Levomilnacipran (LVM; F2695) is the more active enantiomer of the serotonin/norepinephrine (5-HT/NE) reuptake inhibitor (SNRI) milnacipran and is currently under development for the treatment of major depressive disorder. LVM was benchmarked against two other SNRIs, duloxetine and venlafaxine, in biochemical, neurochemical and pharmacological assays. LVM exhibited high affinity for human NE (Ki = 92.2 nM) and 5-HT (11.2 nM) transporters, and potently inhibited NE (IC50 = 10.5 nM) and 5-HT (19.0 nM) reuptake (human transporter) in vitro. LVM had 2-fold greater potency for norepinephrine relative to serotonin reuptake inhibition (i.e. NE/5-HT potency ratio: 0.6) and 17 and 27 times higher selectivity for NE reuptake inhibition compared with venlafaxine and duloxetine, respectively. LVM did not exhibit affinity for 23 off-target receptors. LVM (i.p.) increased cortical extracellular levels of 5-HT, and NE (minimal effective doses: MEDs = 20 and 10 mg/kg, respectively). In anti-depressive/anti-stress models, i.p. LVM diminished immobility time in the mouse forced swim (MED = 20 mg/kg) and tail suspension (MED = 2.5 mg/kg) tests, and reduced shock-induced ultrasonic vocalizations in rats (MED = 5 mg/kg). Duloxetine and venlafaxine were less potent (MEDs ≥ 10 mg/kg). At doses active in these three therapeutically-relevant models, LVM (i.p.) did not significantly affect spontaneous locomotor activity. In summary, LVM is a potent, selective inhibitor of NE and 5-HT transporters with preferential activity at the former. It is efficacious in models of anti-depressive/anti-stress activity, with minimal potential for locomotor side effects.

Background and purpose: F15599, a novel 5‐hydroxytryptamine (5‐HT) 1A receptor agonist with 1000‐fold selectivity for 5‐HT compared with other monoamine receptors, shows antidepressant and procognitive activity at very low doses in animal models. We examined the in vivo activity of F15599 at somatodendritic autoreceptors and postsynaptic 5‐HT 1A heteroreceptors. Experimental approach: In vivo single unit and local field potential recordings and microdialysis in the rat. Key results: F15599 increased the discharge rate of pyramidal neurones in medial prefrontal cortex (mPFC) from 0.2 µg·kg −1 i.v and reduced that of dorsal raphe 5‐hydroxytryptaminergic neurones at doses >10‐fold higher (minimal effective dose 8.2 µg·kg −1 i.v.). Both effects were reversed by the 5‐HT 1A antagonist (±)WAY100635. F15599 did not alter low frequency oscillations (∼1 Hz) in mPFC. In microdialysis studies, F15599 increased dopamine output in mPFC (an effect dependent on the activation of postsynaptic 5‐HT 1A receptors) with an ED 50 of 30 µg·kg −1 i.p., whereas it reduced hippocampal 5‐HT release (an effect dependent exclusively on 5‐HT 1A autoreceptor activation) with an ED 50 of 240 µg·kg −1 i.p. Likewise, application of F15599 by reverse dialysis in mPFC increased dopamine output in a concentration‐dependent manner. All neurochemical responses to F15599 were prevented by administration of (±)WAY100635. Conclusions and implications: These results indicate that systemic administration of F15599 preferentially activates postsynaptic 5‐HT 1A receptors in PFC rather than somatodendritic 5‐HT 1A autoreceptors. This regional selectivity distinguishes F15599 from previously developed 5‐HT 1A receptor agonists, which preferentially activate somatodendritic 5‐HT 1A autoreceptors, suggesting that F15599 may be particularly useful in the treatment of depression and of cognitive deficits in schizophrenia.

Background and purpose: Xaliproden (SR57746A) is a 5‐HT1A receptor agonist and neurotrophic agent that reduces oxaliplatin‐mediated neuropathy in clinical trials. The present study investigated its profile on in vitro transduction, neurochemical responses and acute nociceptive pain tests in rats.Experimental approach: Xaliproden was tested on models associated with 5‐HT1A receptor activation including G‐protein activation, extracellular dopamine and 5‐HT levels measured by microdialysis and formalin‐induced pain. Activation of 5‐HT1A receptors was confirmed by antagonism with WAY100635.Key results: Xaliproden exhibited high affinity for rat (r) and human (h) 5‐HT1A receptors (pKi= 8.84 and 9.00). In [35S]GTPγS (guanosine 5'‐O‐(3‐[35S]thio)triphosphate) assays it activated both hippocampal r5‐HT1A[pEC50/EMAX of 7.58/61% (%5‐HT)] and recombinant h5‐HT1A receptors (glioma C6‐h5‐HT1A: 7.39/62%; HeLa‐h5‐HT1A: 7.24/93%). In functional [35S]GTPγS autoradiography, xaliproden induced labelling in structures enriched with 5‐HT1A receptors (hippocampus, lateral septum, prefrontal and entorhinal cortices). Xaliproden inhibited in vivo binding of [3H]WAY100635 to 5‐HT1A receptors in mouse frontal cortex and hippocampus (ID50: 3.5 and 3.3 mg·kg−1, p.o. respectively). In rat, it increased extracellular dopamine levels in frontal cortex and reduced hippocampal 5‐HT levels (ED50: 1.2 and 0.7 mg·kg−1, i.p. respectively). In a rat pain model, xaliproden inhibited paw licking and elevation (ED50: 1 and 3 mg·kg−1, i.p. respectively) following formalin injection in the paw. All effects were reversed by pretreatment with WAY100635.Conclusions and implications: These results indicate that activation of 5‐HT1A receptors is the principal mechanism of action of xaliproden and provide further support for the utility of 5‐HT1A receptor activation as an anti‐nociceptive strategy.

Background and purpose: Activation of post‐synaptic 5‐HT 1A receptors may provide enhanced therapy against depression. We describe the signal transduction profile of F15599, a novel 5‐HT 1A receptor agonist. Experimental approach: F15599 was compared with a chemical congener, F13714, and with (+)8‐OH‐DPAT in models of signal transduction in vitro and ex vivo . Key results: F15599 was highly selective for 5‐HT 1A receptors in binding experiments and in [ 35 S]‐GTPγS autoradiography of rat brain, where F15599 increased labelling in regions expressing 5‐HT 1A receptors. In cell lines expressing h5‐HT 1A receptors, F15599 more potently stimulated extracellular signal‐regulated kinase (ERK1/2) phosphorylation, compared with G‐protein activation, internalization of h5‐HT 1A receptors or inhibition of cAMP accumulation. F13714, (+)8‐OH‐DPAT and 5‐HT displayed a different rank order of potency for these responses. F15599 stimulated [ 35 S]‐GTPγS binding more potently in frontal cortex than raphe. F15599, unlike 5‐HT, more potently and efficaciously stimulated G αi than G αo activation. In rat prefrontal cortex (a region expressing post‐synaptic 5‐HT 1A receptors), F15599 potently activated ERK1/2 phosphorylation and strongly induced c‐fos mRNA expression. In contrast, in raphe regions (expressing pre‐synaptic 5‐HT 1A receptors) F15599 only weakly or did not induce c‐fos mRNA expression. Finally, despite its more modest affinity in vitro , F15599 bound to 5‐HT 1A receptors in vivo almost as potently as F13714. Conclusions and implications: F15599 showed a distinctive activation profiles for 5‐HT 1A receptor‐mediated signalling pathways, unlike those of reference agonists and consistent with functional selectivity at 5‐HT 1A receptors. In rat, F15599 potently activated signalling in prefrontal cortex, a feature likely to underlie its beneficial effects in models of depression and cognition.

This study investigated the involvement of 5-HT1 and 5-HT2 receptors in the antidepressant-like effect of adenosine in the mouse forced swimming test (FST). The pre-treatment of mice with PCPA (100 mg/kg, i.p., an inhibitor of serotonin synthesis, for four consecutive days), NAN-190 (0.5 mg/kg, i.p., a 5-HT1A receptor antagonist), pindolol (32 mg/kg, i.p., a 5-HT1A/1B receptor/β-adrenoceptor antagonist) or WAY100635 (0.1 and 0.3 mg/kg, s.c., a selective 5-HT1A receptor antagonist), but not with ketanserin (5 mg/kg, i.p., a 5-HT2A/2C receptor antagonist), prevented the antidepressant-like effect of adenosine (10 mg/kg, i.p.) in the FST. Moreover, the pre-treatment of animals with WAY100635 (0.1 mg/kg, s.c.) blocked the decrease in immobility time in the FST elicited by adenosine (5 or 10 mg/kg, i.p.), but produced a synergistic effect with a sub-effective dose of adenosine (1 mg/kg, i.p.) and did not cause any alteration at the highest dose of adenosine administered (50 mg/kg, i.p.). Adenosine (1 mg/kg, i.p.) produced a synergistic antidepressant-like effect with pindolol (32 mg/kg), NAN-190 (0.5 mg/kg, i.p.), WAY100635 (0.03 mg/kg, s.c.), 8-OH-DPAT (1 mg/kg, i.p., a 5-HT1A receptor agonist), but not with DOI (1 mg/kg, i.p., a preferential 5-HT2A receptor agonist) or ketanserin. The pre-treatment of mice with DPCPX (2 mg/kg, i.p., a selective adenosine A1 receptor antagonist) or ZM241385 (1 mg/kg, i.p., a selective adenosine A2A receptor antagonist) did not prevent the effect of fluoxetine (32 mg/kg, i.p., a preferential serotonin reuptake inhibitor) in the FST. Besides that, adenosine (1 mg/kg, i.p.) did not produce a synergistic antidepressant-like effect with fluoxetine (10 mg/kg, i.p.). Taken together, the results indicate that the antidepressant-like effect of adenosine in the FST appears to be mediated, at least in part, by an interaction with 5-HT1A receptors.

l-DOPA is the gold-standard treatment for Parkinson's disease (PD), but induces troublesome dyskinesia after prolonged treatment. This is associated with the ‘false neurotransmitter’ conversion of l-DOPA to dopamine by serotonin neurons projecting from the raphe to the dorsal striatum. Reducing their activity by targeting pre-synaptic 5-HT1A receptors should thus be an attractive therapeutic strategy, but previous 5-HT1A agonists have yielded disappointing results. Here, we describe the activity of a novel, highly selective and potent 5-HT1A agonist, NLX-112 (also known as befiradol or F13640) in rat models relevant to PD and its associated affective disorders.NLX-112 (0.16 mg/kg, i.p.) potently and completely reversed haloperidol-induced catalepsy in intact rats and abolished l-DOPA-induced Abnormal Involuntary Movements (AIMs) in hemiparkinsonian rats, an effect that was reversed by the selective 5-HT1A antagonist, WAY100635. In microdialysis experiments, NLX-112 profoundly decreased striatal 5-HT extracellular levels, indicative of inhibition of serotonergic function. NLX-112 also blunted the l-DOPA-induced surge in dopamine levels on the lesioned side of the brain, an action that likely underlies its anti-dyskinetic effects.NLX-112 (0.16 mg/kg, i.p.) robustly induced rotations in hemiparkinsonian rats, suggesting that it has a motor facilitatory effect. Rotations were abolished by WAY100635 and were ipsilateral to the lesioned side, suggesting a predominant stimulation of the dopamine system on the non-lesioned side of the brain. NLX-112 also efficaciously reduced immobility time in the forced swim test (75% reduction at 0.16 mg/kg, i.p.) and eliminated stress-induced ultrasonic vocalization at 0.08 mg/kg, i.p., effects consistent with potential antidepressant- and anxiolytic-like properties.In other tests, NLX-112 (0.01–0.16 mg/kg, i.p.) did not impair the ability of l-DOPA to rescue forepaw akinesia in the cylinder test but decreased rotarod performance, probably due to induction of flat body posture and forepaw treading which are typical of 5-HT1A agonists upon acute administration. However, upon repeated administration of NLX-112 (0.63 mg/kg, i.p., twice a day), flat body posture and forepaw treading subsided within 4 days of treatment.Taken together, these observations suggest that NLX-112 could exhibit a novel therapeutic profile, combining robust anti-dyskinetic properties without impairing the therapeutic properties of l-DOPA, and with additional beneficial effects on non-motor (affective) symptoms.

Background and purpose:Combining 5‐HT1Areceptor activation with dopamine D2/D3receptor blockade should improve negative symptoms and cognitive deficits in schizophrenia. We describe thein vitroprofile of F15063 (N‐[(2,2‐dimethyl‐2,3‐dihydro‐benzofuran‐7‐yloxy)ethyl]‐3‐(cyclopent‐1‐enyl)‐benzylamine).Experimental approach:F15063 was characterised in tests of binding affinity and in cellular models of signal transduction at monoamine receptors.Key results:Affinities (receptor and pKivalues) of F15063 were: rD29.38; hD2L9.44; hD2S9.25; hD38.95; hD48.81; h5‐HT1A8.37. F15063 had little affinity (40‐fold lower than D2) at other targets. F15063 antagonised dopamine‐activated G‐protein activation at hD2, rD2and hD3receptors with potency (pKbvalues 9.19, 8.29 and 8.74 in [35S]GTPγS binding experiments) similar to haloperidol. F15063 did not exhibit any hD2receptor agonism, even in tests of ERK1/2 phosphorylation and G‐protein activation in cells with high receptor expression. In contrast, like (±)8‐OH‐DPAT, F15063 efficaciously activated h5‐HT1A(Emax70%, pEC507.57) and r5‐HT1Areceptors (52%, 7.95) in tests of [35S]GTPγS binding, cAMP accumulation (90%, 7.12) and ERK1/2 phosphorylation (93%, 7.13). F15063 acted as a partial agonist for [35S]GTPγS binding at hD4(29%, 8.15) and h5‐HT1Dreceptors (35%, 7.68). In [35S]GTPγS autoradiography, F15063 activated G‐proteins in hippocampus, cortex and septum (regions enriched in 5‐HT1Areceptors), but antagonised quinelorane‐induced activation of D2/D3receptors in striatum.Conclusions and implications:F15063 antagonised dopamine D2/D3receptors, a property underlying its antipsychotic‐like activity, whereas activation of 5‐HT1Aand D4receptors mediated its actions in models of negative symptoms and cognitive deficits of schizophrenia (see companion papers).British Journal of Pharmacology(2007)151, 237–252. doi:10.1038/sj.bjp.0707158

Small rodents (mice, rats) are the species of choice for evaluating the pharmacology of centrally acting compounds, such as antipsychotics, whereas toxicology data are routinely obtained from other species (rabbits, dogs, monkeys). Whilst there is a substantial number of “therapeutically relevant” pharmacological models for “antipsychotic-like” activity in small rodents, based on hyperdopaminergic or hypoglutamatergic/NMDA approaches, there is a remarkable paucity of such models in other species. Here, we compared the efficacy and potency of reference and new generation dopamine D2/5-HT1A putative antipsychotics, administered orally, against apomorphine-induced emesis in dogs, a model of central D2 receptor activation that can be implemented with relative ease. Risperidone potently and fully (10 μg/kg) prevented emesis/retching induced by 0.1 mg/kg s.c. apomorphine. SLV313 and F15063 (D2 receptor antagonists/5-HT1A receptor agonists) also abolished emesis/retching, albeit less potently than risperidone (minimal effective dose, MEDs: 10 and 40 μg/kg, respectively). The D2 receptor partial agonists/5-HT1A receptor agonists aripiprazole and bifeprunox, (up to 80 μg/kg) only partially attenuated emesis, as did the peripheral D2 receptor antagonist domperidone. Under the present experimental conditions, haloperidol was only efficacious at the highest dose tested (320 μg/kg). To summarize, dogs are very sensitive to the dopaminergic blocking effects of antipsychotics in this model of D2 receptor activation. This model can thus be advantageously used to investigate the pharmacological activity of novel D2 receptor antagonists/partial agonists in dogs.

Background and purpose: Desensitization of somatodendritic 5-HT1A receptors is involved in the mechanism of action of several antidepressants, but the rapidity of this effect and the amount of agonist stimulation needed are unclear. We evaluated the capacity of the high-efficacy 5-HT1A agonist, F13714 (3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methyl-6-methylaminopyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone) and of the partial agonist, flesinoxan, to desensitize somatodendritic 5-HT1A receptors involved in the control of 5-HT release.Experimental approach: Intracerebral microdialysis in the hippocampus of freely moving rats was used to examine the acute and chronic effects of the two compounds (administered by osmotic pumps for 3, 7 or 14 days) on extracellular 5-HT levels, measured by HPLC with electrochemical detection.Key results: When given acutely, F13714, flesinoxan and the low-efficacy 5-HT1A agonist, buspirone, dose-dependently decreased extracellular 5-HT concentrations (ED50 values: 0.04, 0.77 and 5.6 mg kg(-1), respectively). The selective 5-HT1A antagonist WAY100635 inhibited the effects of the three compounds. F13714 (2.5 mg kg(-1) per day for 3, 7 or 14 days and 0.63 mg kg(-1) for 7 days) significantly attenuated the inhibition of 5-HT release induced by buspirone (10 mg kg(-1)). In contrast, flesinoxan (10 mg kg(-1) per day) failed to alter the response to buspirone at any of the treatment durations.Conclusions and implications: Rat somatodendritic 5-HT1A receptors controlling hippocampal 5-HT release were rapidly desensitized by chronic activation with a high- efficacy 5-HT1A agonist, but not by chronic activation with a partial agonist. Thus, rapid 5-HT1A autoreceptor desensitization by high-efficacy agonists may accelerate the onset of the therapeutic effects of antidepressants.

NT69L is a novel neurotensin (8–13) analog that produces atypical antipsychotic-like effects in animal models. Because atypical antipsychotic drugs increase dopamine (DA) and acetylcholine (ACh) efflux in the medial prefrontal cortex and DA efflux in the nucleus accumbens, the present study sought to further evaluate the putative antipsychotic-like effects of NT69L by assessing DA and ACh efflux in these regions. Dual probe microdialysis was conducted in awake freely moving male rats, without using an acetylcholinesterase inhibitor in the perfusion medium. NT69L (1.0 and 3.0 mg/kg) produced significant increases in extracellular DA and ACh efflux in the medial prefrontal cortex. NT69L (1.0 mg/kg, but not 3.0 mg/kg) produced a significant increase of DA, but not ACh, efflux in the nucleus accumbens. Pretreatment with the serotonin (5-HT)1A receptor antagonist WAY100635 (0.2 mg/kg) significantly attenuated the 3.0 mg/kg NT69L-induced increase in medial prefrontal cortical DA efflux. Pretreatment with NT69L (1.0 mg/kg) significantly potentiated the effects of the atypical antipsychotic drug risperidone (0.1 mg/kg) on DA, but not ACh, efflux in the medial prefrontal cortex, while pretreatment with NT69L 1.0 mg/kg failed to alter the effects of haloperidol (0.1 mg/kg) on DA or ACh efflux in either region. These findings further suggest that NT analogs may be useful alone or adjunctively for the treatment of schizophrenia.

Serotonin 5-HT1A receptors are promising targets in the management of schizophrenia but little information exists about affinity and efficacy of novel antipsychotics at these sites. We addressed this issue by comparing binding affinity at 5-HT1A receptors with dopamine rD2 receptors, which are important targets for antipsychotic drug action. Agonist efficacy at 5-HT1A receptors was determined for G-protein activation and adenylyl cyclase activity. Whereas haloperidol, thioridazine, risperidone and olanzapine did not interact with 5-HT1A receptors, other antipsychotic agents exhibited agonist properties at these sites. E-max values (% effect induced by 10 mu(M) of 5-HT) for G-protein activation at rat brain 5-HT1A receptors: sarizotan (66.5), bifeprunox (35.9), SSR181507 (25.8), nemonapride (25.7), ziprasidone (20.6), SLV313 (19), aripiprazole (15), tiospirone (8.9). These data were highly correlated with results obtained at recombinant human 5-HT1A receptors in determinations of G-protein activation and inhibition of forskolin-stimulated adenylyl cyclase. In binding-affinity determinations, the antipsychotics exhibited diverse properties at r5-HT1A receptors: sarizotan (pK(i)=8.65), SLV313 (8.64), SSR181507 (8.53), nemonapride (8.35), ziprasidone (8.30), tiospirone (8.22), aripiprazole (7.42), bifeprunox (7.19) and clozapine (6.31). The affinity ratios of the ligands at 5-HT1A vs. D2 receptors also varied widely: ziprasidone, SSR181507 and SLV313 had similar affinities whereas aripiprazole, nemonapride and bifeprunox were more potent at D2 than 5-HT1A receptors. Taken together, these data indicate that aripiprazole has low efficacy and modest affinity at 5-HT1A receptors, whereas bifeprunox has low affinity but high efficacy. In contrast, SSR181507 has intermediate efficacy but high affinity, and is likely to have more prominent 5-HT1A receptor agonist properties. Thus, the contribution of 5-HT1A receptor activation to the pharmacological profile of action of the antipsychotics will depend on the relative 5-HT1A/D2 affinities and on 5-HT1A agonist efficacy of the drugs.

Dopamine D2 receptor blockade is thought to be mandatory for antipsychotic action because most of the currently used antipsychotics have high affinity at these receptors. Here, we examined the in vivo binding characteristics of the D2-like receptor antagonist [3H]nemonapride in rat brain areas including the striatum, olfactory lobes and frontal cortex and its inhibition by a series of D2 antagonist antipsychotics. In vivo affinity of [3H]nemonapride was similar (apparent Kd value: 0.05 µmol/kg) in all brain regions examined. The estimated number of binding sites was higher in the striatum (66 fmol/mg wet weight) than in the olfactory lobes (28 fmol/mg wet weight) and the frontal cortex (21 fmol/mg wet weight). In the striatum, [3H]nemonapride binding was inhibited in a dose-dependent manner with the following order of potency (ED50, mg/kg): nemonapride (0.04), raclopride (0.13), spiperone and risperidone (0.14), haloperidol (0.21), clozapine (7.2) and thioridazine (9.4); in the olfactory lobes: nemonapride (0.03), raclopride and spiperone (0.09), haloperidol (0.10), risperidone (0.15), thioridazine and clozapine (11); in the frontal cortex, only the high affinity dopamine D2 antagonist compounds nemonapride (0.05), haloperidol (0.09), and raclopride (0.12) significantly decreased the binding of [3H]nemonapride. The present data suggest that conventional and atypical antipsychotics may be distinguished by their differential occupancy of striatal versus frontocortical D2-like receptors in vivo.

The aim of the present study was to establish the relationship between the plasma and brain concentration-time profiles of F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]methanone, fumaric acid salt] after acute administration and both its hyper- and hypoanalgesic effects in rats. The maximal plasma concentration (C(max)) of F 13640 after i.p. administration of 0.63 mg/kg was obtained at 15 min and decreased to half its maximal value after about 1 h. The amount of F 13640 collected by means of in vivo microdialysis in hippocampal dialysates could be measured reliably after 0.63 and 2.5 mg/kg, reached its maximum at about 1 h, and fell to half of its maximal value at about 3 h. 5-Hydroxytryptamine 1A (5-HT(1A)) receptor occupancy was estimated by ex vivo binding in rat brain sections. F 13640 inhibited [(3)H]8-hydroxy-2-[di-n-propylamino] tetralin binding ex vivo in rat hippocampus, entorhinal cortex, and frontal cortex (ED(50), 0.34 mg/kg i.p.). Maximal inhibition was reached at approximately 30 min after 0.63 mg/kg F 13640 and fell to half of its value after about 4 to 8 h. After injection (15 min) in the paw pressure test, F 13640 (0.63 mg/kg i.p.) induced an initial hyperalgesia that was followed 4 h later by a paradoxical analgesia that lasted until 8 h. In contrast, in the formalin test, F 13640 inhibited pain behaviors until 4 h after drug administration. F 13640 also produced elements of the 5-HT syndrome that lasted up to 4 h after administration. These results demonstrate that F 13640 induces hyperalgesia and/or analgesia with a time course that parallels the occupancy of 5-HT(1A) receptors and the presence of the compound in blood and brain.

Several novel antipsychotics, such as aripiprazole, bifeprunox, SSR181507 [(3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine], and SLV313 [1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-piperazine], activate serotonin 5-hydroxytryptamine (5-HT)1A receptors. Such activity is associated with enhanced treatment of negative symptoms and cognitive deficits, which may be mediated by modulation of cerebral dopamine and serotonin levels. We employed microdialysis coupled to high pressure liquid chromatography with electrochemical detection to examine 5-HT1A receptor activation in the modulation of extracellular dopamine in medial prefrontal cortex and serotonin in hippocampus of freely moving rats. The above compounds were compared with drugs that have less interaction with 5-HT1A receptors (clozapine, nemonapride, ziprasidone, olanzapine, risperidone, and haloperidol). Hippocampal 5-HT was decreased by bifeprunox, SSR181507, SLV313, sarizotan, and nemonapride, effects similar to those seen with the 5-HT1A agonist, (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)8-OH-DPAT], consistent with activation of 5-HT1A autoreceptors. These decreases were reversed by the selective 5-HT1A antagonist, WAY100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide]. In contrast, haloperidol, risperidone, clozapine, olanzapine, ziprasidone, and aripiprazole did not significantly modify hippocampal serotonin levels. In medial prefrontal cortex, dopamine levels were increased by SSR181507, SLV313, sarizotan, and (+)8-OH-DPAT. These effects were reversed by WAY100635, indicating mediation by 5-HT1A receptors. In contrast, the increases in dopamine levels induced by clozapine, risperidone, olanzapine, and ziprasidone were not blocked by WAY100635, consistent with predominant influence of other mechanisms in the actions of these drugs. Haloperidol, nemonapride, and the D2 partial agonists, aripiprazole and bifeprunox, did not significantly alter dopamine release. Taken together, these data demonstrate the diverse contribution of 5-HT1A receptor activation to the profile of antipsychotics and suggest that novel drugs selectively targeting D2 and 5-HT1A receptors may present distinctive therapeutic properties.