Potential Antidepressant Activity of Sigma Ligands

Home , Ditolylguanidine, Panamesine, Siramesine

REVIEW

POTENTIAL ANTIDEPRESSANT ACTIVITY OF SIGMA LIGANDS

Gra¿yna Skuza

Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland

Potential antidepressant activity of sigma ligands. G. SKUZA. Pol. J. Pharmacol., 2003, 55, 923–934.

Despite many years’ studies of antidepressant drugs (ADs), their mechanism of action still remains unclear. Recently, it has been postulated that sub- stances capable of reducing neurotransmission at the NMDA complex may represent a new class of ADs. Since several ADs have a high affinity for s receptors, the s binding site may be a relevant mechanism in antidepressant action. Moreover, s ligands are able to modulate the activity of the central neurotransmitter systems, including noradrenergic, serotonergic, dopaminergic and glutamatergic (NMDA) ones, which are seemingly important for the mechanism of action of known ADs. The existence of at least two different s s s subtypes of receptors, denoted 1 and 2 is now widely accepted. The selective agonists of both s receptor subtypes are available at present. In par- s ticular, a potential antidepressant activity of 1 receptor agonists has been postulated, since the antidepressive-like actions of these compounds have been shown in animal models. This article reviews the findings related to potential antidepressant activity of new, selective s ligands.

Key words: sigma receptors, selective sigma ligands, antidepressant activity, animal models G. Skuza

3 Introduction Table 1. IC50 values for drugs competing with the [ H]ligands for s and phencyclidine (PCP) receptor binding sites (rat brain membranes) The term sigma (s) receptors was first proposed by Martin et al. [49] to explain, on the basis of in IC50 (nM) vivo experiments, the effects of benzomorphans, Compound (+)-[3H]SKF (+)-[3H]SKF [3H]TCP such as N-allyl-normetazocine (SKF 10,047), pen- 10,047 10,047 tazocine and cyclazocine which induced a charac- + TCP* + haloperidol teristic pattern of stimulation (“canine delirium”), (+)-SKF 10,047 55 320 405 differentiating these compounds from morphine- (–)-SKF 10,047 690 530 820 syndrome and ketocyclazocine- syndrome. Though (+)-3-PPP 45 > 50000 > 50000 s initially the receptors were considered to be Haloperidol 8 > 50000 > 50000 m k a type of opiate receptor (beside and ), later TCP 8330 25 10 studies (using more selective ligands and more pre- PCP 1450 48 66 cise techniques) convincingly demonstrated that Pentazocine 55 1520 3310 this opinion was not true. Further investigations have revealed that levorotatory form of SKF 10,047 * 1-[1-(2-thienyl)cyclohexyl]piperidine. According to [23] binds primarily to m and k opioid receptors, while its dextrorotatory analogue is distinguished by much s higher affinity for s site and considerable affinity affinity for site, binds to PCP receptor to much for phencyclidine (PCP) receptor. For these reasons, lesser extent (5–8 times) [23]. Martin et al. [49], who used (±)-SKF 10,047, ob- s served as well antinociceptive effects (resulting Characteristics and functions of receptor from the interaction with m and k opioid receptors The s receptors have been labeled and visualized mediated by (–)-SKF 10,047) as psychotomimetic with various radioligands using autoradiographic symptoms, believed to be an effect of (+)-SKF procedures. The numerous data demonstrate that s 10,047 binding to PCP receptors, not reversed by receptors are unevenly distributed in many brain an opiate antagonist, naloxone. areas and are quite abundant in various peripheral The lack of the selectivity shown by several tissues (the kidneys, lungs, intestine, muscles, and, compounds, including benzomorphans and PCP most of all, the liver). In the central nervous system, derivatives on the one hand, and similarities in bio- s receptors are concentrated in brainstem areas, chemical and behavioral effects of some s ligands certain limbic structures, some predominantly sen- and PCP on the other, suggested actions via the sory areas and brain regions associated with endo- same receptor site, so-called “s/PCP”. Further re- crine function [24, 55, 94]. sults (including autoradiographic studies using more Binding studies and in vivo or in vitro func- selective radioligands) demonstrated that s and tional bioassays led to the distinction of at least two s s s PCP receptors were distinct sites and their distribu- subpopulations of receptors, termed 1 and 2 [5, tion in brain regions was found to differ [23, 48, 55, 34, 65]. This classification is mostly based on dif- s 66]. ferences in binding of radioligands: 1 receptor is The use of nonselective ligands, including the able to distinguish between spatial isomers, show- prototypic agonist, N-allyl-normetazocine, to char- ing preference for dextrorotatory forms [(+)-penta- acterize s receptors resulted in an accumulation of zocine, (+)-SKF 10,047, dextrometorphan], whereas confusing and conflicting data which made the the levorotatory form of these compounds as well progress in this field more difficult. Table 1 pres- as haloperidol or 1,3-di-o-tolylguanidine (DTG) bind s s s ents differences in affinity of some ligands of and with high affinity also to the 2 receptors.The 1 PCP receptor sites. These data indicate that (+)-SKF sites are particularly concentrated in the hippocam- 10,047 shows 12.5 times higher affinity for s re- pal formation and other limbic areas (involved in ceptor than its levorotatory analogue, whereas both cognition and emotion), thus, they are suggested to forms exhibit the affinity for PCP receptor (dextro- play an important role in etiology and therapy of rotatory form is somewhat more potent) (Tab. 1). psychiatric disorders [13, 35, 36, 52, 94]. On the s On the other hand, pentazocine, having comparable other hand, the highest densities of 2 receptors

924 Pol. J. Pharmacol., 2003, 55, 923–934 POTENTIAL ANTIDEPRESSANT ACTIVITY OF SIGMA LIGANDS

were revealed particularly in regions related to mo- Table 2. Affinities of some compounds for s1 and s2 receptor tor functions (e.g. the motor cortex area, cerebel- sites in the rat brain membranes lum) supporting their possible involvement in the modulation of posture and movements induced by Kd or Ki (nM) Compound s ligands [5, 94]. s s s 1 2 However, 2 binding sites are also likely to modulate emotional responses, since Lu 28-179, a new Haloperidol 3.12 ± 0.23 55.0 ± 9.3 s (+)-Pentazocine 4.59 ± 0.26 1,052 ± 30 selective 2 receptor ligand, shows anxiolytic-like effects in mouse and rat black and white two-com- (–)-Pentazocine 7.41 ± 1.65 42.5 ± 1.7 partment box test, the rat social interaction test and DTG 17.9 ± 5.0 22.2 ± 3.5 the Vogel conflict test [71]. (+)-SKF 10,047 19.4 ± 4.6 2680 ± 444 Binding to s receptor is allosterically modu- 1 Progesterone 24.6 ± 6.6 15700 ± 100 lated by phenytoin and sensitive to the modulatory effects of guanosine triphosphate (GTP) and per- Testosteron 49.7 ± 11.7 > 50000 tussis toxin, which suggests its coupling to G pro- (–)-SKF 10,047 84.9 ± 10.7 1100 ± 170 s Dextrometorphan 85.5 ± 8.5 15800 ± 700 teins (Gi/o). It is thought that activation of 1 receptor implicates many second messenger cascades, Dizocilpine (MK-801) 47300 ± 3500 73600 ± 3300 including arachidonic acid cascade, protein kinase C translocation, modulation of the phosphorylation According to [56] state of specific proteins in the brain and phosphatidyl inositol turnover [19, 26, 60, 94]. Moreover, an An electrophysiological in vivo model for studies s interaction between ligands and calcium channels of selective s receptor ligands has been proposed has been suggested [see: 94]. The findings of Brent by Debonnel et al. [2, 12, 13, 59]. Numerous results et al. [7] demonstrated that protein phosphorylation s 2+ from this laboratory demonstrated that several 1 (dependent on extracellular Ca ) may be one of ligands, e.g. (+)-pentazocine, when applied by mi- the important mechanisms through which s ligands croiontophoresis or administered iv at low doses, produce their effects. potentiated the neuronal response to N-methyl-D- The most commonly used selective s receptor 1 aspartate (NMDA) in the CA region of the rat dor- ligand is (+)-pentazocine, although new, more se- 3 sal hippocampus but did not modify kainate- nor lective compounds of this type have been synthe- quisqualate-induced activations. Only a few s li- sized in recent years (e.g. SA4503), while the DTG, s s s gands, including NE-100 (N,N-dipropyl-2-[4-me- mixed 1/ 2 receptor agonist, has been used as 2 receptor ligand or radioligand (in the presence of thoxy-3-(2-phenylethoxy)phenyl]ethylamine) and (+)-pentazocine). As mentioned above, a selective haloperidol, did not modify NMDA-induced firing s receptor ligand, siramesine, has been introduced activity but suppressed the potentiation of NMDA 2 s recently [71, 86]. The s receptor ligands used so response induced by agonists. Thus, they were s s s far showed low selectivity for its two subpopula- denoted antagonists. Similarly to 1 ligands, 2 tions and for other receptors, particularly dopamine agonists also potentiate the NMDA response [12]. s receptors. For instance, haloperidol, a typical neuro- A majority of agonists tested thus far generate s bell-shaped dose-response curves with respect to leptic, shows high affinity particularly for 1 sites s potentiation of NMDA response. It is worth em- and relatively lower for 2 sites. On the other hand, the aforementioned compound DTG binds with phasizing that this dose-response relationship s s seems characteristic of s receptor ligands, and was comparable potency to both 1 and 2 receptor subtypes (Tab. 2). Interestingly, some neurosteroids (e.g. observed in some behavioral models as well [12, progesterone, testosterone) exhibit marked selecti- 54]. Additionally, neuroactive steroids in nanomo- s vity for 1 receptor [53, 91]. Progesterone was the lar range also modulate the NMDA-mediated re- most effective, inhibiting [3H]SKF 10,047 the bind- sponses. DHEA potentiated the NMDA-evoked ing in the rat brain homogenate at nanomolar con- electrical activity of CA3 hippocampal pyramidal s centrations, while pregnenolone, dehydroepiandros- neurons, as do 1 receptor agonists, that could be terone (DHEA) and testosterone effects were rela- blocked by haloperidol or NE-100, as well as by tively weaker. progesterone [3].

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s Recently, the 1 receptor was purified and cloned Moreover, recent reports have confirmed earlier s from several species (guinea pig liver, human pla- suggestions that 2 ligands modulate the dopamine s cental cell line and brain, from mouse kidney and transporter (DAT). Activation of 2 receptors re- brain and from rat brain) and completely sequen- sults in the regulation of DAT activity via a cal- ced, showing that this protein was unrelated to cium- and protein kinase C-dependent signaling s known transmitter receptors [e.g. 58, 77]. The 1 mechanism [14]. Because of the crucial role played receptor is a low molecular weight protein (27 kDa) by DAT in the mechanism of action of several composed of 223 amino acids, and has a single, pu- drugs of abuse, it is possible that drugs with anta- s tative transmembrane segment anchored in the en- gonistic activity at 2 receptors might be of value doplasmic reticulum membrane. This is a unique in treating drug abuse. protein, which does not show homology with any protein present in mammalian brain tissue. The Potential antidepressant activity of s studies using a polyclonal antibody technique re- ligands vealed that the immunolocalization of s receptors 1 Several lines of evidence suggest a possible re- is associated with the mitochondrial membranes lationship of s receptors and psychosis, e.g. psy- and endoplasmic reticulum [58]. chomimetic activity of benzomorphan derivatives Functional effects attributed to s receptor in- 1 exhibiting high affinity for s receptors or high af- clude antipsychotic effects (NE-100, panamesine, finity of many neuroleptics (including haloperidol) E-5842) [25, 61,74], antagonistic action against co- for this receptors [33, 94]. Moreover, activities of caine- and amphetamine-induced excitation and sen- dopaminergic neurons (especially in the substantia sitization, neuroprotection and prevention of experi- nigra and ventral tegmental area, VTA) are vari- mentally evoked amnesia in animals [52, 54, 76, ously modified by the systemic administration of s 98]. The two former effects may be due to the fact ligands [13, 21, 22, 30, 57]. that, besides their well-documented interaction with s s A potential of receptors to be implicated in NMDA system, the 1 agonists are able to modulate AD action started to be considered much later [2, (directly or indirectly) the cholinergic neurotrans- 13, 28, 35]. Many findings implied that ADs, repre- mission. SA4503, DTG and (+)-SKF 10,047 (simi- senting different chemical groups, e.g. iprindol (aty- larly to neurosteroids, e.g. pregnenolone sulfate) pical AD), clorgyline (MAO-I) or sertraline (a se- enhanced acetylcholine release in the rat brain cor- lective serotonin reuptake inhibitor, so-called SSRI) s tex and hippocampus. Moreover, the 1 receptor inhibited binding of selective s receptor radioligands inhibited carbachol-induced phosphatidyl ligands in the mouse and rat brain homogenates inositol turnover in the rat brain and nicotine-sti- [27, 28, 35]. In addition, fluvoxamine, maprotiline mulated catecholamine release [see 53]. It is worth and opipramol (at nanomolar concentrations) showed reminding that many neuroleptics, most of all ha- high affinity for s receptor [72]. A majority of loperidol, are characterized by high affinity for s 22 clinically active ADs inhibited [3H]pentazocine receptor [33]. At present, the selective s receptor s 1 binding to 1 receptor in the mice forebrain ho- ligands, both agonists: (+)-pentazocine, SA4503 m mogenate (IC50 = 0.1–10 M) [see: 35]. Chronic and an antagonist, NE-100, are available [51, 61]. AD administration also modulated the concentra- s Much less is known about 2 receptor. Contrary tion of radioligand binding to s receptors in differ- to s , s receptor has not been cloned as yet but it s 1 2 ent brain regions, usually down-regulated 1 recep- is thought that its protein possesses similar molecu- tors [see: 13, 78]. lar weight between 18–21 kDa. An authoradiogra- Though mechanism of AD action has been s phic study with 2 receptor radioligands revealed studied for many years, it remains unclear in detail its highest densities in the cerebellum, motor cor- and still new hypotheses are proposed. The first tex, and substantia nigra pars reticulata. As well one, developed in the 1960s, was monoaminergic localization as other experimental data (dystonias hypothesis, which linked mechanism of AD action in rats after administration of s receptor ligands to an increase in noradrenaline and/or serotonin s into the red nucleus) indicate a potential of 2 re- level in the synaptic cleft, caused by inhibition of ceptor to contribute to regulation of motor func- either monoamine reuptake or their metabolism af- tions [86, 94]. ter a single drug administration [8, 11, 75]. Accord-

926 Pol. J. Pharmacol., 2003, 55, 923–934 POTENTIAL ANTIDEPRESSANT ACTIVITY OF SIGMA LIGANDS ing to this hypothesis, depression would be an ef- receptors in neocortical membranes, as demonstra- fect of deficient monoamine concentrations, and ted by reduction of the potency of glycine to inhibit thereby reduced neurotransmission. Its core idea, [3H]-5,7-dichlorokynurenic acid binding [64]. This viz. a relationship between antidepressant effect effect showed better correlation with clinical effi- and facilitation of monoaminergic neurotransmis- cacy of ADs than Porsolt’s test or b-adrenergic sion still remains valid, which has been supported down-regulation. Moreover, a small clinical trial by clinical studies. However, clinical experience recently demonstrated that iv infusion of ketamine, indicates that a single administration of ADs it not an uncompetitive NMDA receptor antagonist, pro- enough to achieve therapeutic efficacy, thus, anti- duced a long-lasting (days) antidepressive action [4]. depressant effect is presumably a result of adaptive In general, the Skolnick’s hypothesis combines changes caused by long-term AD treatment. the two different treatment strategies: monoamine The hypothesis of b-adrenoceptor down-regula- and glutamate/NMDA, to produce directly (e.g. tion was the first proposal, that included the above NMDA receptor antagonists) or indirectly (by mo- observations. In the middle of the 1970s, Vetulani dulating other neurotransmitter systems or intracel- and Sulser [93] showed that repeated (but not sin- lular factors, e.g. BDNF) the same endpoint, i.e. re- gle) AD administration reduced reactivity of nor- duction of the NMDA function [79, 80]. adrenergic cyclic AMP generating system in the It is widely accepted that s receptors are able to limbic forebrain. This finding and other data accu- modulate the neuronal activity, especially the ef- mulated within the next years were the basis of the fects of monoaminergic neurons and hippocampal hypothesis which was generally accepted, since the neuron activity. When applied with microionto- most of ADs (representing different mechanism of phoresis, they were reported to increase dopamin- action) therapies with were found to reduce the cy- ergic neuron activity in the VTA. Serotonergic neu- clic AMP response or the density of b-adrenocep- rons in the raphe nucleus and noradrenergic neu- s tors in the cerebral cortex [87, 92]. rons in the locus coeruleus were activated by s More or less at the same time, other theories ligands. In the hippocampus, receptors are thought were created and developed, including serotonin to play a role in the modulation of the glutamater- [9, 20, 31] or dopamine [37, 67, 95] hypotheses. gic neurotransmission, via indirect modulation of The latter has been a focus of many studies con- the NMDA receptor [2, 12, 13, 59, 97]. The results ducted at our Institute [16, 17, 37, 39–42, 44, 45], using extracellular single-unit recordings from py- which demonstrated that repeated treatment with ramidal neurons of CA3 region of the rat dorsal hip- s almost all clinically active ADs activated the dopa- pocampus showed that selective ligands at low mine system by increasing responsiveness to sti- doses exert a potentiating effect on NMDA-induced neuronal activation [12]. Many data have mulants, including dopamine. This finding was s supported by biochemical studies, which revealed focused on involvement of receptors in the that AD treatments might increase the density of modulation of the glutamatergic (NMDA) neuro- dopamine D and D receptors in the respective transmission on the dopaminergic (particularly 2 3 mesocorticolimbic) neurons [e.g. 21, 57]. In addi- brain structures as well as raise the concentration of tion, radioligand binding data indicate the presence mRNA encoding dopamine D receptors in the lim- 2 of a moderate density of s receptors in limbic bic structures of the rat brain [16, 17, 69]. structures, e.g. hippocampus, amygdala, septum and The basis of glutamatergic (NMDA) hypothe- frontal cortex. These findings may have an essen- sis, which was developed in the 1990s, was the dis- tial significance for potential antidepressant activi- covery of Skolnick et al. that NMDA receptor ty of s ligands. changes may be involved in the action of ADs [for review see: 79]. It was found that NMDA receptor SA4503, the selective s receptor agonist antagonists (MK-801, CGP 37849, CGP 40116) 1 decreased the immobility time in the tail suspen- The compound SA4503 is the recently de- sion and in Porsolt’s test as well as in the chronic scribed, selective s receptor ligand, characterized mild stress (CMS) model [46, 47, 62, 63, 89]. On on the basis of biochemical in vitro experiments as the other hand, repeated treatments with ADs its agonist [51]. Preliminary studies indicated that down-regulated the strychnine-insensitive glycine this compound decreased immobility time in tail

ISSN 1230-6002 927 G. Skuza suspension test and in Porsolt’s test in mice [50, desipramine). Some results suggested that SA4503, 90]. Moreover, some authors reported that SA4503 like DTG or (+)-pentazocine, facilitated the dopa- attenuated the learning impairment induced by minergic transmission in the frontal cortex, a brain non-competitive NMDA receptor antagonists in area that is believed to play an important role in the different pharmacological models (spontaneous al- pathophysiology of depression [e.g. 21, 22, 57]. ternation, step-down and step-through type of pas- As mentioned above, SA4503 decreased immo- sive avoidance tests) [54]. bility time in the forced swimming test in mice and Biochemical studies demonstrated that SA4503 rats. Similar effects were observed after admini- increased the level of dopamine and its metabolite, stration of (+)-pentazocine and DTG to mice and dihydroxyphenylacetic acid (DOPAC), in the rat rats [50, 83]. Those antidepressant-like effects were s frontal cortex (but not in the hippocampus, stria- antagonized by the 1 receptor antagonist, NE-100 tum, cerebellum, hypothalamus), which was inhi- [50]. Moreover, SA4503 exerts a synergistic effect s bited by a selective 1 receptor antagonist, NE-100 with imipramine (either compound being used at [30]. The elevated accumulation of L-DOPA in the doses inactive per se) in Porsolt’s test [84]. A simi- frontal cortex was also reported after blockade of lar synergistic effect was observed after imipra- DOPA decarboxylase activity by NSD-1015, sug- mine and other new potential antidepressants, e.g. gesting a rise in dopamine turnover in this brain re- pramipexole [ 43]. It is worth adding that DHEA s gion [30]. On the other hand, electrophysiological sulfate and pregnenolone sulfate acting as 1 recep- studies demonstrated that repeated administration tor agonists, induced a reduction of immobility of SA4503 (once a day for 21 days) produced a sig- time in the forced swimming test, which was re- s nificant increase in the number of spontaneously versed by NE-100, a 1 antagonist [91]. active VTA dopaminergic neurons, which was in- Our results show (Tab. 3) that similarly to a ma- hibited by NE-100 [57]. This alteration produced jority of ADs, repeated (but not acute) treatment by SA4503 resembles that reported for clinically with SA4503 increases amphetamine- and quinpi- active ADs (e.g. paroxetine, fluoxetine, citalopram, role- (but not 7-OH-DPAT)-induced hyperactivity

Table 3. Comparison between effects of SA4503, a selective s1 receptor agonist, and some antidepressant drugs (after their repeated administrations) in behavioral tests

Amphetamine- Quinpirole- 7-OH-DPAT- Apomorphine- Clonidine-induced Phenylephrine- Drug induced hyper- induced hyper- induced hyper- induced stereo- aggressiveness induced hyperactivity (rat) activity (rat) activity (rat) typy (rat) (mouse) exploration (rat)

Imipramine – Citalopram – Milnacipran – – SA4503 ––

See [38, 82, 84]

Table 4. Comparison between effects of SA4503, a selective s1 receptor agonist, and some antidepressant drugs (after their repeated administrations) in biochemical tests (dopaminergic system)

Autoradiography mRNA level (in situ hybridization)

Drug 3 3 3 [ H]Raclopride [ H]Quinpirole [ H]7-OH-DPA D1 D2 (D2/D3 antagonist) (D3/D2 agonist) (D3 agonist) Venlafaxine (30) – () – – Milnacipran (30) ¯ – – – Reboxetine (30) – –(¯) –(¯) – – SA4503 (3) – – – ¯

See [38, 81]

928 Pol. J. Pharmacol., 2003, 55, 923–934 POTENTIAL ANTIDEPRESSANT ACTIVITY OF SIGMA LIGANDS in rats. The lack of influence on the amphetamine- antagonists, showed positive interaction in the induced stereotypy indicates that a pharmacokine- forced swimming test in rats [70]. This interaction tic interaction between SA4503 and D-amphet- is particularly interesting in the case of SSRI (e.g. amine as well as involvement of the nigrostriatal fluoxetine), which did not show an antidepressant- dopamine system, may be excluded. Additionally, like activity in this test carried out in accordance SA4503 given repeatedly, enhanced the effect of with the original method of Porsolt, when given a phenylephrine, an 1-adrenoceptor agonist, and clo- alone [see: 6]. It should be emphasized that combi- a nidine (stimulating the postsynaptic 1-adrenocep- nations of these drugs, administered according to tor at high dose) in behavioral models (hyperex- the same experimental schedule, did not increase ploratory activity in rats and aggressiveness in mice, locomotor or exploratory activity. respectively) [82]. The s receptor ligands (SA4503, DTG) admin- Summing up, enhancement of amphetamine- istered jointly with amantadine (all at inactive and quinpirole-induced locomotor hyperactivities, doses when given alone) showed antidepressant- together with an increase in the behavioral effects like activity in rats [85]. It is noteworthy that both a of treatment with 1-adrenoceptor agonists, may amantadine and memantine exhibit marked affinity suggest that repeated treatment with SA4503 up-re- for s receptor [32]. Moreover, joint administration a gulates D2-mediated dopaminergic and 1-adrene- of SA4503 or DTG with CGP 37849, a competitive rgic transmission, both these effects being impor- NMDA receptor antagonist, elicited positive inter- tant for clinical antidepressant activity [82, 84]. action in Porsolt’s test in rats [own unpublished Biochemical studies show that repeated admini- data]. s stration of typical ADs (e.g. imipramine, citalo- In recent years, a selective 2 receptor ligand, pram or mianserin) increases the binding (density siramesine, has been introduced. It exhibited anxiolytic potential (social interaction test, Vogel’s test) and affinity) to D2 and D3 receptor in the respective brain structures, as well as the concentration of and moderate antidepressant activity in CMS model [71, 73]. Siramesine neither per se affected ac- mRNA coding for dopamine D2 receptors [16, 17, 40, 69], whereas newer ADs (venlafaxine, milnaci- tivity of rats in Porsolt’s test nor did it show any pran, reboxetine) did not evoke such significant activity after combined administration with imipra- changes (Tab. 4). Both an increase, a decrease and mine. However, its co-administration with aman- a lack of any changes in the radioligand binging tadine decreased the immobility time in the forced ([3H]raclopride and [3H]quinpirole) were observed, swimming test, but only at one dose (the same as and the only statistically significant effect in com- that active in CMS test) [85]. The above-described parison with the control group was obtained with and some previous results indicate that activation s s milnacipran, while reboxetine showed only slight of (particularly 1) receptor may be one of possi- activity. SA4503, administered repeatedly, did not ble mechanisms by which drugs induce an antidepressant-like activity in the Porsolt’s test and that influence radioligand binding to D2 and D3 receptors. It should be noted that its effects on expres- this effect is enhanced by NMDA receptor antagonists. Thus, s receptors may be involved in the be- sion of mRNA coding for D1 and D2 receptors were different than responses to both classic (e.g. imi- havioral responses in depression. pramine) and newer (milnacipran or reboxetine) ADs. SA4503 raised the concentration of mRNA Other new s ligands with potential coding for D1 receptor (in the shell of the nucleus antidepressant activity accumbens septi) and reduced D2 mRNA level (in the striatum), whereas tricyclic ADs enhanced ex- Igmesine (JO1783) s pression of mRNA coding for D2 receptor [81] (or Igmesine (JO1783) has been used as receptor did not alter D1 and D2 mRNA level, as milnacipran ligand in different studies (electrophysiological, or reboxetine did) [see: 38]. Further studies are re- behavioral, biochemical). It is now known that it s quired for precise elucidation of the above bio- exhibits high selectivity for 1 receptors (IC50 for s chemical changes exerted by SA4503. 2 receptor is > 1000 nM). Igmesine administered Our latest studies demonstrated that ADs admi- repeatedly (once a day for 21 days) induced a num- nistered in combination with amantadine, meman- ber of interesting changes, e.g. significant decrease tine or neramexan, uncompetitive NMDA receptor in the binding density of b-adrenergic receptors (al-

ISSN 1230-6002 929 G. Skuza though it does not bind to these receptors), thereby and were periodically abandoned, which was mostly resembling most of ADs. Moreover, igmesine in- caused by a lack of appropriate tools and methods. creased noradrenaline release in the rat prefrontal As was demonstrated by recent findings, s receptor cortex (as measured by microdialysis) and decreased is a unique protein, distinct from any known mam- tyrosine hydroxylase activity after its repeated malian receptors. This property can indicate that treatment [10]. mechanism underlying s receptor function is also Although igmesine does not directly interact different. One of the possibilities is that the intra- s with serotonin receptors, upon repeated treatment cellular 1 receptor regulates several components schedule, it augmented serotonin release, measured implicated in plasma membrane related signal trans- with microdialysis in the rat prefrontal cortex [10]. duction. Like imipramine or many s receptor ligands, Though the physiological role of these recep- igmesine inhibited the NMDA-induced increase in tors still remains unclear, their well-documented in- cGMP level in the rat cerebellum slices [1, 68, 94, teraction with NMDA system is worth recognition, 96]. This effect can result from igmesine influence as NMDA receptor complex is known to play an on nitric oxide synthase activity, which was dem- important role in neurodegenerative processes, onstrated for some other s receptor ligands [18]. learning and memory, and, according to glutama- This pathway appears highly probable as one of tergic theory, in the pathomechanism of depression. possible ways in which s ligands can modulate ac- Discovery that some neurosteroids exhibit tivity of NMDA receptor complex. marked affinity for s receptors is another interesting finding of recent years. Among steroids, pro- OPC-14523 s gesterone has the highest affinity for the 1 recep- In vitro studies have demonstrated that OPC- tor and its physiological concentrations in brain 14523 at nanomolar concentrations binds to s re- and plasma may be sufficient to allow for a signifi- s ceptor (to both its subtypes to similar degree), and cant interaction with 1 sites. These data suggest that neurosteroids can be an important link in the to 5-HT1A receptor [29, 88]. Moreover, it might block the serotonin transporter in vivo and suppress mechanism of action of s receptor ligands, and its reuptake but this effect appears to be insufficient they can play a role of their endogenous ligands s to mediate the acute antidepressant-like activity. In- (e.g. progesterone for 1 receptor). vestigations of Tottori et al. [88] suggest that In spite of many unknowns still awaiting clarifi- s s OPC-14523 action in the forced swimming test ap- cation, the recently introduced selective 1 and 2 peared earlier than after fluoxetine and even imi- receptor ligands not only can contribute to under- pramine, since it could be observed already after standing of a role and mechanism essential for a single dose of this compound (with lack of influ- function of these receptors but also they have a potential to be used in the treatment of various dis- ence on basic locomotor activity). The 5-HT1A receptor agonists, e.g. 8-OH-DPAT, induce rapid and eases of the central nervous system, e.g. as antiam- effective antidepressant-like action in the forced nesic, antipsychotic or antidepressant drugs. swimming test [e.g. 15]. OPC-14523-induced decrease in immobility time in this test in mice and s REFERENCES rats was antagonized both by NE-100, a 1 receptor antagonist, and by 5-HT1A receptor antagonist, 1. Akunne H.C., Zoski K.T., Whetzel S.Z., Cordon J.J., WAY-100635 [88]. Brandon R.M., Roman F., Pugsley T.A.: Neurophar- It seems that unique mechanism of action of macological profile of a selective sigma ligand, igmesine: a potential antidepressant. Neuropharmacology, OPC-14523, combining antagonism at 5-HT1A and s receptors, amplifies its antidepressant potential 2001, 41, 138–149. 2. and can manifest itself as quicker and more effi- Bergeron R., Debonnel G., de Montigny C.: Modifica- tion of the NMDA response by antidepressant s-rece- cient clinical effect. ptor ligands. Eur. J. Pharmacol., 1993, 240, 319–323. 3. Bergeron R., de Montigny C., Debonnel G.: Potentia- Summary and conclusions tion of neuronal NMDA response induced by dehy- droepiandrosterone and its suppression by progester- In almost 30-year history of s ligand research, one: effects mediated via s receptors. J. Neurosci., investigations sometimes encountered difficulties 1996, 16, 1193–1202.

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