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P.1.c.017 F15599, a highly selective serotonin 5-HT1A receptor agonist: in vitro affinity and efficacy profile at native rat and recombinant human 5-HT1A receptors
S232
P.1.c Basic neuroscience – Neuropharmacology
The effects of veratrine on lamotrigine-induced behavioural changes in the modified forced swimming test.
Immobility Swimming Climbing
Saline– Saline
Veratrine– Saline
Saline– Lamotrigine
Veratrine– Lamotrigine
35.0±3.3 12.5±1.4 13.5±3.1
34.4±4.1 13.9±2.8 11.7±1.9
15.8±2.8* 20.4±1.7* 24.0±2.6*
25.2±3.3 13.8±1.7 21.0±2.7*
*p < 0.05 compared to saline-saline group (ANOVA followed by NewmanKeuls test), mean±SEM, n = 10/group.
Conclusions: the present study corroborated previous study showing that lamotrigine exerts a dual monoaminergic effect in the modified FST and indicated that its serotonergic effect are related to the voltage-dependent sodium channels and this may represent a new target for the development of novel antidepressant drugs. On the other hand, the noradrenergic effect of lamotrigine was not related to the voltage-dependent sodium channels. Financial support: CNPq, Fundacao Araucaria. References [1] Consoni FT, Vital MABF, Andreatini R., 2006, Dual monoamine modulation for the antidepressant-like effect of lamotrigine in the modified forced swimming test, Eur Neuropsychopharmacol, in press. [2] Cryan J.F., Markou A., Lucki I., 2002, Assessing antidepressant activity in rodents: Recent developments and future needs, Trends Pharmacol. Sci., 23, 5, 238–245. [3] Ketter T.A., Manji H.K., Post R.M., 2003, Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders, J. Clin. Psychopharmacol, 23, 484–495.
“rotarod” (myorelaxant activity). The anticonvulsant effect was determined using antagonism with penthylentetrazole and “maximal electroshock”. The anxiety activity was tests in the black-white box. The depressive activity was study by Porsolt test. Investigations were carried out in the two time interval – short (2 hr 40 min) and long (24 hr). It was discovered that anticonvulsant activity of investigated compounds during short time interval by oral administration is not different from 3-hydroxyphenazepam’s activity. This is an evidence of high pharmacology activity of these compounds. However, in 24 hrs after administration, esters of propionic (C2), enantic (C6) and caprilic (C7) acids show the greater activity than 3-hydroxyphenazepam. That shows that these compounds are prodrugs of 3-hydroxyphenazepam and low speed of ester’s hydrolysis by esters result in prolongation of action. The pharmacology action of esters of 3-hydroxyphenazepam was average 72−96 hr. The maximal anticonvulsant action of these compounds under oral delivery were demonstrated during the period of 0.5−24 hr after delivery. Thereafter, results of study showed, that with oral delivery for esters of 3-hydroxypenazepam we can observe the anticonvulsant, sedative and anxiety action with absence of the muscle relaxation. All compounds have depressive activity too.
P.1.c.017 F15599, a highly selective serotonin 5-HT1A receptor agonist: in vitro affinity and efficacy profile at native rat and recombinant human 5-HT1A receptors
I.A. Kravchenko ° , A.I. Sivko. Odessa National University, Pharmaceutical chemistry, Odessa, Ukraine
A. Newman-Tancredi1 ° , M.B. Assi´e1 , C. Cosi2 , L. Bruins Slot3 , D. Cussac3 , J.C. Martel1 . 1 Centre de Recherche Pierre Fabre, Neurobiology 2 Division, Castres, France; 2 Centre de Recherche Pierre Fabre, Neurobiology 1 Division, Castres, France; 3 Centre de Recherche Pierre Fabre, Cellular & Molecular Biology Dept., Castres, France
The actual problem of modern pharmacology is the development of new drugs for treatment of neurological and mental disorder, derivatives of 1.4-benzdiazepine in particular. Pathological conditions that are corrected by such preparations have different time length of action and symptom manifestation. Hence, the development of such new drugs and their introduction techniques are vital in ensuring the optimal influence on the body. The stress action on the organism has integrated character and has an effect on many physiological systems at once, including the behavior. A common strategy of prodrug’s development for slow release is to include a long-chain aliphatic ester to slow hydrolysis. It is particularly useful for the treatment of psychoses where patients require medication for extended periods and patient compliance is low. A few prodrugs for treatment of CNS are known – haloperidol decanoate and fluphenazine enanthate. The duration of theirs activity is 1 month, in contrast with parent drugs – haloperidol and fluphenazine (duration of activity ~6−8 hr). New esters of 3-hydroxyphenazepam and aliphatic acids with C2 to C17 carbon backbone chain were synthesized. The experiments were conduct on the white mice males with mass of 18−20g. In each group were 5 experimental animals. Dose of esters of 3-hydroxyphenazepam was 1 mg/kg. Animal group without drugs was used as a control. The animals were maintained at 20±1 ºC under light-dark cycle and had free access to standard rogent diet and clean drinking water. The sedative action of esters of 3-hydroxypenazepam was study by method of “open-field test”, the effect of esters of 3-hydroxypenazepam on motor coordination was determined by
Serotonin 5-HT1A receptors are key receptors controlling serotonergic neurotransmission, being localised both pre-synaptically in the Raphe nuclei and post-synaptically in regions associated with control of mood and cognition. Indeed, extensive evidence indicates that activation of serotonin 5-HT1A receptors is a key element in the mechanism of action of antidepressant drugs [1]. F15599 is a novel ligand with marked antidepressant-like activity and a favourable influence on frontal cortex dopamine release (Assie et al., accompanying poster). Here, the profile of F15599 was examined in models of receptor affinity and signal transduction at both native rat and recombinant human serotonin 5-HT1A receptors. In competition binding experiments with the selective 5-HT1A agonist, [3 H]8-OH-DPAT, F15599 exhibited high affinity at 5-HT1A receptors in rat brain membranes (pKi hippocampus 8.47; cortex 8.65) and at recombinant human 5-HT1A receptors stably expressed in CHO cells (pKi 8.57). F15599 exhibited negligible interaction ( < 50% effect at 10 mM) with over 40 different targets including serotonin, dopamine, adrenergic, muscarine and histamine receptors, reuptake sites and enzymes. The 5-HT1A agonist, (+)8-OH-DPAT, exhibited a pKi of 9.2 at h5-HT1A receptors [2]. In models of signal transduction, F15599 efficaciously activated [35S]GTP˜aS binding (a measure of global G-protein activation) to membranes of C6 glial cells expressing h5-HT1A receptors (Emax 72% relative to 10 mM 5-HT, pEC50 6.4). In comparison, (+)8-OH-DPAT exhibited an Emax of 55% and pEC50 of 7.2. F15599 acted as a “full” agonist in sensitive cell-based measures of h5-HT1A signalling, including inhibition of cAMP
P.1.c.016 New tranquilizers – prodrugs for slow and prolonged release by oral administration
P.1.c Basic neuroscience – Neuropharmacology accumulation in HeLa cells (100%, 6.5) and stimulation of Extracellular signal Regulated Kinase (ERK1/2) phosphorylation in CHO cells (99%, 8.0). (+)8-OH-DPAT also exhibited maximal efficacy in these tests [2,3]. F15599 stimulated total [35S]GTP˜aS binding in membranes from rat hippocampus (86%, 6.3). In comparison, (+)8-OH-DPAT yielded an Emax of 67% and pEC50 of 6.9 in this preparation [2]. These effects of F15599 and (+)8OH-DPAT were abolished by the selective 5-HT1A antagonist, WAY100635. In measures of Gao-specific G-protein activation, determined by [35S]GTP˜aS binding coupled to antibody capture and SPA detection, F15599 efficaciously stimulated Gao activation in hippocampal membranes (95%, 6.2). (+)8-OH-DPAT was less efficacious (76%, 7.4). In functional autoradiography experiments on rat brain sections, F15599 (100 mM) increased [35S]GTP˜aS labelling in brain regions expressing 5-HT1A receptors, including frontal and entorhinal cortex, lateral septum, hippocampus and Raphe nuclei. Activation by F15599 in all these brain regions was abolished by co-incubation of sections with WAY100635 (10 mM). In summary, F15599 is a highly selective 5-HT1A receptor ligand with high efficacy at both native rat and recombinant human serotonin 5-HT1A receptors in vitro. F15599 activates 5-HT1A receptors in membrane and whole cell preparations, as well as in brain sections. The efficacy of F15599 for 5-HT1A receptor activation is as high or higher than that of the reference agonist, (+)8-OH-DPAT. Taken together with neurochemical and behavioural data (Assie et al., accompanying abstract), these results suggest that F15599 shows promise for amelioration of CNS disorders involving 5-HT1A receptor dysfunction. References [1] Blier P, Ward NM., 2003, Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiatry, 53, 193–203. [2] Newman-Tancredi A., AssieM.-B., Leduc N., Ormiere A.-M., Danty N., Cosi C., 2005, Novel antipsychotics activate recombinant human and native rat serotonin 5-HT1A receptors: affinity, efficacy and potential implications for treatment of schizophrenia, Int J Neuropsychopharmacol, 8, 341–356. [3] Bruins Slot L., De Vries L., Newman-Tancredi A., Cussac D., 2006, Differential profile of novel antipsychotics at human dopamine D2S and serotonin 5-HT1A receptors: measure of Extracellular signal-Regulated Kinase (ERK) phosphorylation, Eur J Pharmacol, Feb 20, Epub ahead of print.
P.1.c.018 F15599, a highly selective serotonin 5-HT1A receptor agonist: in vivo profile in neurochemical and behavioural models of serotonergic activity M.B. Assi´e1 ° , L. Bardin1 , R. Depoortere1 , E. Carilla-Durand2 , A. Newman-Tancredi1 . 1 Centre de Recherche Pierre Fabre, Neurobiology 2 Division, Castres, France; 2 Centre de Recherche Pierre Fabre, ADMET Dept., Castres, France Serotonin 5-HT1A receptors are involved in the regulation of mood, cognition and analgesia (Blier and Ward 2003; Colpaert 2006). F15599 is a novel ligand with high affinity, selectivity for and efficacy at 5-HT1A receptors (Newman-Tancredi et al., accompanying abstract). Here, we examined its in vivo effects in neurochemical and behavioural models relevant to 5-HT1A receptor activity, including the forced swimming test (FST), predictive of antidepressant properties, extracellular 5-HT levels in the hippocampus using in vivo microdialysis (a read-out of somatodendritic 5-HT1A receptor activation), dopamine levels in
S233
the medial prefrontal cortex (associated with beneficial effects on cognitive and mood parameters) and body temperature, plasma corticosterone and induction of 5-HT behavioural syndrome, parameters that are modified by post-synaptic 5-HT1A receptor agonists. F15599 totally abolished immobility in the FST at low doses (ED50 = 0.05 mg/kg p.o.), an effect that was blocked by the 5-HT1A antagonist, WAY100635. In comparison, the 5-HT1A agonist flesinoxan diminished, but did not abolish, immobility (ED50 : 0.22 mg/kg p.o.). Following acute administration, F15599 increased dopamine levels in medial prefrontal cortex of freely moving rats (ED50 = 0.03 mg/kg i.p.) but required higher doses (ED50 = 0.24 mg/kg i.p.) to decrease hippocampal 5-HT levels. In contrast, flesinoxan influenced dopamine and 5-HT levels at similar doses: ED50 values 0.60 and 0.77 mg/kg i.p., respectively. Upon chronic treatment (14 days subcutaneous minipumps), a high dose (10 mg/kg/day) of F15599 did not desensitize somatodendritic 5-HT1A receptors: an acute challenge (day 15) with buspirone (10 mg/kg i.p.) was still able to lower hippocampal 5-HT levels. A higher dose of F15599 (20 mg/kg/day) was needed to reduce the response to buspirone, i.e. to desensitize somatodendritic 5-HT1A receptors. In comparison, a similar chronic treatment (20 mg/kg/day) with the serotonin reuptake inhibitor, citalopram, a drug that is poorly active in the FST (ED50 > 10 mg/kg Skrebuhhova et al., 1999), significantly diminished the response to acute buspirone. In other acute measures of 5-HT1A receptor activation, F15599 was active at higher doses: it induced hypothermia (ED50 = 0.88 mg/kg p.o.) and increased plasma corticosterone (ED50 = 0.45 mg/kg p.o.). F15599 also induced lower lip retraction (ED50 = 0.33 mg/kg p.o.) and elements of the 5-HT behavioural syndrome: forepaw treading (ED50 = 1.5 mg/kg p.o.) and flat body posture (ED50 = 8.3 mg/kg p.o.). In summary, the reduction of immobility in the FST, and the increase in frontal cortex dopamine levels, after acute administration, are observed at doses lower than those that produce other effects of 5-HT1A activation (decreased hippocampal serotonin, increased plasma corticosterone and hypothermia). After 14day chronic administration, F15599 desensitized somatodendritic 5-HT1A receptors only at a dose substantially higher than that active in the FST. Taken together, these data suggest that F15599 activates postsynaptic 5-HT1A receptors in the frontal cortex, but interacts more weakly with raphe-localised 5-HT1A autoreceptors controlling serotonin release. References [1] Blier P., Ward N.M., 2003, Is there a role for 5-HT1A agonists in the treatment of depression? Biol. Psychiatry, 53, 193–203. [2] Colpaert F.C., 2006, 5-HT1A receptor activation: new molecular and neuroadaptive mechanisms of pain relief, Opin. Investig. Drugs, 7, 40−47. [3] Skrebuhhova T., Allikmets L., Matto V., 1999, Effects of anxiogenic drugs in rat forced swimming test, Methods Find. Exp. Clin. Pharmacol, 21, 173–178.
P.1.c Basic neuroscience – Neuropharmacology
The effects of veratrine on lamotrigine-induced behavioural changes in the modified forced swimming test.
Immobility Swimming Climbing
Saline– Saline
Veratrine– Saline
Saline– Lamotrigine
Veratrine– Lamotrigine
35.0±3.3 12.5±1.4 13.5±3.1
34.4±4.1 13.9±2.8 11.7±1.9
15.8±2.8* 20.4±1.7* 24.0±2.6*
25.2±3.3 13.8±1.7 21.0±2.7*
*p < 0.05 compared to saline-saline group (ANOVA followed by NewmanKeuls test), mean±SEM, n = 10/group.
Conclusions: the present study corroborated previous study showing that lamotrigine exerts a dual monoaminergic effect in the modified FST and indicated that its serotonergic effect are related to the voltage-dependent sodium channels and this may represent a new target for the development of novel antidepressant drugs. On the other hand, the noradrenergic effect of lamotrigine was not related to the voltage-dependent sodium channels. Financial support: CNPq, Fundacao Araucaria. References [1] Consoni FT, Vital MABF, Andreatini R., 2006, Dual monoamine modulation for the antidepressant-like effect of lamotrigine in the modified forced swimming test, Eur Neuropsychopharmacol, in press. [2] Cryan J.F., Markou A., Lucki I., 2002, Assessing antidepressant activity in rodents: Recent developments and future needs, Trends Pharmacol. Sci., 23, 5, 238–245. [3] Ketter T.A., Manji H.K., Post R.M., 2003, Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders, J. Clin. Psychopharmacol, 23, 484–495.
“rotarod” (myorelaxant activity). The anticonvulsant effect was determined using antagonism with penthylentetrazole and “maximal electroshock”. The anxiety activity was tests in the black-white box. The depressive activity was study by Porsolt test. Investigations were carried out in the two time interval – short (2 hr 40 min) and long (24 hr). It was discovered that anticonvulsant activity of investigated compounds during short time interval by oral administration is not different from 3-hydroxyphenazepam’s activity. This is an evidence of high pharmacology activity of these compounds. However, in 24 hrs after administration, esters of propionic (C2), enantic (C6) and caprilic (C7) acids show the greater activity than 3-hydroxyphenazepam. That shows that these compounds are prodrugs of 3-hydroxyphenazepam and low speed of ester’s hydrolysis by esters result in prolongation of action. The pharmacology action of esters of 3-hydroxyphenazepam was average 72−96 hr. The maximal anticonvulsant action of these compounds under oral delivery were demonstrated during the period of 0.5−24 hr after delivery. Thereafter, results of study showed, that with oral delivery for esters of 3-hydroxypenazepam we can observe the anticonvulsant, sedative and anxiety action with absence of the muscle relaxation. All compounds have depressive activity too.
P.1.c.017 F15599, a highly selective serotonin 5-HT1A receptor agonist: in vitro affinity and efficacy profile at native rat and recombinant human 5-HT1A receptors
I.A. Kravchenko ° , A.I. Sivko. Odessa National University, Pharmaceutical chemistry, Odessa, Ukraine
A. Newman-Tancredi1 ° , M.B. Assi´e1 , C. Cosi2 , L. Bruins Slot3 , D. Cussac3 , J.C. Martel1 . 1 Centre de Recherche Pierre Fabre, Neurobiology 2 Division, Castres, France; 2 Centre de Recherche Pierre Fabre, Neurobiology 1 Division, Castres, France; 3 Centre de Recherche Pierre Fabre, Cellular & Molecular Biology Dept., Castres, France
The actual problem of modern pharmacology is the development of new drugs for treatment of neurological and mental disorder, derivatives of 1.4-benzdiazepine in particular. Pathological conditions that are corrected by such preparations have different time length of action and symptom manifestation. Hence, the development of such new drugs and their introduction techniques are vital in ensuring the optimal influence on the body. The stress action on the organism has integrated character and has an effect on many physiological systems at once, including the behavior. A common strategy of prodrug’s development for slow release is to include a long-chain aliphatic ester to slow hydrolysis. It is particularly useful for the treatment of psychoses where patients require medication for extended periods and patient compliance is low. A few prodrugs for treatment of CNS are known – haloperidol decanoate and fluphenazine enanthate. The duration of theirs activity is 1 month, in contrast with parent drugs – haloperidol and fluphenazine (duration of activity ~6−8 hr). New esters of 3-hydroxyphenazepam and aliphatic acids with C2 to C17 carbon backbone chain were synthesized. The experiments were conduct on the white mice males with mass of 18−20g. In each group were 5 experimental animals. Dose of esters of 3-hydroxyphenazepam was 1 mg/kg. Animal group without drugs was used as a control. The animals were maintained at 20±1 ºC under light-dark cycle and had free access to standard rogent diet and clean drinking water. The sedative action of esters of 3-hydroxypenazepam was study by method of “open-field test”, the effect of esters of 3-hydroxypenazepam on motor coordination was determined by
Serotonin 5-HT1A receptors are key receptors controlling serotonergic neurotransmission, being localised both pre-synaptically in the Raphe nuclei and post-synaptically in regions associated with control of mood and cognition. Indeed, extensive evidence indicates that activation of serotonin 5-HT1A receptors is a key element in the mechanism of action of antidepressant drugs [1]. F15599 is a novel ligand with marked antidepressant-like activity and a favourable influence on frontal cortex dopamine release (Assie et al., accompanying poster). Here, the profile of F15599 was examined in models of receptor affinity and signal transduction at both native rat and recombinant human serotonin 5-HT1A receptors. In competition binding experiments with the selective 5-HT1A agonist, [3 H]8-OH-DPAT, F15599 exhibited high affinity at 5-HT1A receptors in rat brain membranes (pKi hippocampus 8.47; cortex 8.65) and at recombinant human 5-HT1A receptors stably expressed in CHO cells (pKi 8.57). F15599 exhibited negligible interaction ( < 50% effect at 10 mM) with over 40 different targets including serotonin, dopamine, adrenergic, muscarine and histamine receptors, reuptake sites and enzymes. The 5-HT1A agonist, (+)8-OH-DPAT, exhibited a pKi of 9.2 at h5-HT1A receptors [2]. In models of signal transduction, F15599 efficaciously activated [35S]GTP˜aS binding (a measure of global G-protein activation) to membranes of C6 glial cells expressing h5-HT1A receptors (Emax 72% relative to 10 mM 5-HT, pEC50 6.4). In comparison, (+)8-OH-DPAT exhibited an Emax of 55% and pEC50 of 7.2. F15599 acted as a “full” agonist in sensitive cell-based measures of h5-HT1A signalling, including inhibition of cAMP
P.1.c.016 New tranquilizers – prodrugs for slow and prolonged release by oral administration
P.1.c Basic neuroscience – Neuropharmacology accumulation in HeLa cells (100%, 6.5) and stimulation of Extracellular signal Regulated Kinase (ERK1/2) phosphorylation in CHO cells (99%, 8.0). (+)8-OH-DPAT also exhibited maximal efficacy in these tests [2,3]. F15599 stimulated total [35S]GTP˜aS binding in membranes from rat hippocampus (86%, 6.3). In comparison, (+)8-OH-DPAT yielded an Emax of 67% and pEC50 of 6.9 in this preparation [2]. These effects of F15599 and (+)8OH-DPAT were abolished by the selective 5-HT1A antagonist, WAY100635. In measures of Gao-specific G-protein activation, determined by [35S]GTP˜aS binding coupled to antibody capture and SPA detection, F15599 efficaciously stimulated Gao activation in hippocampal membranes (95%, 6.2). (+)8-OH-DPAT was less efficacious (76%, 7.4). In functional autoradiography experiments on rat brain sections, F15599 (100 mM) increased [35S]GTP˜aS labelling in brain regions expressing 5-HT1A receptors, including frontal and entorhinal cortex, lateral septum, hippocampus and Raphe nuclei. Activation by F15599 in all these brain regions was abolished by co-incubation of sections with WAY100635 (10 mM). In summary, F15599 is a highly selective 5-HT1A receptor ligand with high efficacy at both native rat and recombinant human serotonin 5-HT1A receptors in vitro. F15599 activates 5-HT1A receptors in membrane and whole cell preparations, as well as in brain sections. The efficacy of F15599 for 5-HT1A receptor activation is as high or higher than that of the reference agonist, (+)8-OH-DPAT. Taken together with neurochemical and behavioural data (Assie et al., accompanying abstract), these results suggest that F15599 shows promise for amelioration of CNS disorders involving 5-HT1A receptor dysfunction. References [1] Blier P, Ward NM., 2003, Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiatry, 53, 193–203. [2] Newman-Tancredi A., AssieM.-B., Leduc N., Ormiere A.-M., Danty N., Cosi C., 2005, Novel antipsychotics activate recombinant human and native rat serotonin 5-HT1A receptors: affinity, efficacy and potential implications for treatment of schizophrenia, Int J Neuropsychopharmacol, 8, 341–356. [3] Bruins Slot L., De Vries L., Newman-Tancredi A., Cussac D., 2006, Differential profile of novel antipsychotics at human dopamine D2S and serotonin 5-HT1A receptors: measure of Extracellular signal-Regulated Kinase (ERK) phosphorylation, Eur J Pharmacol, Feb 20, Epub ahead of print.
P.1.c.018 F15599, a highly selective serotonin 5-HT1A receptor agonist: in vivo profile in neurochemical and behavioural models of serotonergic activity M.B. Assi´e1 ° , L. Bardin1 , R. Depoortere1 , E. Carilla-Durand2 , A. Newman-Tancredi1 . 1 Centre de Recherche Pierre Fabre, Neurobiology 2 Division, Castres, France; 2 Centre de Recherche Pierre Fabre, ADMET Dept., Castres, France Serotonin 5-HT1A receptors are involved in the regulation of mood, cognition and analgesia (Blier and Ward 2003; Colpaert 2006). F15599 is a novel ligand with high affinity, selectivity for and efficacy at 5-HT1A receptors (Newman-Tancredi et al., accompanying abstract). Here, we examined its in vivo effects in neurochemical and behavioural models relevant to 5-HT1A receptor activity, including the forced swimming test (FST), predictive of antidepressant properties, extracellular 5-HT levels in the hippocampus using in vivo microdialysis (a read-out of somatodendritic 5-HT1A receptor activation), dopamine levels in
S233
the medial prefrontal cortex (associated with beneficial effects on cognitive and mood parameters) and body temperature, plasma corticosterone and induction of 5-HT behavioural syndrome, parameters that are modified by post-synaptic 5-HT1A receptor agonists. F15599 totally abolished immobility in the FST at low doses (ED50 = 0.05 mg/kg p.o.), an effect that was blocked by the 5-HT1A antagonist, WAY100635. In comparison, the 5-HT1A agonist flesinoxan diminished, but did not abolish, immobility (ED50 : 0.22 mg/kg p.o.). Following acute administration, F15599 increased dopamine levels in medial prefrontal cortex of freely moving rats (ED50 = 0.03 mg/kg i.p.) but required higher doses (ED50 = 0.24 mg/kg i.p.) to decrease hippocampal 5-HT levels. In contrast, flesinoxan influenced dopamine and 5-HT levels at similar doses: ED50 values 0.60 and 0.77 mg/kg i.p., respectively. Upon chronic treatment (14 days subcutaneous minipumps), a high dose (10 mg/kg/day) of F15599 did not desensitize somatodendritic 5-HT1A receptors: an acute challenge (day 15) with buspirone (10 mg/kg i.p.) was still able to lower hippocampal 5-HT levels. A higher dose of F15599 (20 mg/kg/day) was needed to reduce the response to buspirone, i.e. to desensitize somatodendritic 5-HT1A receptors. In comparison, a similar chronic treatment (20 mg/kg/day) with the serotonin reuptake inhibitor, citalopram, a drug that is poorly active in the FST (ED50 > 10 mg/kg Skrebuhhova et al., 1999), significantly diminished the response to acute buspirone. In other acute measures of 5-HT1A receptor activation, F15599 was active at higher doses: it induced hypothermia (ED50 = 0.88 mg/kg p.o.) and increased plasma corticosterone (ED50 = 0.45 mg/kg p.o.). F15599 also induced lower lip retraction (ED50 = 0.33 mg/kg p.o.) and elements of the 5-HT behavioural syndrome: forepaw treading (ED50 = 1.5 mg/kg p.o.) and flat body posture (ED50 = 8.3 mg/kg p.o.). In summary, the reduction of immobility in the FST, and the increase in frontal cortex dopamine levels, after acute administration, are observed at doses lower than those that produce other effects of 5-HT1A activation (decreased hippocampal serotonin, increased plasma corticosterone and hypothermia). After 14day chronic administration, F15599 desensitized somatodendritic 5-HT1A receptors only at a dose substantially higher than that active in the FST. Taken together, these data suggest that F15599 activates postsynaptic 5-HT1A receptors in the frontal cortex, but interacts more weakly with raphe-localised 5-HT1A autoreceptors controlling serotonin release. References [1] Blier P., Ward N.M., 2003, Is there a role for 5-HT1A agonists in the treatment of depression? Biol. Psychiatry, 53, 193–203. [2] Colpaert F.C., 2006, 5-HT1A receptor activation: new molecular and neuroadaptive mechanisms of pain relief, Opin. Investig. Drugs, 7, 40−47. [3] Skrebuhhova T., Allikmets L., Matto V., 1999, Effects of anxiogenic drugs in rat forced swimming test, Methods Find. Exp. Clin. Pharmacol, 21, 173–178.