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© 2020 Elsevier Ltd To date, there are no interventions that impede the inexorable progression of Alzheimer's disease (AD), and currently-available drugs cholinesterase (AChE) inhibitors and the N-Methyl-D-Aspartate receptor antagonist, memantine, offer only modest symptomatic benefit. Moreover, a range of mechanistically-diverse agents (glutamatergic, histaminergic, monoaminergic, cholinergic) have disappointed in clinical trials, alone and/or in association with AChE inhibitors. This includes serotonin (5-HT) receptor-6 antagonists, despite compelling preclinical observations in rodents and primates suggesting a positive influence on cognition. The emphasis has so far been on high selectivity. However, for a multi-factorial disorder like idiopathic AD, 5-HT6 antagonists possessing additional pharmacological actions might be more effective, by analogy to “multi-target” antipsychotics. Based on this notion, drug discovery programmes have coupled 5-HT6 blockade to 5-HT4 agonism and inhibition of AchE. Further, combined 5-HT6/dopamine D3 receptor (D3) antagonists are of especial interest since D3 blockade mirrors 5-HT6 antagonism in exerting broad-based pro-cognitive properties in animals. Moreover, 5-HT6 and dopamine D3 antagonists promote neurocognition and social cognition via both distinctive and convergent actions expressed mainly in frontal cortex, including suppression of mTOR over-activation and reinforcement of cholinergic and glutamatergic transmission. In addition, 5-HT6 blockade affords potential anti-anxiety, anti-depressive and anti-epileptic properties, and antagonising 5-HT6 receptors may be associated with neuroprotective (“disease-modifying”) properties. Finally D3 antagonism may counter psychotic episodes and D3 receptors themselves offer a promising hub for multi-target agents. The present article reviews the status of “R and D” into multi-target 5-HT6 and D3 ligands for improved treatment of AD and other neurodegenerative disorders of aging. This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’.

RATIONALE: Serotonin (5-HT)(2C) receptors are implicated in the control of mood, and their blockade is of potential interest for the management of anxiodepressive states. OBJECTIVES: Herein, we characterized the in vitro and in vivo pharmacological profile of the novel benzourea derivative, S32006. MATERIALS AND METHODS: Standard cellular, electrophysiological, neurochemical, and behavioral procedures were used. RESULTS: S32006 displayed high affinity for human (h)5-HT(2C) and h5-HT(2B) receptors (pK (i)s, 8.4 and 8.0, respectively). By contrast, it had negligible (100-fold lower) affinity for h5-HT(2A) receptors and all other sites examined. In measures of Gq-protein coupling/phospholipase C activation, S32006 displayed potent antagonist properties at h5-HT(2C) receptors (pK (B) values, 8.8/8.2) and h5-HT(2B) receptors (7.8/7.7). In vivo, S32006 dose-dependently (2.5-40.0 mg/kg, i.p. and p.o.) abolished the induction of penile erections and a discriminative stimulus by the 5-HT(2C) receptor agonist, Ro60,0175, in rats. It elevated dialysis levels of noradrenaline and dopamine in the frontal cortex of freely moving rats, and accelerated the firing rate of ventrotegmental dopaminergic and locus ceruleus adrenergic neurons. At similar doses, S32006 decreased immobility in a forced-swim test in rats, reduced the motor depression elicited by 5-HT(2C) and alpha(2)-adrenoceptor agonists, and inhibited both aggressive and marble-burying behavior in mice. Supporting antidepressant properties, chronic (2-5 weeks) administration of S32006 suppressed "anhedonia" in a chronic mild stress procedure and increased both expression of BDNF and cell proliferation in rat dentate gyrus. Finally, S32006 (0.63-40 mg/kg, i.p. and p.o) displayed anxiolytic properties in Vogel conflict and social interaction tests in rats. CONCLUSION: S32006 is a potent 5-HT(2C) receptor antagonist, and possesses antidepressant and anxiolytic properties in diverse rodent models.

“Ecstasy” [3,4-methylenedioxymetamphetamine (MDMA)] is of considerable interest in light of its prosocial properties and risks associated with widespread recreational use. Recently, it was found to bind trace amine-1 receptors (TA1Rs), which modulate dopaminergic transmission. Accordingly, using mice genetically deprived of TA1R (TA1-KO), we explored their significance to the actions of MDMA, which robustly activated human adenylyl cyclase-coupled TA1R transfected into HeLa cells. In wild-type (WT) mice, MDMA elicited a time-, dose-, and ambient temperature-dependent hypothermia and hyperthermia, whereasTA1-KOmice displayed hyperthermia only. MDMA-induced increases in dialysate levels of dopamine (DA) in dorsal striatum were amplified inTA1-KOmice, despite identical levels of MDMA itself. A similar facilitation of the influence of MDMA upon dopaminergic transmission was acquired in frontal cortex and nucleus accumbens, and induction of locomotion by MDMA was haloperidol-reversibly potentiated inTA1-KOversus WT mice. Conversely, genetic deletion of TA1R did not affect increases in DA levels evoked by para-chloroamphetamine (PCA), which was inactive at hTA1sites. The TA1R agonisto-phenyl-3-iodotyramine (o-PIT) blunted the DA-releasing actions of PCA bothin vivo(dialysis) andin vitro(synaptosomes) in WT but notTA1-KOanimals. MDMA-elicited increases in dialysis levels of serotonin (5-HT) were likewise greater inTA1-KOversus WT mice, and 5-HT-releasing actions of PCA were bluntedin vivoandin vitrobyo-PIT in WT mice only. In conclusion, TA1Rs exert an inhibitory influence on both dopaminergic and serotonergic transmission, and MDMA auto-inhibits its neurochemical and functional actions by recruitment of TA1R. These observations have important implications for the effects of MDMA in humans.

Though neurokinin(1) (NK(1)) receptors are implicated in depressed states and their treatment, selective antagonists have disappointed in clinical trials. Accordingly, we designed a novel ligand, S41744 (2-piperazin-1-yl-indan-2-carboxylic-acid-(3-chloro-5-fluoro-benzyl)-methyl-amide), which both blocks NK(1) receptors and interferes with serotonin (5-HT) reuptake. S41744 mimicked the selective antagonist aprepitant in binding human (h)NK(1) receptors and in antagonising Substance-P-mediated Extracellular-Regulated-Kinase phosphorylation (pK(B), 7.7). Further, it dose-dependently (0.63-40.0 mg/kg, i.p.) displaced ex vivo [(3)H]-[Sar(9),Met(O(2))(11)]-Substance P binding to gerbil striatum, attenuated formalin-induced hind-paw licking in gerbils, and antagonised locomotion induced by i.c.v. administration of the NK(1) agonist GR73632 to guinea pigs. Like paroxetine, S41744 recognised h5-HT transporters, reduced synaptosomal uptake of 5-HT (pK(B), 7.9), and dose-dependently (0.63-10.0 mg/kg) elevated dialysis levels of 5-HT in the hippocampus and frontal cortex of freely-moving guinea pigs. Further, S41744 increased extracellular levels of 5-HT in frontal cortex and hippocampus of rats to a greater extent than paroxetine, and its inhibitory influence upon serotonergic perikarya was blunted relative to its affinity for 5-HT transporters. S41744 more potently blocked stress-induced vocalizations in guinea pigs than aprepitant and paroxetine, and it was active in forced-swim and marble-burying procedures of putative antidepressant properties in mice. While aprepitant displayed anxiolytic actions in stress-induced foot-tapping and social interaction tests in gerbils, paroxetine was anxiogenic and S41744 "neutral", reflecting balanced NK(1) antagonism and suppression of 5-HT reuptake. Moreover, S41744 shared anxiolytic actions of aprepitant in the rat Vogel Conflict Test. In conclusion, S41744 is an innovative NK(1) antagonist/5-HT reuptake inhibitor justifying further evaluation for treatment of stress-related disorders.

Despite evidence linking dopamine D3 receptors to the etiology of Parkinson's disease and l -DOPA-induced dyskinesia, the potential therapeutic utility of D3 receptor ligands remains unclear. In the present study, we investigated whether the selective D3 receptor antagonist, S33084, affects development and expression of abnormal involuntary movements (AIMs), a behavioural correlate of dyskinesia, in rats hemi-lesioned with 6-hydroxydopamine and chronically treated with l -DOPA. The ability of S33084, alone or in combination with l -DOPA, to attenuate 6-hydroxydopamine induced motor deficits was also investigated employing a battery of behavioural tests. Acute administration of S33084 (0.64 mg/kg, s.c.) did not attenuate the induction of AIMs in dyskinetic rats upon challenge with l -DOPA (6 mg/kg, s.c.). Moreover, S33084 (0.64 mg/kg) did not prevent the development of AIMs affecting axial, limb and orolingual muscles when chronically administered together with l -DOPA (6 mg/kg for 21 days). However, both acute and chronic administration of S33084 enhanced l -DOPA-induced contralateral turning, suggesting potential antiparkinsonian properties. Furthermore, S33084 (0.01–0.64 mg/kg) dose-dependently attenuated parkinsonian disabilities, including bradykinesia, in drag and rotarod tests, although, in these procedures, the combination of S33084 with l -DOPA did not produce synergistic effect. It is concluded that sustained D3 receptor blockade does not blunt l -DOPA-induced dyskinesia in hemiparkinsonian rats. However, D3 receptor antagonism may be associated with antiparkinsonian properties. The clinical relevance of these observations will be of interest to explore further.

Though neurokinin(1) (NK(1)) receptor antagonists are active in experimental models of depression, clinical efficacy has proven disappointing. This encourages interest in association of NK(1) receptor blockade with inhibition of serotonin (5-HT) reuptake. The selective NK(1) antagonist, GR205171, dose-dependently enhanced citalopram-induced elevations of extracellular levels of 5-HT in frontal cortex, an action expressed stereospecifically vs its less active distomer, GR226206. Further, increases in 5-HT levels in dorsal hippocampus, basolateral amygdala, nucleus accumbens, and striatum were likewise potentiated, and GR205171 similarly facilitated the influence of fluoxetine upon levels of 5-HT, as well as dopamine and noradrenaline. In parallel electrophysiological studies, the inhibitory influence of citalopram and fluoxetine upon raphe-localized serotonergic neurones was stereospecifically blunted by GR205171. Antidepressant actions of citalopram in a forced-swim test in mice were stereospecifically potentiated by GR205171, and it also enhanced attenuation by citalopram of stress-related ultrasonic vocalizations in rats. Further, GR205171 and citalopram additively abrogated the advance in circadian rhythms provoked by exposure to light in hamsters. By contrast, GR205171 stereospecifically blocked anxiogenic actions of citalopram in social interaction procedures in rats and gerbils, and stereospecifically abolished facilitation of fear-induced foot tapping by fluoxetine in gerbils. By analogy to GR205171, a further NK(1) antagonist, RP67580, enhanced the influence of citalopram upon frontocortical levels of 5-HT and potentiated its actions in the forced swim test. In conclusion, NK(1)receptor blockade differentially modulates functional actions of SSRIs: antidepressant properties are reinforced, whereas anxiogenic effects are attenuated. Combined NK(1) receptor antagonism/5-HT reuptake inhibition may offer advantages in the management of depressed and anxious states.

This study characterized the novel neurokinin (NK)(1) antagonist, vestipitant, under clinical evaluation for treatment of anxiety and depression. Vestipitant possessed high affinity for human NK(1) receptors (pK(i), 9.4), and potently blocked Substance P-mediated phosphorylation of Extracellular-Regulated-Kinase. In vivo, it occupied central NK(1) receptors in gerbils (Inhibitory Dose(50), 0.11 mg/kg). At similar doses, it abrogated nociception elicited by formalin in gerbils, and blocked foot-tapping and locomotion elicited by the NK(1) agonist, GR73632, in gerbils and guinea pigs, respectively. Further, vestipitant attenuated fear-induced foot-tapping in gerbils, separation-induced distress-vocalizations in guinea pigs, marble-burying behaviour in mice, and displayed anxiolytic actions in Vogel conflict and fear-induced ultrasonic vocalization procedures in rats. These actions were mimicked by CP99,994, L733,060 and GR205,171 which acted stereoselectively vs its less active isomer, GR226,206. In conclusion, vestipitant is a potent NK(1) receptor antagonist: its actions support the utility of NK(1) receptor blockade in the alleviation of anxiety and, possibly, depression.

In contrast to clinically available antipsychotics, the novel benzopyranopyrrolidine derivative, S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), behaves as a preferential antagonist of D(3) versus D(2) receptors and does not interact with histamine H(1) and muscarinic receptors. In contrast to haloperidol, clozapine, olanzapine, and risperidone, S33138 (0.16-2.5 mg/kg s.c.) did not disrupt performance in passive-avoidance and five-choice serial reaction time procedures. Furthermore, upon either systemic administration (0.04-2.5 mg/kg s.c.) or introduction into the frontal cortex (0.04-0.63 mug/side), S33138 potently attenuated the perturbation of social recognition by scopolamine or a prolonged intersession delay. Over a comparable and low-dose range, S33138 (0.04-0.63 mg/kg s.c.) elevated dialysis levels of acetylcholine in the frontal cortex of freely moving rats. At higher doses (2.5-10.0 mg/kg s.c.), S33138 also increased frontocortical levels of histamine, whereas monoamines, glutamate, glycine, and GABA were unaffected. By analogy to the other antipsychotics, S33138 (0.63-10.0 mg/kg s.c.) inhibited conditioned avoidance responses in rats, apomorphine-induced climbing in mice, and hyperlocomotion elicited by amphetamine, cocaine, dizocilpine, ketamine, and phencyclidine in rats. S33138 (0.16-2.5 mg/kg s.c.) also blocked the reduction of prepulse inhibition elicited by apomorphine. In comparison with the above actions, only "high" doses of S33138 (10.0-40.0 mg/kg s.c.) elicited catalepsy. To summarize, reflecting preferential blockade of D(3) versus D(2) receptors, S33138 preserves and/or enhances cognitive function, increases frontocortical cholinergic transmission, and is active in models of antipsychotic properties at doses well below those inducing catalepsy. In comparison with clinically available agents, S33138 displays, thus, a distinctive and promising profile of potential antipsychotic properties.

The novel benzopyranopyrrolidine, S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], is a preferential antagonist of cloned human D(3) versus D(2L) and D(2S) receptors. In mice, S33138 (0.04-2.5 mg/kg i.p.) increased levels of mRNA encoding c-fos in D(3) receptor-rich Isles of Calleja and nucleus accumbens more potently than in D(2) receptor-rich striatum. Furthermore, chronic (3 weeks) administration of S33138 to rats reduced the number of spontaneously active dopaminergic neurones in the ventral tegmental area (0.16-10.0 p.o.) more potently than in the substantia nigra (10.0). In primates treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, antiparkinson actions of the D(3)/D(2) agonist, ropinirole, were potentiated by low doses of S33138 (0.01-0.16 p.o.) but diminished by a high dose (2.5). Consistent with antagonism of postsynaptic D(3)/D(2) sites, S33138 attenuated hypothermia and yawns elicited by the D(3)/D(2) agonist 7-OH-DPAT [(+)-7-dihydroxy-2-(di-n-propylamino)-tetralin] in rats, and it blocked (0.01-0.63, s.c.) discriminative properties of PD128,907 [(+)-(4aR,10bR)-3,4, 4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol; trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide]. Suggesting antagonist properties at D(3)/D(2) autoreceptors, S33138 prevented (0.16-2.5 s.c.) the inhibitory influence of PD128,907 upon dopamine release in frontal cortex, nucleus accumbens, and striatum and abolished (0.004-0.25 i.v.) its inhibition of ventral tegmental dopaminergic neuron firing. At higher doses, antagonist actions of S33138 (0.5-4.0 i.v.) at alpha(2C)-adrenoceptors were revealed by an increased firing rate of adrenergic perikarya. Finally, antagonism of 5-hydroxytryptamine (5-HT(2A) and 5-HT(7)) receptors was shown by blockade of 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane-induced head twitches (0.63-10.0 s.c.) and 5-carboxytryptamine-induced hypothermia (2.5-20.0 i.p.), respectively. In conclusion, S33138 displays modest antagonist properties at central alpha(2C)-adrenoceptors, 5-HT(2A) and 5-HT(7) receptors. Furthermore, in line with its in vitro actions, it more potently blocks cerebral populations of D(3) versus D(2) receptors.

The dopamine D2/D3 receptor agonist and alpha2 adrenergic receptor antagonist, piribedil, is used clinically as monotherapy and as an adjunct to L-3,4-dihydroxyphenylalanine in the treatment of Parkinson's disease. As it appears to improve mood, we examined its actions in rodent models of antidepressant properties, in comparison with the prototypical anti-Parkinson agent, apomorphine, the D2/D3 receptor agonist, quinpirole, and the antidepressants, imipramine and fluvoxamine. In the mouse forced-swim test, acute administration of imipramine, fluvoxamine, apomorphine or quinpirole decreased immobility time, actions dose dependently mimicked by piribedil (2.5-10.0 mg/kg, subcutaneously). In rats, acute and subchronic administration of piribedil similarly reduced immobility (0.63-10.0 mg/kg, subcutaneously) and apomorphine, quinpirole and imipramine were also active in this test, whereas fluvoxamine was inactive. Both in mice and in rats, the D2/D3 receptor antagonist, raclopride, and the D2 receptor antagonist, L741,626, dose dependently blocked the antidepressant properties of piribedil, whereas the selective D3 receptor antagonists, S33084 and SB277,011, were ineffective. In a chronic mild stress model in rats, piribedil (2.5-40.0 mg/kg, subcutaneously) restored sucrose intake in stressed animals exerting its actions more rapidly (by week 1) than imipramine. Imipramine, fluvoxamine, apomorphine, quinpirole and piribedil dose dependently (0.63-10.0 mg/kg, subcutaneously) suppressed aggressive and marble-burying behaviour in mice. In the latter procedure, raclopride and L741,626, but not S33084, attenuated the actions of piribedil. Over a dose range (0.63-10.0 mg/kg, subcutaneously) equivalent to those active in models of antidepressant activity, piribedil did not stimulate locomotor behaviour. In conclusion, principally via recruitment of D2 receptors, piribedil exerts robust and specific antidepressant-like actions in diverse rodent models.

The novel antidepressant agent, agomelatine, behaves as an agonist at melatonin receptors and as an antagonist at serotonin (5-HT)(2C) receptors.To determine whether, by virtue of its antagonist properties at 5-HT(2C) receptors, agomelatine elicits anxiolytic properties in rats.Employing a combined neurochemical and behavioural approach, actions of agomelatine were compared to those of melatonin, the selective 5-HT(2C) receptor antagonist, SB243,213, and the benzodiazepine, clorazepate.In unfamiliar pairs of rats exposed to a novel environment, agomelatine enhanced the time devoted to active social interaction, an action mimicked by clorazepate and by SB243,213. In a Vogel conflict procedure, agomelatine likewise displayed dose-dependent anxiolytic activity with a maximal effect comparable to clorazepate, and SB243,213 was similarly active in this procedure. In a plus-maze procedure in which clorazepate significantly enhanced percentage entries into open arms, agomelatine revealed only modest activity and SB243,213 was inactive. Further, like SB243,213, and in contrast to clorazepate, agomelatine did not suppress ultrasonic vocalizations emitted by rats re-exposed to an environment associated with an aversive stimulus. Whereas clorazepate reduced dialysate levels of 5-HT and noradrenaline in hippocampus and frontal cortex of freely moving rats, agomelatine did not affect extracellular levels of 5-HT and elevated those of noradrenaline. SB243,213 acted similarly to agomelatine. Melatonin, which did not modify extracellular levels of 5-HT or noradrenaline, was ineffective in all models of anxiolytic activity. Furthermore, the selective melatonin antagonist, S22153, did not modify anxiolytic properties of agomelatine in either the social interaction or the Vogel Conflict tests.In contrast to melatonin, and reflecting blockade of 5-HT(2C) receptors, agomelatine is active in several models of anxiolytic properties in rodents. The anxiolytic profile of agomelatine differs from that of benzodiazepines from which it may also be distinguished by its contrasting influence on corticolimbic monoaminergic pathways.

Though 5-HT plays an important role in the modulation of motor function, which is perturbed in depressive states, little is known concerning the influence of serotonin reuptake inhibitors (SSRIs) on locomotor activity (LA). Recently, we demonstrated that SSRIs, such as citalopram, enhance LA in mice exposed to a novel environment.This study examined the role of multiple classes of 5-HT receptor in citalopram-induced LA.The most selective antagonists currently available were used.Citalopram-induced LA was dose-dependently attenuated by the 5-HT1B/1D receptor antagonists, S18127, GR125,743 and GR127,935, and by the selective 5-HT1B antagonist, SB224,289, but unaffected by the selective 5-HT1A antagonist, WAY100,635. The selective antagonists at 5-HT2A receptors, MDL100,907 and SR46,349 also dose-dependently attenuated induction of locomotion by citalopram, whereas the 5-HT2B antagonist, SB204,741, and the 5-HT2B/2C antagonist, SB206,553 were ineffective. Further, the selective 5-HT2C antagonist, SB242,084, potentiated the response to citalopram. Selective antagonists at 5-HT3 (ondansetron), 5-HT4 (GR125,487), 5-HT6 (SB271,046) and 5-HT7 (SB269,970) receptors did not significantly modify the action of citalopram. Underpinning these findings, SB224,289, GR125,743, MDL100,907 and SR46,349 likewise attenuated induction of locomotion by a further SSRI, fluvoxamine.The locomotor response to SSRIs of mice exposed to a novel environment is mediated via 5-HT1B and 5-HT2A receptors. In view of the importance of motor function to the etiology and treatment of depression, the significance of these observations to the clinical actions of SSRIs will be of interest to elucidate.

A multitude of mechanisms are involved in the control of emotion and in the response to stress. These incorporate mediators/targets as diverse as γ-aminobutyric acid (GABA), excitatory amino acids, monoamines, hormones, neurotrophins and various neuropeptides. Behavioural models are indispensable for characterization of the neuronal substrates underlying their implication in the etiology of anxiety, and of their potential therapeutic pertinence to its management. Of considerable significance in this regard are conflict paradigms in which the influence of drugs upon conditioned (trained) behaviours is examined. For example, the Vogel conflict test, which was introduced some 30 years ago, measures the ability of drugs to release the drinking behaviour of water-deprived rats exposed to a mild aversive stimulus (“punishment”). This model, of which numerous procedural variants are discussed herein, has been widely used in the evaluation of potential anxiolytic agents. In particular, it has been exploited in the characterization of drugs interacting with GABAergic, glutamatergic and monoaminergic networks, the actions of which in the Vogel conflict test are summarized in this article. More recently, the effects of drugs acting at neuropeptide receptors have been examined with this model. It is concluded that the Vogel conflict test is of considerable utility for rapid exploration of the actions of anxiolytic (and anxiogenic) drugs. Indeed, in view of its clinical relevance, broader exploitation of the Vogel conflict test in the identification of novel classes of anxiolytic agents, and in the determination of their mechanisms of action, would prove instructive.

This study characterized the influence of acute administration of diverse classes of antidepressant agent upon the spontaneous locomotor activity (LA) of mice in a novel, open-field environment. The selective serotonin (5-HT) reuptake inhibitors (SSRIs), citalopram, fluoxetine, paroxetine, fluvoxamine, litoxetine and zimelidine, dose-dependently enhanced LA. Their actions were mimicked by the mixed 5-HT/noradrenaline (NA) reuptake inhibitors (SNRIs), venlafaxine, duloxetine and S33005. In contrast, clomipramine only slightly elevated LA and two further tricyclics, imipramine and amitriptyline, were inactive. Further, the selective NA vs. 5-HT reuptake inhibitors (NARIs), reboxetine, desipramine, maprotiline, nisoxetine and nortriptyline all failed to increase LA. The "atypical antidepressants," mianserin and mirtazapine, neither of which modify 5-HT reuptake, as well as the mixed SSRI/5-HT(2) antagonists, nefazodone and trazodone, also failed to increase LA. Doses of SSRI and SNRI which increased LA did not modify motor performance in the rotarod test. Further, they did not enhance LA in rats, suggesting that this response is characteristic of mice. Finally, upon prehabituation of mice to the activity chamber, the SSRI, citalopram, and the SNRI, venlafaxine, failed to increase LA. In conclusion, in mice exposed to a novel environment, inhibition of 5-HT reuptake by SSRIs and SNRIs enhances spontaneous LA in the absence of a generalized influence upon motor function. This response provides a simple parameter for characterization of SSRIs and SNRIs, and differentiates them from other classes of antidepressant agent. Although an influence upon arousal and/or anxiety is likely related to the increase in LA, the functional significance of this response requires additional elucidation.

The high efficacy methoxynaphtylpiperazine 5-HT1A receptor agonists, S 14506 (1-[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphtyl)piper azine) and S 14671 (1-[2-(2-thenoylamino)ethyl]-4[1-(7-methoxynaphtyl]piperazin e), potently reduced the duration of immobility in the forced swimming test in rats [minimal effective dose (MED): 0.01 mg/kg, s.c., in each case]; in contrast, the prototypic 5-HT1A receptor agonist, 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide], was much less potent (MED: 0.63 mg/kg). The action of S 14671 (0.16 mg/kg) was completely blocked by the potent 5-HT1A receptor antagonist, SDZ 216-525 (4-(4-[4-(1,1,3-trioxo-2H-1,2-benzoisothiazol-2- yl)butyl]-1-piperazinyl)1H-indole-2-carboxylate) (0.63 mg/kg) and by the novel, selective 5-HT1A receptor antagonist, (+)-WAY 100,135 (N-tertiobutyl-3-[4-(2-methoxyphenyl)piperazinylphenyl propanamide): the effect of the latter was expressed dose dependently (Inhibitory Dose50: 35 mg/kg). Similarly, in the presence of (+)-WAY 100,135, S 14506 (0.63 mg/kg) failed to reduce immobility. Pretreatment with parachlorophenylalanine (3 x 300 mg/kg per day, i.p.), which profoundly depleted cerebral pools of 5-HT, modified neither baseline immobility nor the actions of S 14506 and S 14671. It is concluded that S 14506 and S 14671 possess exceptionally potent activity in the forced swimming test and that their actions reflect the activation of postsynaptic 5-HT1A receptors.

The present studies characterized the functional profile of N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3-H-benzo[e]indole-3-carboxamide) (S32212), a combined serotonin (5-HT)(2C) receptor inverse agonist and α(2)-adrenoceptor antagonist that also possesses 5-HT(2A) antagonist properties (J Pharmacol Exp Ther 340:750-764, 2012). Upon parenteral and/or oral administration, dose-dependent (0.63-40.0 mg/kg) actions were observed in diverse procedures. Both acute and subchronic administration of S32212 reduced immobility time in a forced-swim test in rats. Acutely, it also suppressed marble burying and aggressive behavior in mice. Long-term administration of S32212 was associated with rapid (1 week) and sustained (5 weeks) normalization of sucrose intake in rats exposed to chronic mild stress and with elevated levels of mRNA encoding brain-derived neurotrophic factor in hippocampus and amygdala (2 weeks). S32212 accelerated the firing rate of adrenergic perikarya in the locus coeruleus and elevated dialysis levels of noradrenaline in the frontal cortex and hippocampus of freely moving rats. S32212 also elevated the frontocortical levels of dopamine and acetylcholine, whereas 5-HT, amino acids, and histamine were unaffected. These neurochemical actions were paralleled by "promnemonic" properties: blockade of scopolamine-induced deficits in radial maze performance and social recognition and reversal of delay-induced impairments in social recognition, social novelty discrimination, and novel object recognition. It also showed anxiolytic actions in a Vogel conflict procedure. Furthermore, in an electroencephalographic study of sleep architecture, S32212 enhanced slow-wave and rapid eye movement sleep, while decreasing waking. Finally, chronic administration of S32212 neither elevated body weight nor perturbed sexual behavior in male rats. In conclusion, S32212 displays a functional profile consistent with improved mood and cognitive performance, together with satisfactory tolerance.

The novel benzodioxopiperazine, S 15535 (4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine), displayed high affinity for 5-HT 1A binding sites (1.8 nM) whereas its affinity was 100-fold lower at other 5-HT 1A receptor types, at α 1 , α 2 - and β-adrenoceptors dopamine D 1 and D 2 receptors. In vivo, S 15535 (0.16–10 mg/kg s.c.) acted as an antagonist at postsynaptic 5-HT 1A receptors in completely blocking the flat-body posture and hypothermia elicited by the 5-HT 1A receptor agonist, 8-OH-DPAT. It had no effect when applied alone. At presynaptic 5-HT 1A receptors, S 15535 acted as an agonist in inhibiting striatal accumulation of 5-hydroxytryptophan (0.04–0.63 mg/kg s.c.) and in spiperone reversibly reducing electrical activity of the dorsal raphe nucleus (0.004–0.031 mg/kg i.v.). At doses up to 40.0 mg/kg s.c., S 15535 neither inhibited methylphenidate-induced gnawing nor elicited ptosis suggesting a lack of antagonist properties at, respectively, dopamine D 2 receptors and α 1 -adrenoceptors. In conclusion, S 15535 is a potent 5-HT 1A ligand which acts, in vivo, as a highly selective agonist and antagonist at presynaptic and postsynaptic 5-HT 1A receptors, respectively.

Benzocycloalkyl and benzocycloalkenyl moities linked, directly or via an alkyl chain, to oxygen-bearing heteroarylpiperazines were synthesized, in an attempt to obtain potent and selective antagonists at postsynaptic 5-HT 1A receptors. From the numerous arylpiperazines described in the literature, 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3a) was chosen as a model of an arylpiperazine in view of its selectivity for 5-HT 1A receptors versus α 1 -, α 2 -, and β-adrenergic receptors, as well as dopamine D 1 and D 2 receptors. Two other closely-related arylpiperazines, 1-(1,5-benzodioxepin-6-yl)piperazine (3b) and 1-(benzofuran-7-yl)piperazine (3c), were also examined in this study. All compounds showed high affinity at 5-HT 1A sites (8.10 ≤ pK i s ≤ 9.35), and the majority behaved as antagonists in vivo in blocking the hypothermia induced by the 5-HT 1A agonist 8-OH-DPAT in the absence of a marked effect alone at equivalent doses. An in vivo evaluation of dopamine D 2 receptor antagonist properties revealed that the majority of compounds was devoid of activity at this site, in marked contrast to BMY 7378 which displayed virtually no selectivity for 5-HT 1A versus dopamine D 2 receptors. Moreover, six compounds of the present series, 8, 10, 11, 14, 25, and, 37, showed > 10-fold selectivity in vitro for 5-HT 1A versus α1-adr>nargin receptors. Compound 14 displayed an optimal compromise between potency (pK i = 8.75), marked antagonist activity, and selectivity toward α 1 -adrenergic (81-fold) and dopamine D 2 (195-fold) receptors. These characteristics clearly distinguish 14 from previously-reported ligands such as the postsynaptic 5-HT 1A antagonist BMY 7378 and the weak partial agonist NAN 190 which, in contrast to the compounds of this series, belong to the well-exemplified class of imido derivatives of (o-methoxyphenyl)piperazines. The availability of 14 (S 15535) should facilitate the further elucidation of the functional role and potential therapeutic significance of 5-HT 1A receptors.

In vivo animal models are indispensable both for clarifying the pathological bases of schizophrenia, and for evaluating the potential benefits and disadvantages of novel therapy. Procedures that model mnemonic impairment are of particular interest since currently-available drugs do little to improve cognitive symptoms: this is hardly surprising, in fact, since most of them potently antagonise histamine H(1), muscarinic, and/or alpha(1)-adrenergic receptors. Further, their blockade of D(2) receptors likewise compromises cognitive performance. By contrast, D(3) receptor antagonism improves certain cognitive domains, suggesting that preferential antagonism of D(3) vs. D(2) receptors may permit enhanced effectiveness against cognitive dysfunction. The novel agent, S33138, possesses such an "optimised" profile and shows a unique and broad-based pattern of pro-cognitive properties in rodents and primates, in the absence of extrapyramidal and metabolic side-effects. The present article surveys the preclinical pharmacology of S33138. It also reviews developmental and genetic risk factors for schizophrenia and their experimental modeling in rodents, with a particular emphasis on sensorimotor gating and cognitive deficits.

Melanin-concentrating hormone (MCH) 1 receptors are widely expressed in limbic structures and cortex. Their inactivation is associated with anxiolytic and antidepressive properties but little information is available concerning cognition. This issue was addressed using the selective antagonists, SNAP-7941 and GW3430, in a social recognition paradigm in rats. The muscarinic blocker, scopolamine (1.25 mg/kg s.c.), reduced social recognition, an action dose-dependently blocked by SNAP-7941 and GW3430 (0.63-10.0 and 20.0-80.0 mg/kg i.p., respectively) which did not themselves display amnesic properties. Further, in a protocol where a spontaneous deficit was induced by a prolonged inter-session delay, SNAP-7941 and GW3430 dose-dependently enhanced social recognition. In dialysis studies, SNAP-7941 (0.63-40.0 mg/kg i.p.) and GW3430 (10.0-40.0 mg/kg i.p.) elevated extracellular levels of acetylcholine (ACh) in the frontal cortex (FCX) of freely moving rats. The SNAP-7941 effect was specific, as it did not increase levels of ACh in ventral and dorsal hippocampus: moreover, it did not modify levels of noradrenaline, dopamine, serotonin and glutamate in FCX. Active doses of SNAP-7941 and GW3430 corresponded to doses (2.5-40.0 and 10.0-80.0 mg/kg i.p., respectively) exerting anxiolytic properties in Vogel conflict and ultrasonic vocalization tests, and antidepressant actions in forced swim, isolation-induced aggression and marble-burying procedures. In contrast to SNAP-7941 and GW3430, the benzodiazepine, diazepam, decreased social recognition and dialysate levels of ACh, while the tricyclic, imipramine, reduced social recognition and failed to enhance cholinergic transmission. In conclusion, at anxiolytic and antidepressant doses, SNAP-7941 and GW3430 improve social recognition and elevate extracellular ACh levels in FCX. This profile differentiates MCH 1 receptor antagonists from conventional anxiolytic and antidepressant agents.

In contrast to clinically available antipsychotics, the novel benzopyranopyrrolidine derivative, S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), behaves as a preferential antagonist of D(3) versus D(2) receptors and does not interact with histamine H(1) and muscarinic receptors. In contrast to haloperidol, clozapine, olanzapine, and risperidone, S33138 (0.16-2.5 mg/kg s.c.) did not disrupt performance in passive-avoidance and five-choice serial reaction time procedures. Furthermore, upon either systemic administration (0.04-2.5 mg/kg s.c.) or introduction into the frontal cortex (0.04-0.63 mug/side), S33138 potently attenuated the perturbation of social recognition by scopolamine or a prolonged intersession delay. Over a comparable and low-dose range, S33138 (0.04-0.63 mg/kg s.c.) elevated dialysis levels of acetylcholine in the frontal cortex of freely moving rats. At higher doses (2.5-10.0 mg/kg s.c.), S33138 also increased frontocortical levels of histamine, whereas monoamines, glutamate, glycine, and GABA were unaffected. By analogy to the other antipsychotics, S33138 (0.63-10.0 mg/kg s.c.) inhibited conditioned avoidance responses in rats, apomorphine-induced climbing in mice, and hyperlocomotion elicited by amphetamine, cocaine, dizocilpine, ketamine, and phencyclidine in rats. S33138 (0.16-2.5 mg/kg s.c.) also blocked the reduction of prepulse inhibition elicited by apomorphine. In comparison with the above actions, only "high" doses of S33138 (10.0-40.0 mg/kg s.c.) elicited catalepsy. To summarize, reflecting preferential blockade of D(3) versus D(2) receptors, S33138 preserves and/or enhances cognitive function, increases frontocortical cholinergic transmission, and is active in models of antipsychotic properties at doses well below those inducing catalepsy. In comparison with clinically available agents, S33138 displays, thus, a distinctive and promising profile of potential antipsychotic properties.

The novel benzopyranopyrrolidine, S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], is a preferential antagonist of cloned human D(3) versus D(2L) and D(2S) receptors. In mice, S33138 (0.04-2.5 mg/kg i.p.) increased levels of mRNA encoding c-fos in D(3) receptor-rich Isles of Calleja and nucleus accumbens more potently than in D(2) receptor-rich striatum. Furthermore, chronic (3 weeks) administration of S33138 to rats reduced the number of spontaneously active dopaminergic neurones in the ventral tegmental area (0.16-10.0 p.o.) more potently than in the substantia nigra (10.0). In primates treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, antiparkinson actions of the D(3)/D(2) agonist, ropinirole, were potentiated by low doses of S33138 (0.01-0.16 p.o.) but diminished by a high dose (2.5). Consistent with antagonism of postsynaptic D(3)/D(2) sites, S33138 attenuated hypothermia and yawns elicited by the D(3)/D(2) agonist 7-OH-DPAT [(+)-7-dihydroxy-2-(di-n-propylamino)-tetralin] in rats, and it blocked (0.01-0.63, s.c.) discriminative properties of PD128,907 [(+)-(4aR,10bR)-3,4, 4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol; trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide]. Suggesting antagonist properties at D(3)/D(2) autoreceptors, S33138 prevented (0.16-2.5 s.c.) the inhibitory influence of PD128,907 upon dopamine release in frontal cortex, nucleus accumbens, and striatum and abolished (0.004-0.25 i.v.) its inhibition of ventral tegmental dopaminergic neuron firing. At higher doses, antagonist actions of S33138 (0.5-4.0 i.v.) at alpha(2C)-adrenoceptors were revealed by an increased firing rate of adrenergic perikarya. Finally, antagonism of 5-hydroxytryptamine (5-HT(2A) and 5-HT(7)) receptors was shown by blockade of 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane-induced head twitches (0.63-10.0 s.c.) and 5-carboxytryptamine-induced hypothermia (2.5-20.0 i.p.), respectively. In conclusion, S33138 displays modest antagonist properties at central alpha(2C)-adrenoceptors, 5-HT(2A) and 5-HT(7) receptors. Furthermore, in line with its in vitro actions, it more potently blocks cerebral populations of D(3) versus D(2) receptors.

In forced-swim tests in mice and rats, the novel D3/D2 receptor agonist S32504 [(+)- trans -3,4,4 a ,5,6,10 b -hexahydro-9-carbamoyl-4-propyl-2 H -naphth[1,2- b ]-1,4-oxazine] dose-dependently (0.04–2.5 mg/kg) and stereospecifically suppressed immobility compared with its enantiomer S32601 [(-)- trans -3,4,4 a ,5,6,10 b -hexahydro-9-carbamoyl-4-propyl-2 H -naphth-[1,2- b ]-1,4-oxazine]. Ropinirole was less potent than S32504 in this procedure, and it was likewise less potent than S32504 (0.04–2.5 mg/kg) in attenuating motor-suppressant properties of the α2-adrenoceptor agonist S18616 [( S )-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4,2′-(1′,2′,3′,4′-tetrahydronaphthalene)]]. In a learned helplessness paradigm, S32504 (0.08–2.5 mg/kg) suppressed escape failures. Furthermore, in a chronic mild stress model of anhedonia, S32504 (0.16–2.5 mg/kg) rapidly restored the suppression of sucrose consumption. S32504 inhibited marble-burying behavior in mice (0.04–0.16 mg/kg) and aggressive behavior in isolated mice (0.04–2.5 mg/kg): only higher doses of ropinirole mimicked these actions of S32504. In tests of anxiolytic activity, S32504 was more potent (0.0025–0.16 mg/kg) than ropinirole in suppressing fear-induced ultrasonic vocalizations, and S32601 was inactive. Furthermore, in contrast to ropinirole, S32504 modestly enhanced punished responses in a Vogel conflict procedure and increased open-arm entries in a plus-maze. At doses active in the above-described procedures, S32504 did not elicit hyperlocomotion. In the forced-swim, marble-burying, and ultrasonic vocalization models, actions of S32504 were blocked by the D2/D3 antagonists haloperidol and raclopride and by the D2 antagonist L741,626 [4-(4-chlorophenyl)-1-(1 H -indol-3-ylmethyl)piperidin-4-ol], but not by the D3 receptor antagonist S33084 [(3 aR ,9 bS )- N -[4-(8-cyano-1,3 a ,4,9 b -tetrahydro-3 H -benzopyrano[3,4- c ]pyrrole-2-yl)-butyl]-(4-phenyl)benzamide. Finally, chronic administration of S32504 did not, in contrast to venlafaxine, modify corticolimbic levels of serotonin2A receptors or brain-derived neurotrophic factor. In conclusion, S32504 displays a broad and distinctive profile of activity in models of potential antidepressive and anxiolytic properties. Its actions are more pronounced than those of ropinirole and principally involve engagement of D2 receptors.

These studies evaluated the potential antiparkinsonian properties of the novel dopamine D(3)/D(2) receptor agonist S32504 [(+)-trans-3,4,4a,5,6, 10b-hexahydro-9-carbamoyl-4-propyl-2H-naphth[1,2-b]-1,4-oxazine] in comparison with those of the clinically employed agonist ropinirole. In rats with a unilateral, 6-hydroxydopamine lesion of the substantia nigra, S32504 (0.0025-0.04 mg/kg, s.c.) more potently elicited contralateral rotation than S32601 [(-)-trans-3,4,4a,5,6, 10b-hexahydro-9-carbamoyl-4-propyl-2H-naphth-[1,2-b]-1,4-oxazine (its less active enantiomer)], ropinirole, and l-3,4-dihydroxyphenylalanine (l-DOPA). Rotation elicited by S32504 was blocked by the D(2)/D(3) receptor antagonists haloperidol and raclopride and by the D(2) antagonist L741,626 [4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol], but not by the D(3) antagonist S33084 [(3aR,9bS)-N-[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl]-(4-phenyl)benzamide]. As assessed by dialysis in both lesioned and nonlesioned animals, S32504 (0.04-2.5 mg/kg, s.c.) reduced striatal levels of acetylcholine. This effect was blocked by raclopride, haloperidol, and L741,626 but not S33084. In rats treated with reserpine, hypolocomotion was reversed by S32504 and, less potently, by ropinirole. In "unprimed" marmosets treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, both s.c. (0.01-0.04 mg/kg) and p.o. (0.04-1.25 mg/kg) administration of S32504 dose-dependently and rapidly (within 10 min) increased locomotor activity and reduced disability. Furthermore, S32504 dose-dependently reversed bradykinesia and improved posture in "L-DOPA-primed" animals, whereas eliciting less pronounced dyskinesia than l-DOPA. Finally, in terminally differentiated SH-SY5Y cells presenting a dopaminergic phenotype, S32504, but not S32601, abrogated the neurotoxic effects of 1-methyl-4-phenylpyridinium, an action inhibited by raclopride and S33084 but not L741,626. Ropinirole was weakly neuroprotective in this model. In conclusion, S32504 displays potent and stereospecific activity in rodent, primate, and cellular models of antiparkinsonian properties. Although activation of D(2) receptors is crucial to the motor actions of S32504, engagement of D(3) receptors contributes to its neuroprotective properties.

The role of dopamine D(3)/D(2) receptors in the control of locomotion is poorly understood.To examine the influence of selective antagonists at D(3) or D(2) receptors on locomotion in rats, alone and in interaction with the preferential D(3) versus D(2) receptor agonist, PD128,907.Affinities of ligands at rat D(2) and cloned, human hD(3), hD(2S), hD(2L) and hD(4) sites were determined by standard procedures. Locomotion was monitored automatically in rats pre-habituated for 30 min to an open-field environment. Extracellular levels of dopamine (DA) were determined by dialysis in the nucleus accumbens and striatum. Drugs were given acutely via the systemic route.PD128,907, which preferentially recognised D(3) versus D(2) sites, biphasically reduced and enhanced locomotion at "low" (0.01-0.63 mg/kg) and "high" (2.5-10 mg/kg) doses, respectively. L741,626 and S23199, which behaved as preferential D(2) versus D(3) receptor antagonists, enhanced the reduction in locomotion evoked by the low dose of PD128,907, blocked the increase provoked by the high dose and suppressed spontaneous locomotion alone. Analogous findings were obtained with haloperidol and raclopride which showed equilibrated affinity at D(2) and D(3) receptors. UH232 and AJ76, which showed a mild preference for D(3) versus D(2) sites, did not modify the effect of a low dose of PD128,907, slightly enhanced the hyperlocomotion elicited by the high dose and exerted little influence on locomotion alone. S14297 and U99194, which acted as preferential D(3) versus D(2) receptor antagonists, abolished the reduction in locomotion elicited by a low dose of PD128,907, potentiated the induction of locomotion by a high dose, and failed to influence locomotion alone. The actions of S14297 were stereoselective inasmuch as they were mimicked by the racemic form, S11566, but not by the inactive enantiomer, S17777. In contrast to S14297, S11566 and U99194, however, S33084, SB269,652, GR218,231 and N-[-4-['-(1-naphtyl)piperazine-1-yl]butyl] anthracene-2-carboxamide ("NGB-1"), highly selective D(3) versus D(2) receptor antagonists, were inactive under all conditions. PD128,907 (0.01-10.0 mg/kg) suppressed dialysate levels of DA in the nucleus accumbens and striatum, actions blocked by L741,626 and haloperidol, yet unaffected by S14297 and S33084.The facilitatory influence of a "high" dose of PD128,907 upon locomotion is mediated by postsynaptic D(2) receptors and, possibly, countered by their D(3) counterparts. Correspondingly, selective blockade of D(2) but not of D(3) receptors alone suppresses motor function. The reduction in locomotion provoked by a "low" dose of PD128,907 may be mediated by D(2) autoreceptors, but a role of postsynaptic D(3) receptors cannot be excluded. Finally, mechanisms underlying the contrasting influence of chemically diverse D(3) receptor antagonists upon locomotion remain to be elucidated.

By analogy with the selective serotonin reuptake inhibitor, fluvoxamine, and the tricyclic agent, clomipramine, the novel, selective, non-peptidergic NK 1 receptor antagonist, GR205,171, dose-dependently and completely blocked marble-burying behaviour in mice: Inhibitory Dose 50 s (ID 50 s), 4.5, 4.8 and 7.6 mg/kg, respectively. In contrast to GR205,171, its isomer, GR226,206, which displays substantially lower affinity for NK 1 receptors, was inactive (> 40.0 mg/kg). By analogy with GR205,171, a further, selective NK 1 antagonist, RP67,580, abolished marble-burying behaviour with an ID 50 of 11.9 mg/kg. At doses significantly reducing marble-burying behaviour, GR205,171 and RP67,580 little influenced motor behaviour. In conclusion, like fluvoxamine and clomipramine, selective, non-peptidergic NK 1 receptor antagonists block marble-burying in mice. Although the biological bases of this behaviour remain unclear, these observations underpin the contention that NK 1 receptors may be implicated in affective disorders.

This study characterized the influence of acute administration of diverse classes of antidepressant agent upon the spontaneous locomotor activity (LA) of mice in a novel, open-field environment. The selective serotonin (5-HT) reuptake inhibitors (SSRIs), citalopram, fluoxetine, paroxetine, fluvoxamine, litoxetine and zimelidine, dose-dependently enhanced LA. Their actions were mimicked by the mixed 5-HT/noradrenaline (NA) reuptake inhibitors (SNRIs), venlafaxine, duloxetine and S33005. In contrast, clomipramine only slightly elevated LA and two further tricyclics, imipramine and amitriptyline, were inactive. Further, the selective NA vs. 5-HT reuptake inhibitors (NARIs), reboxetine, desipramine, maprotiline, nisoxetine and nortriptyline all failed to increase LA. The "atypical antidepressants," mianserin and mirtazapine, neither of which modify 5-HT reuptake, as well as the mixed SSRI/5-HT(2) antagonists, nefazodone and trazodone, also failed to increase LA. Doses of SSRI and SNRI which increased LA did not modify motor performance in the rotarod test. Further, they did not enhance LA in rats, suggesting that this response is characteristic of mice. Finally, upon prehabituation of mice to the activity chamber, the SSRI, citalopram, and the SNRI, venlafaxine, failed to increase LA. In conclusion, in mice exposed to a novel environment, inhibition of 5-HT reuptake by SSRIs and SNRIs enhances spontaneous LA in the absence of a generalized influence upon motor function. This response provides a simple parameter for characterization of SSRIs and SNRIs, and differentiates them from other classes of antidepressant agent. Although an influence upon arousal and/or anxiety is likely related to the increase in LA, the functional significance of this response requires additional elucidation.

Unilateral 6-hydroxydopamine (6-OHDA) lesions of substantia nigra pars compacta (SNPC) neurons in rats induce behavioural hypersensitivity to dopaminergic agonists. However, the role of specific dopamine receptors is unclear, and potential alterations in their transduction mechanisms remain to be evaluated. The present study addressed these issues employing the dopaminergic agonist, quinelorane, which efficaciously stimulated G-protein activation (as assessed by [35S]GTPgammaS binding) at cloned hD2 (and hD3) receptors. At rat striatal membranes, dopamine stimulated [35S]GTPgammaS binding by 1.9-fold over basal, but its actions were only partially reversed by the selective D2/D3 receptor antagonist, raclopride, indicating the involvement of other receptor subtypes. In contrast, quinelorane-induced stimulation (48% of the effect of dopamine) was abolished by raclopride, and by the D2 receptor antagonist, L741,626. Further, novel antagonists selective for D3 and D4 receptors, S33084 and S18126, respectively, blocked the actions of quinelorane at concentrations corresponding to their affinities for D2 receptors. Quinelorane potently induced contralateral rotation in unilaterally 6-OHDA-lesioned rats, an effect abolished by raclopride and L741,626, but not by D3 and D4 receptor-selective doses of S33084 and S18126, respectively. In functional ([35S]GTPgammaS) autoradiography experiments, quinelorane stimulated G-protein activation in caudate putamen and, to a lesser extent, in nucleus accumbens and cingulate cortex of naive rats. In unilaterally SNPC-lesioned rats, quinelorane-induced G-protein activation in the caudate putamen on the non-lesioned side was similar to that seen in naive animals (approximately 50% stimulation), but significantly greater on the lesioned side (approximately 80%). This increase was both pharmacologically and regionally specific since it was reversed by raclopride, and was not observed in nucleus accumbens or cingulate cortex. In conclusion, the present data indicate that, in rat striatum, the actions of quinelorane are mediated primarily by D2 receptors, and suggest that behavioural hypersensitivity to this agonist, induced by unilateral SNPC lesions, is associated with an increase in D2, but not D3 or D4, receptor-mediated G-protein activation.

The selective, non-peptidergic corticotropin-releasing factor (CRF)(1) receptor antagonists, CP154,526 and DMP695, dose-dependently increased punished responses of rats in a Vogel conflict test and enhanced social interaction (SI) of rats in an unfamiliar environment. They were, however, inactive in a plus-maze procedure and failed to reduce ultrasonic vocalizations (USV) associated with an aversive environment. In contrast, the benzodiazepine, chlordiazepoxide, was effective in all these procedures. Further, the serotonin (5-HT)(1A) agonist, flesinoxan, was active in each paradigm (except the plus-maze) while the 5-HT(2C) antagonist, SB242,084, was effective in the SI and Vogel but not the plus-maze and USV procedures. In contrast to chlordiazepoxide, flesinoxan and SB242,084, CP154,526 did not modify dialysate levels of 5-HT, norepinephrine (NE) and dopamine (DA) in the frontal cortex (FCX) of freely moving rats. In conclusion, CP154,526 and DMP695 possess a common and distinctive profile of anxiolytic action expressed in the absence of an intrinsic influence upon monoamine release.

Rationale: The benzodioxane, S15535, possesses low intrinsic activity and marked selectivity at 5-HT1A receptors, hippocampal populations of which are implicated in anxious states. Objective: Herein, we examined its potential anxiolytic actions in relation to its influence upon extracellular levels of 5-HT in the dorsal hippocampus of freely-moving rats. Its effects were compared with those of other anxiolytic agents: the 5-HT1A agonists, buspirone and 8-hydroxy-2-(di-n-propylamino)-tetralin HBr (8-OH-DPAT), the 5-HT2C antagonist, SB206,553 and the benzodiazepine, diazepam. Methods: Potential anxiolytic actions were evaluated in the Vogel conflict paradigm (increase in punished responses) and the social interaction (SI) test (increase in active SI) in rats. Extracellular levels of 5-HT were determined by microdialysis. Results: In analogy to diazepam, S15535 increased punished responses in the Vogel test. This action was dose dependently expressed over a broad (16-fold) dose range. Buspirone and 8-OH-DPAT were likewise active, but yielded highly biphasic dose–response curves. SB206,553 was dose dependently active in this model. In the SI test, S15535 similarly mimicked the anxiolytic-like effect of diazepam and was active over a broad dose range. Buspirone and 8-OH-DPAT again showed biphasic dose–response curves, as did SB206,553. In both the Vogel and SI tests, the anxiolytic-like effects of S15535 were abolished by the selective 5-HT1A receptor antagonist, WAY100,635, which was inactive alone. S15535 exerted its anxiolytic-like effects with a more pronounced separation to motor-disruptive doses than the other drugs. Finally, S15535 suppressed dialysate levels of 5-HT in the dorsal hippocampus, an action abolished by WAY100,635. Buspirone, 8-OH-DPAT and diazepam, but not SB206,553, also reduced 5-HT levels. Conclusion: Likely reflecting its distinctive ability to selectively and preferentially activate pre- versus postsynaptic 5-HT1A receptors, S15535 suppresses hippocampal 5-HT release and displays marked anxiolytic-like effects over a broad dose range in the relative absence of motor perturbation.

The open channel blocker at N-methyl-D-aspartate (NMDA) receptors, dizocilpine, stereospecifically elicited spontaneous tail-flicks in rats - a reaction similar to those elicited by other drugs (tenocyclidine, phencyclidine and ketamine) acting as open channel blockers. Their relative potencies were strongly correlated with affinities at NMDA binding sites and labeled by [3H]dizocilpine in the frontal cortex (r=0.94) and, as determined previously [Millan, M. J., Seguin, L., 1994. Chemically-diverse ligands at the glycine B site coupled to N-methyl-D-aspartate (NMDA) receptors selectively block the late phase of formalin-induced pain in mice, Neurosci. Lett., 178 (1994) 139-143], potency for eliciting antinociception (0. 93). The competitive antagonists at the NMDA receptor recognition site, (+/-)3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), 4-phosphonomethyl-2-piperidine carboxylic acid (CGS19755), D, L-(E)-2-amino-4-methylphosphono-3-pentanoic acid (CGP37849) and (3E)-1-ethyl ester-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP39551), likewise dose-dependently evoked spontaneous tail-flick. In contrast, antagonists/weak partial agonists at the coupled, glycine B site, 7-chloro-4-hydroxy-3-(3-phenoxy) phenyl-2(H)-quinolinone (L701,324), (+)-1-hydroxy-3-aminopyrrolidine-2-one ((+)-HA966), (3R, 4R)-3-amino-1-hydroxy-4-methyl-2-pyrrolidinone (L687,414), 6, 7-dichloro-1, 4-dihydro-5-nitro, 2,3 quinoxalinedione (ACEA1021) and 2-carboxy-4,6-dichloro (1H)-indole-3-propanoic acid (MDL29,951), were inactive. NMDA abolished induction of spontaneous tail-flick by CPP and CGS19755, but not by dizocilpine. Upon bilateral injection into the nucleus accumbens, dizocilpine immediately and dose-dependently elicited spontaneous tail-flick, but it was ineffective in the ventrotegmental area and striatum. Similarly, injection of CPP into the nucleus accumbens elicited spontaneous tail-flick. Neither dizocilpine nor CPP elicited spontaneous tail-flick upon administration onto lumbar spinal cord. In conclusion, a pharmacologically specific spontaneous tail-flick-response is elicited by both open channel blockers and recognition site antagonists, but not glycine B site antagonists, at NMDA receptors. Their actions, mediated in the nucleus accumbens, may be differentiated by their respective resistance and sensitivity to NMDA.

The mixed serotonin and noradrenaline reuptake inhibitor, duloxetine, (5.0 mg/kg, s.c.), increased levels of serotonin (220%), dopamine (180%) and noradrenaline (470%) in individual dialysates of frontal cortex of freely moving rats. Its influence on serotonin, but not dopamine or noradrenaline, levels was enhanced by the 5-HT1A receptor antagonist, WAY 100,635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide 3HCl) (0.16 mg kg(-1), s.c). In the forced swimming test, although duloxetine was inactive alone, it dose dependently reduced immobility in the presence of WAY 100,635. Thus, blockade of 5-HT1A (auto)receptors selectively facilitates the influence of duloxetine on serotonin levels in the frontal cortex in rats and, in the forced swimming model, enhances its 'antidepressant' properties in parallel.

In contrast to haloperidol, the selective dopamine D3 receptor antagonist, (+)-S 11566 {(±)-[7-(N,N-dipropylamino)-5,6,7,8-tetrahydro-naphtho(2,3b)dihydro,2,3-furane]} and its active isomer, (+)-S 14297, induced neither catalepsy nor reduced conditioned avoidance responses in rats. (+)-S 11566 and (+)-S 14297 did, however, dose-dependently abolish the cataleptic actions of haloperidol. This action was expressed stereospecifically inasmuch as (−)-S 17777, the inactive distomer of (+)-S 14297, was ineffective. Further, the influence of haloperidol upon conditioned avoidance responses was not affected by (+)-S 14297. These data suggest that blockade of dopamine D3 receptors may inhibit the extrapyramidal but not – as based on the conditioned avoidance response paradigm – antipsychotic actions of neuroleptics. © 1997 Elsevier Science B.V. All rights reserved.

In the pigeon conflict test of anxiety, the novel, high efficacy 5-HT1A receptor ligand, S 14671, very potently [minimal effective dose (MED): 0.0025 mg/kg, IM] and markedly (maximal percentage increase relative to control: 17232%) increased punished responding. In analogy, its structural analogue, the 5-HT1A receptor agonist, S 14506, equipotently, though less markedly, augmented punished responding (MED: 0.0025 mg/kg; maximal effect: 5557%). In contrast, the arylpiperazine 5-HT1A receptor agonists, LY 165,163 and tandospirone, increased punished responding only at higher doses (MED: 0.16 and 0.63 mg/kg, respectively), and also with a lesser maximal effect (2065% and 3695%, respectively). Although S 14671 and S 14506 showed a 16-fold separation between doses, increasing punished and decreasing unpunished responding, respectively, this separation was only fourfold for LY 165,163 and tandospirone. The anticonflict activity of S 14671 (0.01 mg/kg) was significantly antagonised by the 5-HT1A receptor antagonist, (-)-alprenolol (10 mg/kg), but not by combined treatment with the selective beta 1 receptor antagonist, betaxolol, and the selective beta 2 receptor antagonist, ICI 118,551. Further, a correlation analysis across each of the above agonists, as well as 8-OH-DPAT, buspirone, and (+)-flesinoxan, revealed a significant correlation for their relative potency in augmenting punished responding and their affinity for 5-HT1A receptors in vitro (r = +0.95, p0.001). It is concluded that S 14671 is an exceptionally potent and efficacious ligand in the pigeon conflict test and that its anxiolytic action reflects the activation of 5-HT1A receptors.

In a drug discrimination paradigm, the 5-HT2A/2C receptor antagonists, ritanserin, ICI 169,369 (2-(2-dimethylaminoethylthio-3-phenylquinoline hydrochloride) and mianserin, and the preferential 5-HT2A receptor antagonist, ketanserin, antagonised the discriminative stimulus effects of the 5-HT2A/2C receptor agonist, DOI ((2,5-dimethoxy-4-iodohenyl)-2-aminopropan) (0.63 mg/kg i.p.). Effective dose50 (ED50) values were: 0.32, 0.39, 0.15 and 0.03 mg/kg s.c., respectively. While the novel, selective 5-HT2C receptor antagonist, SB 200,646 (N-(1-methyl-5-iodolyl)-N'-(3-pyridyl) urea hydrochloride) was inactive (10 mg/kg s.c. and 20 mg/kg p.o.), the highly selective 5-HT2A receptor antagonist, MDL 100,907 (R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl]-4- piperidine-methanol) very potently (ED50 = 0.0006) abolished the action of DOI. MDL 100,907 may display antipsychotic properties and the 'atypical' antipsychotics, clozapine, risperidone and sertindole, each of which possesses marked affinity at 5-HT2A receptors, abolished the discriminative stimulus effects of DOI (ED50 values of 0.07, 0.03 and 0.33 mg/kg, respectively). In contrast, haloperidol (0.16) was ineffective. These data demonstrate that 5-HT2A receptors mediate the discriminative stimulus effects of DOI and support the hypothesis that an antagonistic action at 5-HT2A receptors contributes to the in vivo actions of 'atypical' antipsychotics.