly identical to those of other D2-like receptor ligands, [3H]quinpirole binding was appropriate for the D2-like receptors with respect to pharmacological profile, guanine nucleotide and sodium regulation, and regional distribution of binding sites [22–25]. Of note, dopaminergic agonists and antagonists inhibit [3H]quinpirole binding with a rank order of potencies similar to the pharmacological profile of the classical D2-like receptor radioligand [3H]spiperone (Table 1) [23]. In addition, the regional distribution of [3H]quinpirole binding sites is similar to [3H]spiperone binding sites with high density in the striatum, nucleus accumbens, and olfactory tubercles; moderate density in the substantia nigra/ventral tegmental area, pituitary, and hypothalamus; and low density in the cortex and cerebellum. Autoradiographic localization of [3H]quinpirole binding parallels the regional binding distributions found in the radioligand binding studies. Although initial reports of the cloning of the D3 receptor suggested that quinpirole might possess significant selectivity for the D3 receptor over D2, subsequent studies failed to support the observation [1]. However, some differentiation of

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Table 1 Pharmacological profile of [3H]quinpirole binding in rat striatal membranes. Comparison with [3H]spiperone binding [3H]Quinpirole Ki (nM)

[3H]Spiperone Ki (nM)

Ki ([3H]Spiperone)/ Ki ([3H]Quinpirole)

Dopaminergic compounds 6,7-ADTN Bromocriptine (+)-Butaclamol Haloperidol SCH 23390

6.1 83 16 23 2,367

24 54 7.0 7.9 5,560

3.9 0.65 0.43 0.34 2.3

Monoamine oxidase inhibitors Clorgyline Ro 41-1049 Phenelzine Pargyline Tranylcypromine ( )-Deprenyl (+)-Deprenyl Isocarboxazid Nialamide Ro 16-6491 Iproniazid Moclobemide

14 27 95 164 269 445 650 2,160 4,486 5,357 15,405 18,700

>50,000 >100,000 >100,000 >100,000 6,633 11,325 >50,000 >100,000 >100,000 >100,000 >100,000 >100,000

>3,000 >3,000 >1,000 >600 25 25 >77 >46 >22 >19 >6 >5

Other Compounds Debrisoquin Phenylbiguanide Procainamide

369 2,867 4,379

>50,000 >100,000 >100,000

>135 >35 >23

764 715 4,931 >100,000

0.84 0.49 0.51 –

Compound

Tricyclic, SSRI, and other antidepressants Doxepin 902 Amitriptyline 1,473 Fluoxetine 9,693 Buproprion >100,000

Rat striatal membranes were incubated with either [3H]quinpirole ( f 2 nM) or [3H]spiperone ( f 100 pM) and up to 11 concentrations of competing ligand (10 10 to 10 4 M). Nonspecific binding was defined by (+)-butaclamol (1 AM). Data were analyzed using the non-linear curve-fitting program LIGAND. Data represent the mean of 3 – 5 independent determinations. 6,7-ADTN: ( F )-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene. Adapted from [28,29].

dopamine D2 and D3 receptors in certain brain regions has been observed in autoradiographic studies [22,24]. Although the in vitro binding profile of [3H]quinpirole is generally appropriate for a D2-like receptor agonist, two noteworthy inconsistencies have been noted. First, [3H]quinpirole exhibited biphasic association kinetics [23]. Biphasic association kinetics may result from association of a ligand with two distinct sites [26]. However, no other evidence suggestive of [3H]quinpirole binding at multiple binding sites, aside from multiple D2-like receptors, has been reported [23,25,27]. The second inconsistency is the observation that a number of non-dopaminergic compounds, most notably MAOIs, inhibit equilibrium binding of [3H]quinpirole (see below).

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Modulation of [3H]quinpirole binding by MAOIs MAOIs are a structurally diverse group of compounds that have been used to treat major depression since the 1960s. Surprisingly, MAOIs competitively inhibit equilibrium [3H]quinpirole binding in rat striatal membranes in vitro [28]. This observation was not dependent on specific in vitro assay conditions, such as membrane concentration; the presence or absence of Na + , K + , Mg2 + , or Ca2 + ; or incubation time or temperature [29] although another study using [3H]quinpirole under different in vitro assay conditions failed to detect inhibition of [3H]quinpirole binding by MAOIs [27]. The MAOIs that inhibited [3H]quinpirole binding exhibit a range of potencies (Table 1). A number of structurally related, non-dopaminergic propargylamines and N-acetylethylenediamines, as well as other drugs such as debrisoquin and phenylbiguanide, also inhibit binding of [3H]quinpirole [29]. Interestingly, while these compounds potently inhibit the binding of [3H]quinpirole, they exhibit very low affinity in competition with either the D2 antagonist [3H]spiperone or agonist [3H]( )-N-n-propylnorapomorphine [28]. This suggests that the binding interaction could be unique to ergoline dopaminergic agonists or perhaps to quinpirole alone. These observations raise several important questions. First, is [3H]quinpirole binding associated with a site other than the D2 receptor? Although the vast majority of data obtained with [3H]quinpirole is consistent with the extensive body of work on D2-like receptors, the two inconsistencies noted above suggest that [3H]quinpirole could interact with another, as yet unidentified, binding site in addition to, or instead of, D2-like receptors. Alternatively, [3H]quinpirole could bind to the active site of the D2 receptor through unique ionic interactions or to a distinct binding site on the receptor. Second, what is the site of action for the MAOIs? These compounds could modulate [3H]quinpirole binding by any of a number of potential mechanisms. For example, [3H]quinpirole could compete with an endogenous ligand that is ordinarily degraded by MAO. Alternatively, [3H]quinpirole could require metabolic activation by MAO. On the other hand, protein-protein interactions could occur between MAO and the [3H]quinpirole binding site to modulate binding. These issues remain to be completely resolved. However, as presented below, studies to date have tested a number of these hypotheses and indicate that MAOIs interact with a binding site in brain to modulate [3H]quinpirole binding at D2 receptors. Substantial evidence indicates that MAOIs modulate [3H]quinpirole binding at the D2 receptor. First, MAOIs inhibit [3H]quinpirole binding in all brain regions in which binding is observed in parallel with the distribution of D2-like receptors [29]. Likewise, MAOIs inhibit [3H]quinpirole binding in subcellular fractions of rat striatum in parallel with spiperone-defined, ‘‘D2-like’’ [3H]quinpirole binding [32]. Finally, [3H]quinpirole binding is decreased by 97% in the striata of D2 receptor-deficient mice compared to wild-type controls [31]. The remaining 3% of [3H]quinpirole binding in the D2 receptordeficient animals can be reasonably attributed to the D3 receptor, which is present in low density in that brain region and for which [3H]quinpirole has roughly equal affinity [1]. Taken together, these observations indicate that [3H]quinpirole binding in striatal membranes is almost entirely associated with the D2 receptor and that [3H]quinpirole does not interact with non-dopaminergic sites. Accordingly, it can be concluded that MAOIs inhibit binding of [3H]quinpirole at the D2 receptor. Although MAOIs share the ability to inhibit MAO, several lines of evidence suggest that neither the enzymatic activity of MAOA or MAOB nor the MAOA protein are involved in the interaction with [3H]quinpirole. First, (+)-deprenyl, which is inactive at MAO, has similar affinity in competition with [3H]quinpirole to its active isomer ( )-deprenyl. Second, many of the MAOIs, such as clorgyline, are irreversible inhibitors of MAO, whereas the interaction of clorgyline with [3H]quinpirole binding is

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reversible. Third, quinpirole is not a substrate for MAO. In addition, MAOIs inhibit [3H]quinpirole binding after steady state has been reached [28]. Finally, although the rank order of affinities of the MAOIs in competition with [3H]quinpirole binding is similar to their potencies at MAOA [30], MAOIs inhibit [3H]quinpirole binding in MAOA-deficient mice indicating that MAOA is not the site of action for MAOIs in the modulation [3H]quinpirole binding [31]. Taken together, these data rule out the involvement of either the enzymatic activity of MAO or protein-protein interaction involving MAO in the observed interactions. The elimination of a role for MAO suggests that MAOIs modulate [3H]quinpirole binding through actions at a specific binding site. Efforts to identify the binding site for MAOIs have examined several receptors and binding sites. Although some MAOIs have been shown to possess significant affinity for the sigma site, imidazoline site, and dopamine transporter [26,33,34], the potency of MAOIs in competition for [3H]quinpirole binding correlates poorly with their potencies at these sites [28,29] suggesting that they are not involved in the modulation of [3H]quinpirole binding. An alternative approach to identify the site involved in the modulation of [3H]quinpirole binding used the radiolabeled MAOI [3H]Ro 41-1049 [31]. This radioligand was chosen because, unlike many MAOIs, it exhibits high affinity in competition with [3H]quinpirole but has relatively low affinities at the dopamine transporter and sigma and imidazoline sites. In rat striatal membranes, [3H]Ro 41-1049 binding is consistent with labeling of a single, high density, population of sites with a pharmacological profile with respect to MAOIs that is similar to both [3H]quinpirole binding (Fig. 1) and MAOA activity

Fig. 1. Correlation of the affinities of MAOIs in competition with [3H]quinpirole and [3H]Ro 41-1049 in rat striatal membranes (Spearman r = 0.976). From [31] with permission.

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[30]. Ninety-three percent of [3H]Ro 41-1049 binding was eliminated in MAOA-deficient mice compared to wild-type controls indicating that the majority of binding is associated with MAOA. However, the density of [3H]Ro 41-1049-labeled sites in rat striatum was roughly 15-fold higher than the density of [3H]quinpirole-labeled sites. As such, the density of [3H]Ro 41-1049-labeled sites remaining in the MAOA-deficient mice is of comparable density to [3H]quinpirole-labeled D2 receptors. It is therefore reasonable to speculate that the low-density [3H]Ro 41-1049-labeled sites detected in the MAOA-deficient mice may represent the [3H]quinpirole binding modulatory site. Thus, this site appears to be a novel binding site with MAOA-like pharmacology. Although experiments with mutant mice support D2-like dopamine receptors as the sole binding sites for [3H]quinpirole and implicate a novel binding site with MAOA-like pharmacology as the modulatory site of action for MAOIs, it is not clear if this MAOA-like site is associated with the D2 receptor. Whereas it would be expected that [3H]Ro 41-1049 binding would be decreased in striata of D2 receptordeficient mice if the modulatory binding site is localized on the D2 receptor protein, the density of sites labeled by the MAOI is increased relative to wild-type controls [31]. This increase in binding may be a compensatory adaptation resulting from the deletion of the D2 receptor and could represent an increase in the density of MAOA and/or other [3H]Ro 41-1049 binding sites. Although this could represent an increase in the density of the site involved in the modulation of [3H]quinpirole binding, it is equally likely that the observed increase in [3H]Ro 41-1049 binding could mask the loss of any D2 receptorassociated [3H]Ro 41-1049 binding. The latter is particularly likely since the density of D2 sites is substantially lower than the density of [3H]Ro 41-1049 binding to MAOA. Accordingly, future studies must address the question of whether the [3H]quinpirole binding modulatory site is associated with the D2 receptor or another protein. Altogether, these findings suggest that MAOIs, a group of compounds heretofore not noted for activity at dopaminergic receptors, interact at a specific binding site in brain to modulate the binding of [3H]quinpirole to the D2 receptor. This raises fundamental questions about receptor-ligand interactions at that receptor. Hydrophobicity analysis indicates that the most probable tertiary structure of the cloned D2 receptor is consistent with those of the seven transmembrane-spanning, G-protein coupled receptors (for review see: [35]). Amino acid residues believed to be of importance in ligand binding include Asp-80 (TM2), Asp-114 (TM3), Cys-118 (TM3), Ser-193, 194, and 197 (TM5), and Asn-390 (TM6) [36–40]. The differential abilities of agonists and antagonists to elicit activation of the receptor is most likely due to differences in interactions with one, or more, or these residues via electrostatic interactions and/or hydrogen bonds. Accordingly, [3H]quinpirole might interact with the binding site of the D2 receptor in a manner that differs from that of other agonists and antagonists. Alternatively, [3H]quinpirole might bind to a unique site on the D2 receptor that is distinct from, but that interacts with, the binding site for [3H]spiperone, thus enabling competition with classical D2-like ligands. In either case, binding of a given ligand at a particular site might be inhibited by certain compounds, while that of other ligands is not. Such mechanisms would also be consistent with the observations that dopaminergic compounds, but not MAOIs, modulate quinpirole-stimulated [35S]GTPgS binding [41] and that the ability of quinpirole to inhibit [3H]spiperone binding is not altered in the presence of a MAOI [28]. Whether [3H]quinpirole interacts with the same binding site as [3H]spiperone or a separate site on the D2 receptor, the present data suggest that the modulation of [3H]quinpirole binding by MAOIs most likely occurs by an allosteric mechanism. If this modulation occurs via multiple binding sites on the D2 receptor or protein-protein interactions remains to be determined.

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Functional significance of the [3H]quinpirole-MAOI interaction As discussed above, repeated, intermittent administration of quinpirole in rats produces greater augmentation of locomotor activity than a single dose. This effect is known as behavioral sensitization. Consistent with the in vitro interactions between MAOIs and [3H]quinpirole-labeled sites, the MAOIs clorgyline and Ro 41-1049, which have high affinity in competition with [3H]quinpirole [28], block both the development and maintenance of quinpirole-induced sensitized locomotor behavior in rats [42,43]. In contrast, moclobemide, a MAOI with low potency vs. [3H]quinpirole in vitro [29], failed to block sensitization while producing alterations in monoamine turnover, attributable to inhibition of MAO, that were similar to those produced by clorgyline [42–44]. These observations demonstrate that MAOIs block development and maintenance of sensitization to quinpirole with a pharmacological profile similar to that observed for [3H]quinpirole binding in vitro. Furthermore, the mechanism by which sensitization is blocked cannot be attributed to altered dopaminergic tone resulting from the inhibition of MAO. This suggests that the actions of these drugs at the [3H]quinpirole binding modulatory site modifies the behavioral effects of quinpirole. Interestingly, although quinpirole-sensitized locomotor activity is inhibited by clorgyline, animals receiving the MAOI during the course of quinpirole treatment exhibit increased self-directed mouthing behavior [44], suggesting that the quinpirole-MAOI interaction may modulate complex behaviors rather than simply blocking the actions quinpirole. Sensitization to quinpirole has been of interest because sensitized animals exhibit a syndrome of compulsive revisiting of specific places in the rat’s environment, similar to the symptom of ‘‘checking’’ found in obsessive-compulsive disorder (OCD) patients [45,46]. Thus, quinpirole sensitization appears to have face validity as an animal model of checking in OCD. In this respect, it is noteworthy that some MAOIs were occasionally used in the treatment of OCD [47–49] though in a recent double-blind study, phenelzine did not prove better than placebo [50]. Conceivably, an interaction at the [3H]quinpirole binding modulatory site may be important in a subtype of OCD characterized by a predominance of checking compulsions. Whereas sensitization to quinpirole is of specific interest because of its relevance to OCD, the sensitization phenomenon, which can occur with any of a variety of psychostimulants and other drugs of abuse, is highly relevant to the development of addiction. According to the incentive-sensitization theory of addiction [51], repeated, intermittent drug use, which is the typical pattern of illicit drug use in humans, produces sensitization of the mesolimbic dopamine system that results in the user’s perception of the illicit drug changing from an ordinary stimulus into an incentive, ‘‘wanted’’ stimulus. These neuroadaptations appear to play a central role in the transition from drug use to addiction. In addition, sensitization, or a process analogous to sensitization, is hypothesized to contribute to a variety of other neuropsychiatric disorders including psychosis, mania, post-traumatic stress disorder, and panic disorder [21,45,52–55]. Accordingly, the [3H]quinpirole binding modulatory site may represent a potential therapeutic target in the treatment or prevention of these disorders. In addition to blocking sensitization to quinpirole, the actions of MAOIs at a specific non-MAO binding site in brain may be important in the drugs’ pharmacological effects. MAOIs have been used extensively in the treatment of major depression, panic disorders, bulimia, borderline personality disorder, and post-traumatic stress disorder [47]. The antidepressant effects of MAOIs are believed to result from the common ability of these drugs to block the catabolism of the monoamine neurotransmitters (serotonin, norepinephrine, and dopamine), thereby increasing their concentration in the synapse. In clinical practice however, maximal inhibition of MAO activity can precede antidepressant

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effects by as much as two weeks suggesting that the therapeutic effects of these drugs are mediated by a target other than MAO [56]. Accordingly, the interactions of MAOIs with the [3H]quinpirole binding modulatory site may represent a potential therapeutic target in the treatment of depression. It must be noted, however, that other classes of efficacious antidepressants, such as the tricyclic antidepressants and the uptake inhibitors fluoxetine and bupropion, do not possess high affinity for either [3H]quinpirolelabeled sites or [3H]spiperone-labeled sites [29] (Table 1). Thus, although therapeutic relevance is not necessarily predicated by a common mechanism, these data do not support a role for the [3H]quinpirole binding modulatory site in the antidepressant activity of MAOIs. Although the [3H]quinpirole binding modulatory site does not appear to underlie the antidepressant actions of MAOIs, the interaction may mediate certain side effects produced by the drugs. MAOIs are noteworthy in producing a wide array of side effects including weight gain, insomnia, daytime sleepiness, and sexual dysfunction [56]. These untoward effects could result from interactions at the [3H]quinpirole binding modulatory site associated with the tuberohypophysial and incertohypothalamic dopamine projections. Likewise, the [3H]quinpirole binding modulatory site in limbic brain areas may contribute to the hypomania that sometimes occurs with MAOI treatment.

Conclusion Taken together, these data indicate that certain presumably non-dopaminergic compounds, most notably MAOIs, modulate the binding of [3H]quinpirole at the D2 dopamine receptor. This interaction appears to mitigate the development and maintenance of behavioral sensitization to quinpirole. Moreover, MAOIs appear to inhibit [3H]quinpirole binding through actions at a specific binding site in brain that has similar pharmacology to, but is distinct from, MAOA. The specific identity of the [3H]quinpirole binding modulatory site must be elucidated in future studies, as must the mechanism by which binding at this site alters [3H]quinpirole binding at the D2 receptor.

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