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Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 362 – 373 www.elsevier.com/locate/pnpbp Mechanisms of action of current and potential pharmacotherapies of obsessive-compulsive disorder Mostafa El Mansari, Pierre Blier * University of Ottawa Institute of Mental Health Research, Lady Grey Building, 1145 Carling Avenue, Ottawa, ON, Canada K1Z 7K4 Available online 20 January 2006 Abstract A significant body of evidence documented that the orbitofrontal cortex (OFC) and the head of caudate nucleus are involved in the mediation of obsessive-compulsive disorder (OCD) symptoms. Potent serotonin (5-HT) reuptake inhibitors (SRIs) are the only antidepressant agents thus far shown to be effective in the treatment of OCD. The present review summarizes information on 5-HT release and the adaptive changes in pre- and postsynaptic 5-HT receptors sensitivity induced by SRI treatment in rat and guinea pig structures involved in OCD. It emphasizes that the time course for the occurrence of increased 5-HT release and terminal 5-HT1D desensitization is congruent with the delayed therapeutic response to SRI in OCD. In addition, a greater dose of SRI inducing a greater degree of reuptake inhibition may play an essential role in this phenomenon. This is consistent with the common clinical observation that high doses of SRIs are sometimes necessary to obtain an anti-OCD effect, and with the results of some fixed-dose double blind trials showing a dose-dependent therapeutic effect of SRIs. It is hypothesized that enhanced 5-HT release in the OFC is mediated by the activation of normosensitive postsynaptic 5-HT2-like receptors and underlies the therapeutic action of SRI in OCD. This is supported by the beneficial effect of some hallucinogens with 5-HT2 agonistic properties in obtaining a more rapid therapeutic response. Finally, based on this knowledge, new strategies aimed at producing more rapid, effective and safe anti-OCD drugs, such as a selective action on terminal 5-HT1D receptors, on 5-HT2 receptors as well as on the glutamate system, are discussed. D 2005 Published by Elsevier Inc. Keywords: Glutamate; Obsessive-compulsive disorder; Orbitofrontal cortex; Serotonin; Serotonin reuptake inhibitor; 5-HT1A receptor; 5-HT2 receptor; 5QHT1D receptor 1. Introduction Although there are few data to support a primary involvement of the brain serotonergic systems in the pathogenesis of obsessive-compulsive disorder (OCD), a substantial body of evidence clearly indicates a pivotal role of this neurotransmitter in the pharmacotherapy of this syndrome (see review Park et al., 1997; Insel et al., 1985). In OCD patients, only the potent Abbreviations: 5-CT, 5-carboxamidotryptamine; 5-HIAA, 5-hydroxyindoleacetic acid; 8-OH-DPAT, 8-hydroxy-2-di-n-propylamino-tetralin; ACTH, adrenocorticotropic hormone; DBS, deep brain stimulation; DOI, 1-(2,5dimethoxy-4-iodophenyl)-2-aminopropane; mCPP, 1-(3-chlorophenyl)piperazine; MAOI, monoamine oxidase inhibitor; mPFC, medial prefrontal cortex; NMDA, N-methyl-d-asparate; OCD, obsessive-compulsive disorder; OFC, orbitofrontal cortex; serotonin, (5-hydroxytryptamine, 5-HT); SRI, serotonin reuptake inhibitor; TCA, tricyclic antidepressant. * Corresponding author. University of Ottawa Institute of Mental Health Research, 1145 Carling Avenue, Lady Grey Building, Room 2043, Ottawa, ON, Canada K1Z 7K4. Tel.: +1 613 722 6521x6908; fax: +1 613 792 3935. E-mail address: [email protected] (P. Blier). 0278-5846/$ - see front matter D 2005 Published by Elsevier Inc. doi:10.1016/j.pnpbp.2005.11.005 serotonin (5-HT) reuptake inhibitors (SRIs) are consistently effective (Jenike, 1993). For instance fluoxetine, paroxetine, sertraline, fluvoxamine and citalopram have been demonstrated to significantly attenuate OCD symptoms in placebo-controlled trials (Fontaine and Chouinard, 1985; Bergeron et al., 2002; Denys et al., 2004; Goodman et al., 1997; Gorman and Kent, 1999). In addition, the tricyclic antidepressant (TCA) clomipramine, which is a potent 5-HT reuptake inhibitor, produces an anti-OCD effect, but a relapse takes place when patients are switched in a double-blind fashion to the TCA desipramine, which is a selective noradrenergic reuptake inhibitor (Leonard et al., 1991). It was reported also that the addition of desipramine to OCD patients does not produce a therapeutic effect (Barr et al., 1997). Clearly then, the anti-OCD effect, unlike the antidepressant response, rests largely on the inhibition of the 5-HT reuptake process (Goodman et al., 1989, 1990). Positron-emission tomography studies have implicated specific brain areas in OCD, in particular a neuronal loop P.M. as indicated by the (À) sign. the reduction of OFC and caudate nucleus activity has been associated with clinical improvement in OCD patients who responded to either therapy (Baxter. 1992. however. 1.. the head of the caudate nucleus. Brody et al. . 1992. 1998)... 1985. Le Poul et al. All 5-HT receptors and a2-adrenoceptors located on 5-HT neurons exert a negative feedback influence on 5-HT release. Moret and Briley.1. 1999). mediated via different mechanisms (Fig. provocative stimuli that induce OCD symptoms increase regional cerebral blood flow in the OFC and the head of caudate nucleus (Rauch et al.. Indeed. and the thalamus (Baxter et al. Repeated but not single electroconvulsive shock administration induces a sensitization to 5-HT in the hippocampus. Effects of antidepressant treatments on 5-HT neurotransmission Several studies using a variety of techniques have documented that many types of antidepressant treatments enhance 5-HT neurotransmission in the rat hippocampus (see Blier and de Montigny. taking in account a requirement for a much longer delay of treatment and higher doses of SRIs in OCD than in depression. Brody et al. 1991. 1998.. Only the 5-HT receptors for which an electrophysiological response has been identified in unitary recording studies are depicted. Interestingly.. 1983.. an increased metabolic activity has been observed in these brain regions in OCD and successful treatment. Presynaptic and postsynaptic factors regulating the efficacy of serotonin (5-hydroxytryptamine. Baxter.. 1986. 1989.. 1987. 1). followed by a gradual recovery of this parameter following continuation of treatment for 2 – 3 weeks (Blier and de Montigny. Based on the adaptive changes induced by SRIs on 5-HT neurotransmission. 1994).. Saxena et al. Swedo et al. 1. 1994). MAOIs enhance 5-HT transmission Fig. leaving unaltered the function of 5-HT neurons (De Montigny. 5-HT) neurotransmission. those induced in brain regions involved in OCD are summarized. Blier and Bouchard. 1990).. whether it be pharmacologic or behavioral. HoehnSaric et al. Blier / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 362 – 373 363 involving the orbitofrontal cortex (OFC). SRIs and monoamines oxidase inhibitors (MAOIs) induced an initial attenuation of the firing activity of 5-HT neurons on treatment initiation. Schwartz. 1992. El Mansari. 1990. 1995). 1992). Nordahl et al. is associated with a normalization of their metabolic activity (Benkelfat et al. largely investigated in depression related brain structures studies. 1984. This net effect that is common to the major types of antidepressant treatments is. or neuronal firing in the case of the 5-HT1A autoreceptor.. This is paralleled by the desensitization of terminal 5-HT autoreceptors that exert a major influence on the amount of 5-HT that is released per impulse (Chaput et al. 1991. Swedo et al. Furthermore. 1998). 1992. It is possible that the difference in time constants of autoreceptor desensitization in the hypothalamus/hippocampus versus the OFC reflects distinct autoreceptors and/or different mechanisms modulating the function of this receptor. Pharmacological evidence already shows distinct properties of pre.... Blier / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 362 – 373 by increasing the amount of 5-HT released per action potential as result of a greater concentration of 5-HT in the terminals (Blier et al.. El Mansari et al. might underlie at least in part. 1994. The desensitization of the 5-HT1D autoreceptor in OFC after 8-week paroxetine treatment stands in contrast with the one obtained after only 3-week in hippocampus and hypothalamus. with 10 mg/kg/day of fluoxetine but not with 5 mg/kg/day (Fig. that the maximal therapeutic effect of SRI is obtained after a longer delay in OCD than in depression (Fineberg et al. the electrically evoked release of [3H]-5-HT from preloaded guinea pig brain slices was enhanced in the frontal cortex and hypothalamus. the increase in such evoked 5-HT release in OFC was found only after an 8-week treatment with paroxetine or fluoxetine (Fig. 1999a)... 1986. Chaput et al. 1992).2. whereas the one activated by 5methoxytryptamine is not (El Mansari and Blier. 1994). 1. Bergqvist et al. 1999a). 1996).. 1988. The (À) sign indicate a decrease in activity in the orbitofrontal cortex and the caudate nucleus. 2. El Mansari et al. 1995). the therapeutic efficacy of SRI in major depression.. The neuronal loop involved in mediating obsessive-compulsive disorder symptoms and sites of action of different therapeutic measures. 1995. 1990). (2) a larger dose of SRI inducing a greater degree of reuptake inhibition may play an essential role in the desensitization of terminal 5-HT autoreceptor. Interestingly. 2 and 3. it has been shown that following a 3week paroxetine treatment. 5. Bergqvist et al... This is consistent with the common clinical observation that high doses of SRIs are sometimes necessary to obtain an anti-OCD effect. but not in the OFC or in the head of caudate nucleus (Figs. 1990). 1995. 1993.than postsynaptic 5-HT1D receptors (Beattie and Connor. 1986). 1991. 1993). CP122. these data indicate that (1) the time course for the occurrence of this adaptive change in the OFC is congruent with the delayed therapeutic response to SRI in OCD and that this phenomenon could underlie the therapeutic effect of SRIs in OCD. However. Moret and Briley.. it is well documented clinically. Finally. 1995. a brain region also involved in OCD syndrome (El Mansari et al. Wilkinson et al. 1995). SRI stands for serotonin reuptake inhibitor. after the same period of treatment. This increase was more important in the OFC compared to the dorsal frontal cortex of the same animal and was reported to be attributable to a desensitization of the terminal 5-HT autoreceptor in the former brain region. 1. Tollefson et al. Bergqvist et al. El Mansari et al. based upon the differential potency of the 5-HT1/2 antagonist methiothepin against 5-HT versus the 5-HT1D agonist sumatriptan and the 5-HT1 agonist 5-carboxamidotryptamine (5-CT). 4. The bar between the orbitofrontal cortex and the head of caudate nucleus indicates a lesion of the internal capsule where fibres pass to link the two structures. 1995. Gupta et al. It is thus conceivable that postsynaptic 5-HT receptors in the OFC could become desensitized following prolonged administration of SRIs.and postsynaptic 5-HT1D receptors. 5-HT1A receptor agonists produce an enhanced tonic activation of postsynaptic 5-HT1A receptors in the presence of the exogenous 5-HT1A agonist acting on normosensitive postsynaptic 5-HT1A receptors following normalized firing activity of 5-HT neurons and 5-HT release as well (Blier and de Montigny. suggested the existence of two receptors mediating the inhibition of [3H]5-HT release in the guinea pig hippocampus. thereby dampening the effect of the enhanced 5-HT Fig. 1992.. suggesting a differential effect on 5-HT uptake.. Altogether.364 M. El Mansari. P. but not in the frontal cortex (Wilkinson and Middlemiss. Effects of SRIs on postsynaptic 5-HT receptors in brain regions involved in OCD It is important to emphasize that not only alterations of presynaptic neurotransmitter components can underlie the effectiveness of drug treatments but also that the responsiveness of postsynaptic 5-HT receptors can be important and may contribute as well to alter overall 5-HT transmission. . 5-HT release and autoreceptor sensitivity were still unaltered in the head of the caudate nucleus.. 1995). and with the results of some fixed-dose double blind trials showing a dosedependent therapeutic effect of SRIs (Montgomery et al. Wilkinson et al. Greist et al. Moreover. Furthermore..3. an analogue of sumatriptan is at least 3 times more potent at pre. However. 1992. such as the hippocampus and hypothalamus (Blier and Bouchard.. Montgomery and Manceaux. Consistent with this clinical observation. 1999a). Blier et al. Effects of SRIs on presynaptic 5-HT receptors in brain regions involved in OCD It was proposed that the enhanced 5-HT transmission occurring through terminal 5-HT autoreceptor desensitization in certain brain regions.. A similar increase in 5-HT release and a desensitization of terminal 5-HT autoreceptors was also obtained in the guinea pig OFC. El Mansari et al. Indeed. it was demonstrated that the 5-HT1D autoreceptor subtype activated by sumatriptan. This increase in 5-HT release is entirely attributable to a desensitization of the 5-HT transporter in the frontal cortex and to terminal 5-HT1D autoreceptor desensitization in the hypothalamus (Blier and Bouchard. 1994. 1995. is coupled with G proteins in hippocampus.288. The concentration effect curves were compared using two-way analysis of variance. is attenuated (Blier et al. El Mansari and Blier. In fact. a small but significant desensitization of 5-HT1A receptors was observed in constitutional 5-HT transporter knockout mice (Gobbi et al. indicating a desensitization of postsynaptic 5-HT1A receptor in this rat brain region (Fig. 2001. 2005). 3. no modification in the inhibitory effect of 5-HT itself.S.M.. El Mansari. P. 1996a. 1998. Raap et al. In the hippocampus.. and B on the inhibitory effect of the 5-HT autoreceptor agonist 5methoxytryptamine. It is thus likely that the activation of normosensitive postsynaptic 5-HT2-like receptors mediate the effect of the enhanced 5-HT release in the OFC.. Similarly. Effect of 3 weeks administration of the selective 5-HT reuptake inhibitor paroxetine (10 mg/kg/day. as the inhibitory effect of 8-OH-DPAT is not blocked by the 5HT1A receptor antagonists WAY 100635 or BMY7378 (El . 2000).c. it was reported that the administration of the SRI paroxetine for 3 and 8 weeks induced an attenuation of the inhibitory effect of the 5-HT1A receptor agonist 8-OH-DPAT in the OFC. It is important to emphasize that the pharmacological properties of 5-HT1A receptors appear atypical in the OFC.. the agonist was introduced 20 min before the second stimulation period. respectively (El Mansari and Blier.. 6. after long-term treatment with citalopram. Haddjeri et al. Consequently this population of 5-HT1A receptors does have the capacity to desensitize following their exposure to increased levels of synaptic 5-HT.. 1986). The numbers at the bottom of each column indicate the number of slices prepared from controls (open circle) and treated (black circle) guinea pigs processed in parallel on the same day. fluoxetine and paroxetine (Bosker et al. release produced by these drugs. In (B). Blier / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 362 – 373 365 Fig.05 when compared to the control value using the two-tailed Student’s t-test. or of the preferential 5-HT2A receptor and 5-HT2C receptor agonists DOI and mCPP. but they do not after SRI administration. However. which is mediated by 5-HT1A receptors. 1999. N. 2000.. not statistically significant.. Le Poul et al.. Li et al. 1996b. the responsiveness of pyramidal neurons to 5-HT itself. *p < 0. and the overflow in the latter trial was always compared to that obtained in the first stimulation period in the absence of any drug for the same slices. 2001). 2005). s. following a 3-week treatment with the selective monoamine oxidase-A inhibitor clorgyline. Such a desensitization of postsynaptic 5-HT1A receptors had already been reported in the amygdala and hypothalamus but not in the hippocampus. using minipumps) on the (A) electrically evoked release of [3H]5-HT in guinea pig brain slices prepared 2 days after removing the minipumps. still have the same effect in rats treated with paroxetine (El Mansari and Blier. using two-tailed Student’s t-test. While the atypical antipsychotic risperidone. 1997).366 M. has been clearly shown to exert a therapeutic effect in SRIresistant OCD patients (McDougle et al. 1989. 1992. 2003). an attenuation of inhibitory 5-HT2 receptor neurotransmission at any point in the neuronal OCD circuitry. buspirone would be expected not to alter 5HT1A transmission at pre. Indeed. a low dose of risperidone.05) when compared to the mean value in the control group. 2005). Similarly.and postsynaptic 5-HT1A receptors (Blier et al. . Rueter et al. 1999). but not by ritanserin or the 5HT1/2 antagonist metergoline in the OFC. as also observed in the rat hypothalamus after chronic administration of paroxetine and fluoxetine (Li et al.. by combining different strategies. The concentration effect curves were compared using two-way analysis of variance. 1993). administered at low doses. For instance. 1990). This delayed response is in line with a report showing that such subacute administration of metergoline does attenuate the responsiveness of the 5-HT2 agonist DOI in the caudate nucleus (El Mansari and Blier. The exact receptor subtype mediating the effect of DOI and mCPP in OFC remains controversial in the absence of more specific ligands. 1996b. This is supported by the existence of three mRNA bands coding for 5-HT1A receptors in the rat brain (Albert et al. 4. suggesting that the 5-HT1A receptor is desensitized in this brain region. because of the peculiar behavior of such null mutant mice (i. a regional difference in the functional and regulatory properties of 5-HT1A sites was reported within the same brain structure i. (2000) showed that DOI may predominantly be acting via a 5-HT2A receptor and that the effect of mCPP is mediated by both 5-HT2A and 5-HT2C receptor in the OFC of 5-HT2C receptor knockout mice..and postsynaptic receptors because these receptors would have been desensitized by prior SRI administration... after 4 days of administration (Benkelfat et al. (1991) showed that chronic administration of fluoxetine attenuated the hypothalamic ACTH response to the 5-HT1A receptor agonist ipsapirone in patients with OCD... 1998). the inhibitory effect of DOI and mCPP is attenuated by 5-HT2 receptor antagonists ritanserin and risperidone in the medial prefrontal cortex (mPFC). Greenberg et al. Evidence from clinical studies suggested that blockade of 5HT2 receptors may play a role in the generation of OCD symptoms in patients with a psychotic disorder.e.. Clinical studies have indeed shown that drugs with 5-HT2 receptor affinity can exert significant actions in OCD patients. McDougle et al. Consequently. 1997). The asterisk indicates a statistically significant difference ( p < 0. These observations indicate that 5-HT2 receptor responses may be mediated by an atypical 5-HT2 receptor in the OFC of rats and guinea pigs (El Mansari and Blier. On the other hand. The numbers at the bottom of each column indicate the number of slices prepared from controls (open circle) and treated (black circle) guinea pigs processed in parallel on the same day. On the other hand. P. On the one hand. whether it be at the 5-HT2 receptors in the caudate or those in the OFC. 1997. Bergqvist et al.c. 1992). reflects the presence of distinct 5-HT1A receptors or of different mechanisms modulating the function of this receptors. Indeed. Lesch et al. Effect of 8 weeks treatment with the selective 5-HT reuptake inhibitor paroxetine (10 mg/kg/day. should reinstate the initial hyperactivity in the neuronal loop and trigger symptom exacerbation in SRIimproved OCD patients. 1999b)... compulsive marble burying) it has been suggested to be an animal model for OCD (Chou-Green et al.. It was thus suggested that the difference in the effect of WAY100635. CA1 versus dentate gyrus in hippocampus (Radja et al. 1996a. exacerbation of OCD symptoms using high doses of clozapine and risperidone may be due to the antagonism of 5HT2 receptors in OFC. El Mansari. The desensitization of 5-HT1A receptors in OFC could explain the lack of beneficial effect of the addition of the 5HT1A receptor agonist buspirone to the regimen of SRIresistant OCD patients (Pigott et al. Indeed. Interestingly. Erzegovesi et al. The experiments were carried out 48 h after removing the minipumps to allow elimination of the drug. using an osmotic minipump) on the electrically evoked release of [3H]5-HT from preloaded guinea pig brain slices in (A). In the presence of desensitized 5-HT1A receptors in OFC following long-term paroxetine treatment. Mansari and Blier. 2000. 1993). the inhibitory effect of 5-HT could be mediated by 5-HT2 receptors since the preferential 5-HT2A receptor agonist DOI. Raap et al. s.. electrophysiological studies have documented distinct pharmacological differences between pre.e. the administration of the 5-HT2 antagonist metergoline causes an exacerbation of OCD symptoms in those subjects... However. Blier / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 362 – 373 Fig.. it was concluded that 5-HT2 receptors in OFC are pharmacologically distinct from those in other regions of the cerebral cortex. and on the sensitivity of the terminal 5-HT1D autoreceptor (B). 2005). and the preferential 5-HT2C receptor agonist mCPP. . high doses of the same drug attenuate the responsiveness of 5-HT2 receptors in the OFC (Bergqvist et al. which blocks 5-HT2 receptor-mediated electrophysiological response in the mPCF. whereas that of 5-HT2 receptors remains unaltered. Bergqvist et al. does not affect it in the OFC (Bergqvist et al. 2004. 1995. *p < 0. This would result in enhanced 5-HT release and may be a more rapid action in OCD patients. The experiments were carried out 96 hours after removing the minipumps to allow elimination of the drug. Moreover. point to terminal 5-HT autoreceptors as potentially playing a major role in the anti-OCD effect of SRIs (El Mansari et al. Novel targets for anti-OCD drugs 2. In contrast. Stein et al.M. 1998).. On the other hand. 5. 5 mg/kg/day and 10 mg/kg/day (s. using an osmotic minipump) for 8 weeks on the electrically evoked release of [3H]5-HT from preloaded guinea pig brain slices as well as on the sensitivity of the terminal 5-HT1D autoreceptor. 1999a).S. 2004). Effect of the selective 5-HT reuptake inhibitor fluoxetine administered at different regimens. Indeed. the sensitivity of 5-HT1A receptors is attenuated. Camarena et al. genetic studies have also shown that a specific polymorphism of the 5-HT1Dh gene may be preferentially transmitted in patients with OCD (Mundo et al. N. although controversial. the experiments already described above. Blier / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 362 – 373 367 Fig. 2001. Pian et al... a new anti-OCD medication could be a selective 5-HT1D receptor antagonist that prevent the negative feedback these autoreceptors exert normally on 5-HT release.1. = not statistically significant. Presynaptic 5-HT1D autoreceptor as a target for anti-OCD medications Research conducted in animals and humans support the involvement of 5-HT1D receptors in OCD and related condi- tions. repeated administration of the 5-HT1D agonist sumatriptan was reported to be associated with a therapeutic effect (Zohar et al. a .c.. Taken together.. these data suggest that the activation of 5HT2 receptors mediates the effect of SRI following their longterm administration. On the one hand. 1999b). El Mansari. 2... 1999b). The numbers at the bottom of each column indicate the number of slices prepared from controls (open circle) and treated (black circle) guinea pigs processed in parallel on the same day. 1999. The concentration – effect curves were compared using two-way analysis of variance. Koran et al.. (2001) have shown that the level of 5HT evoked by an acute administration of LY393558. Mitchell et al. P.. 2002.. Hence.05 using the two-tailed Student’s t-test. expressed as the number of action potentials suppressed by microiontophoretic ejection of drug (in nanoamper: nA). El Mansari and Blier. Taken together. such as LSD and psilocybin in relieving OCD symptoms (Leonard and Rapoport. This would explain why 5-HT1D antagonists alone generally produce a marginal increase in [3H]-5-HT release. induced a greater increase in extracellular 5-HT in rat frontal cortex and guinea pig hypothalamus. However.. an increase in the frequency of À 1438A allele was reported in OCD patients compared to controls (Enoch et al. as described previously long-term SRI administration appears to enhance 5HT transmission through 5-HT2 receptor in the OFC. Although genotype frequencies did not differ.. First. besides their localization on 5-HT terminals.368 M..2. Enoch et al. a beneficial effect in OCD might be obtained. respectively. after both 3. Although controversial. 1987. Furthermore.3. 6. *** indicates p < 0. but not in the hippocampus where the effect of 5-HT is principally mediated by 5-HT1A receptors (Zghoul and Blier. the number in the columns indicates the number of neurons tested. 1989. this knowledge allows us to postulate that a potentially clinically active antagonist should be selective for terminal 5-HT autoreceptors. it was demonstrated using electrophysiological techniques that LSD enhances the inhibitory effect of 5-HT in the OFC. 1996. 1996. 2000.and 8-week treatment. 2004). an exacerbation of OCD symptoms may occur in patients improved by a SRI. thereby decreasing 5-HT neuron firing. Note the decrease in the number of spikes suppressed by nA of 8-OH-DPAT but not of 5-HT. 2. Frisch et al. both after acute and long-term administration. Hanes. The simultaneous blockade of pre. Finally.. Interestingly.. but produces a robust increase in the presence of WAY 100635 to block 5-HT1A autoreceptors. or produced de novo in patients with schizophrenia.. than fluoxetine alone. compound which blocks both 5-HT reuptake and 5-HT1B/1D receptors. there are some limitations to this hypothesis since 5HT1D receptors.. Responsiveness of OFC neurons to 5-HT and 8-OH-DPAT in controls and rats treated with paroxetine for 3 or 8 weeks. indicating that this antagonist should be selective for the terminal 5-HT autoreceptors. 1996. 1996). P. 1997). Thus this receptor subtype could constitute a novel target to improve the anti-OCD response. SB224289 and LY310762 (Pullar et al. a positive association between OCD and the Aallele of the 5-HT2A receptor promoter polymorphism-1438GA has been reported in humans (Nicolini et al. are also present on the body and on postsynaptic 5-HT neurons (Waeber et al. Postsynaptic 5-HT2 receptor as a target for anti-OCD medications The possibility that enhanced postsynaptic 5-HT2 receptor activation might be responsible for the beneficial effect of SRIs is supported by the beneficial action of some hallucinogens with 5-HT2 receptor agonistic properties. El Mansari. 1998). Pineyro and Blier.and postsynaptic 5-HT1D receptors could dampen the effect of the antagonist on net 5-HT transmission. 2003). Furthermore.001. The authors suggested an association between those polymorphisms and the severity of OCD (Tot et al. Moreno and Delgado. 1998. a positive association . 2. possibly through 5-HT2 receptors. The antagonism of 5-HT1D autoreceptor in the raphe dorsalis would locally increase 5-HT release and trigger an activation of 5-HT1A autoreceptors. indicating a specific desensitization of the 5HT1A receptor. a potentiation of the effects of fluoxetine was obtained with the addition of 5-HT1B and 5-HT1D receptor antagonists. Glutamate system as a target for anti-OCD medications Several lines of evidence indicate that the glutamatergic system is involved in OCD. Blier / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 362 – 373 Fig. Tot et al. 2003). whereas by decreasing transmission at these sites with high doses of antagonists. 2003). observations using 5-HT2 receptor agonists and antagonists indicate that by enhancing the activation of 5HT2 receptors with selective agonists. frequencies of the TT genotype for T102C polymorphism and the AA genotype for À 1438 G/A polymorphism were significantly higher in patients with severe OCD. Therefore. This is supported by the observation that systemic injection of the non-selective 5-HT antagonist methiotepin does not increase 5-HT level in postsynaptic region.. 2 and 9).M. Achieving this end result through blockade of postsynaptic receptors with a potent antagonist like Dizocilpine (MK-801) may be a delicate and risky strategy. (2004) showed a lack of association between the kainate subtype of glutamate receptors GRIK2 and GRIK3 and OCD. Both projections from thalamus to orbitofrontal cortex and from the latter structure to caudate nucleus are monosynaptic glutamatergic in nature. In contrast. 7. Such a net effect could be achieved by acting on pre. Using transgenic mice presenting an increased glutamatergic excitation in different brain regions including OFC. 2005). 1989). there was a positive association of the 5072G-5988T halotype with OCD diagnosis and quantitative phenotype of lifetime symptom severity. . Blier / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 362 – 373 369 Fig. Since efferent axons from OFC are from the pyramidal neurons. the inhibitory action of an increase in 5-HT release occurring in the OFC requires the desensitization of the terminal 5-HT autoreceptor. 2). 2004). These investigators speculated that DBS may have interrupted white matter projections between OFC and thalamus thus mimicking capsulotomy (Modell et al. 8. 2001). the mGLUR2 is not activated by endogenous glutamate and the activation does not modify glutamate release in this normal range. Evidence supporting a hyperglutamatergic activity in OCD has also come in part from the therapeutic action of a specific neurosurgical intervention lesioning part of the anterior limb of the internal capsule can produce significant improvement in treatment-refractory OCD patients (Fig. Glutamate synapse showing various elements controlling glutamate release in normal state as well as sites of action of mGLUR2 agonist. induce a rapid onset of action (Figs. The (À) sign indicates a potential decrease in glutamatergic activity in the orbitofrontal cortex and the caudate nucleus following mGLUR2 agonist. Bolton et al. it is thus likely that the neurochemical effect of capsulotomies is to interrupt increased glutamatergic transmission between the OFC and the caudate nucleus (Figs. Nordstrom and Burton (2002) showed that this model mimic OCD-like behavior and also Tourette’s syndrome-like behavior. OCD symptoms were shown to be associated with abnormally increased levels of striatal glutamate that normalized following SRI treatment (Rosenberg et al. 7 –9). However. between a glutamate system gene and OCD has been recently reported. and that these neurons are glutamatergic neurons. The mGLUR2 is represented on the side of the bouton to indicate its extrasynaptic localization. El Mansari. Second. given the availability of the low Fig. As summarized above. which takes several weeks to develop. Recent preliminary PET study has shown that OFC deactivation was seen in patients who responded positively to deep brain stimulation (DBS) than those who did not (Abelson et al. P. encoded by the subtype of glutamate receptor NMDA subunit 2B gene (GRIN2B) was reported to be associated with susceptibility to OCD (Arnold et al.. In contrast.. Under normal physiological conditions. using magnetic resonance spectroscopy glutamate imaging techniques. for the OCD symptomatology and would constitute the substrate upon which SRIs act to decrease such hyperactivity.. 2001. In addition.. in theory. Neurocircuitry of OCD and putative sites of action of the metabotropic glutamate type 2 receptor (mGLUR2) agonist.or postsynaptic glutamate receptors. It is therefore conceivable that the glutamate hyperactivity of OFC could account.. 2000. the mGLUR7 being another inhibitory autoreceptor. Indeed. the NR2B subunit. a drug that could directly decrease glutamate neurotransmission would. It is in that specific location that projections from the OFC course to the caudate nucleus. Delorme et al. at least in part. Glutamate neurons have other type of autoreceptors. 174:530 – 8. Curtis GC. The high price of this medication would preclude its use in regular clinical practice. A synapse depicting a putative increased glutamate release in OCD patients. currently marketed for the management of amyotrophic lateral sclerosis. Arnold PD.. however. 8). Mundo E. 9.370 M. Van Tol HH. Rosenberg DR. but positive results could nevertheless serve as proof-of-concept for the glutamate hypothesis. interconnected neurons with at least two positive feedback mechanisms.57:510 – 6. Albert PR. Bunzow JR. Agents with greater brain penetration. symptoms improvement is more the rule whereas remission is the exception in the therapeutic management of OCD. Civelli O. Zarate et al. and mRNA tissue distribution of the rat 5-hydroxytryptamine1A receptor gene. Zhou QY. the activation of the mGLUR2 by an exogenous agonist attenuates glutamate release. this supports the notion that it takes supranormal glutamate release to produce a significant activation of this autoreceptor. Under such conditions.e. 2001). This drug has. 2003. a 5-week treatment with LY354740 was associated with significantly greater attenuation compared with placebo in patients with generalized anxiety disorder (Levine et al. Conclusion There is now a better understanding of the brain structures involved in OCD and of the possible mechanisms of action of drugs that help attenuate OCD symptoms. References Abelson JL. P. Unfortunately. Kendell et al. Tharmalingam S. This approach could lead to therapeutic effect that is also superior to that of SRIs. Blier / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 362 – 373 Fig. The study of this drug for this indication is currently ongoing in our clinical research unit. El Mansari. This knowledge now puts the research community in a favorable position to develop new anti-OCD drugs. a glutamate drug could also act on afferent glutamate projections to the head of the caudate nucleus and to the OFC from the thalamus. this possibility could currently be explored. 2004. affinity uncompetitive NMDA receptor antagonist Memantine. Taylor SF. Richter MA. Indeed. thereby attenuating muscle spasticity. physiological stimulations in the presence of glutamate reuptake inhibition do not lead to its activation. Furthermore.. SRIs do not increase 5-HT transmission in all structures of the OCD circuitry.. Another approach to attenuate excessive glutamate release would be to use the drug riluzole. 3. Deep brain stimulation for refractory obsessive-compulsive disorder. Therefore. This is supported by the observation that the signs of opiate withdrawal are blocked in rats by acute administration of LY354740 (Schoepp. In contrast. 2005). The mGLUR2 agonist LY354740 attenuates glutamate release in pathological states but not under normal conditions (Schoepp. there is only a case report on the beneficial action in a patient with severe treatment-resistant depression with OCD. Sagher O. and endowed with greater affinity for the mGLUR2 may be more helpful in putting to the test this hypothesis. i. J Biol Chem 1990. Riluzole is believed to act in the latter neurological disorder by decreasing glutamate release. poor oral bioavailability. 2003).. This receptor is an autoreceptor that appears to be located extrasynaptically because it does not seem to be activated under normal physiological conditions (Fig. Kennedy JL. One potential target receptor to achieve an attenuation of glutamate hyperactivity would be the metabotropic glutamate type 2 receptor (mGLUR2). The therapeutic effect of such a drug should thus depend only on reaching an adequate steady state level in the brain. 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