In vivo electrophysiological and neurochemical effects of the selective 5-HT1A receptor agonist, F13640, at pre- and postsynaptic 5-HT1A receptors in the rat (original) (raw)
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British Journal of Pharmacology, 2010
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-HT1A 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 mg·kg -1 i.v and reduced that of dorsal raphe 5-hydroxytryptaminergic neurones at doses >10-fold higher (minimal effective dose 8.2 mg·kg -1 i.v.). Both effects were reversed by the 5-HT1A antagonist (Ϯ)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-HT1A receptors) with an ED50 of 30 mg·kg -1 i.p., whereas it reduced hippocampal 5-HT release (an effect dependent exclusively on 5-HT1A autoreceptor activation) with an ED50 of 240 mg·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 (Ϯ)WAY100635.
European Journal of Pharmacology, 2007
High-efficacy activation of central 5-HT 1A receptors by means of the recently discovered, selective 5-HT 1A receptor ligand, F 13640 [(3chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]methyl}piperidin-1-yl]methanone, fumaric acid salt] causes an unprecedented, broad-spectrum analgesia in rat models of acute and chronic pain of nociceptive and neuropathic origin; it also is effective in conditions where opioids either are ineffective, induce analgesic tolerance, or elicit persistent hyperalgesia/allodynia. Inversely mirroring morphine's actions, F 13640's ("curative-like") analgesic effects persist after the discontinuation of treatment. Here, we examined the relationships, if any, between the dose and the duration of F 13640 treatment on the one hand, and the duration of persistent analgesia on the other. Rats received unilateral infraorbital nerve injury and developed allodyniaas assessed by an increased response to von Frey filament stimulationwithin 24 days; thereafter, using osmotic pumps, rats were subcutaneously infused with F 13640 in two experiments. In one, a one-week infusion was instituted at 0.04-10-mg/day doses; in a second experiment, a 0.63-mg/day dose was implemented for a duration ranging from 1 to 56 days. These 250-and 56-fold variations of the dose and duration of treatment caused post-treatment, persistent analgesia for about 10 and 40 days, respectively. At least as much as dose, the duration of F 13640 treatment determines F 13640-induced persistent analgesia. Neuroadaptive modulations at pre-and postsynaptic, brain and spinal cord 5-HT 1A receptors may be involved in the dynamical, dose-and time-dependent, pretreatment rise and post-treatment decay of the analgesia induced by high-efficacy 5-HT 1A receptor activation.
Large-amplitude 5-HT1A receptor activation: a new mechanism of profound, central analgesia
Neuropharmacology, 2002
We report the discovery of F 13640 and evidence suggesting this agent to produce powerful, broad-spectrum analgesia by novel molecular and neuroadaptative mechanisms. F 13640 stimulates G αο protein coupling to 5-HT 1A receptors to an extent unprecedented by selective, non-native 5-HT 1A ligands. Fifteen minutes after its injection in normal rats, F 13640 (0.01-2.5 mg/kg) decreases the vocalization threshold to paw pressure; 15 min upon injection in rats that are exposed to formalin-induced tonic nociception, F 13640 inhibits pain behavior. The initial hyperalgesia induced by 0.63 mg/kg F 13640 was followed, 8 hrs later, by paradoxical hypo-algesia; 5 mg/kg of morphine produces the opposite effects (i.e., hypo-algesia followed by hyper-algesia). Repeated F 13640 injections cause an increase in the basal vocalization threshold and a reduction of F 13640-produced hyperalgesia; in these conditions, morphine causes basal hyperalgesia and antinociceptive tolerance. Continuous two-week infusion of F 13640 (0.63 mg/day) exerts little effect on the threshold in normal rats, but markedly reduces analgesic self-administration in arthritic rats. F 13640 infusion also decreases allodynic responses to tactile and thermal stimulations in rats sustaining spinal cord or sciatic nerve injury. In these models of chronic nociceptive and neuropathic pain, the analgesia afforded by F 13640 consistently surpasses that of morphine (5 mg/day), imipramine (2.5 mg/day), ketamine (20 mg/day) and gabapentin (10 mg/day). Very-high-efficacy 5-HT 1A receptor activation constitutes a novel mechanism of central analgesia that grows rather than decays with chronicity, that is amplified by nociceptive stimulation, and that may uniquely relieve persistent nociceptive and neuropathic pains.
5-HT3-like receptors in the rat medial prefrontal cortex: further pharmacological characterization
Brain Research, 1996
The aim of the study was to further characterize the pharmacological properties of 5-hydroxytryptamine (5-HT)3-1ike receptors in the rat medial prefrontal cortex (mPFC) using combinations of biochemical and electrophysiological approaches. Phenylbiguanide (PBG) and three chlorinated derivatives, ortho-chloro-PBG (oCPBG), meta-chloro-PBG (mCPBG) and para-chloro-PBG (pCPBG), dose-dependently stimulated phosphoionositide (PI) turnover in fronto-cingulate cortical slices. All three chloro-isomers of PBG were equipotent in stimulating PI turnover. SR 57227A ((4-amino)-(6-chloro-2-pyridyl) L-piperidine hydrochloride, a novel compound with high affinity and selectivity for peripheral and central 5-HT 3 receptors) dose-dependently stimulated PI turnover in fronto-cingulate cortical slices. The rank order of potency of all the 5-HT 3 receptor agonists tested in the PI assay as compared to 5-HT was: 5-HT > 2-Me-5-HT > SR57227A > PBG = mCPBG = oCPBG = mCPBG. 5-HT and 5-HT receptor agonists depressed the firing rate of both spontaneously active and glutamate-activated quiescent mPFC cells in a current (dose)-dependent fashion. The rank order of effectiveness of these compounds was: 5-HT > SR57227A = 2-Me-5-HT = mCPBG = oCPBG = pCPBG = PBG. Unlike its action on the 5-HT 3 receptors in the periphery or cultured cell lines, D-tubocurarine chloride appears to be non-specific in blocking the depressant action of 2-Me-5-HT, 3,-aminobutyric acid and dopamine. Our results combined support the view that the pharmacological properties of 5-HT3-1ike receptors in the mPFC are not identical to those located in peripheral tissues and in cultured cell lines.
European Journal of Nuclear Medicine and Molecular Imaging, 2007
Purpose: To determine whether brain and plasma equilibrium of a proposed PET tracer for 5-HT 1A , [ 18 F]FPWAY, can be achieved in a sufficiently short time for practical use of the brain to plasma equilibrium distribution ratio (DR) to monitor receptor availability with and without isoflurane anesthesia. Methods: Awake (n=4) and isoflurane-anesthetized (n=4) rats were administered a continuous 60 min intravenous infusion of [ 18 F]FPWAY with timed arterial blood sampling. Brains of the isoflurane-anesthetized rats were scanned with the ATLAS small animal PET scanner; awake rats were not. All rats were killed at 60 min and scanned postmortem for 15 min, followed by brain slicing for autoradiography. Several regions of interest (ROIs) were defined in the PET images as well as in the autoradiographic images. Regional DRs were calculated as total activity in the brain ROI divided by plasma [ 18 F] FPWAY activity. Results: DRs in the anesthetized animals were constant between 30 and 60 min, indicating that near equilibrium between brain and plasma had been achieved by ∼30 min. DRs determined from postmortem PET data were higher in the isoflurane-anesthetized rats by 24% (not significant) and 33% (p=0.065) in whole brain and hippocampus, respectively. DRs determined from autoradiographic data were greater in isoflurane-anesthetized rats in medial hippocampus, lateral hippocampus, and cerebellum by 33% (p=0.054), 63% (p<0.01), and 32% (p<0.05), respectively.
Behavioural Brain Research, 1997
The deep layers of the superior colliculus (DLSC) and the dorsal periaqueductal gray matter (DPAG) have been implicated in the control of defensive-like behaviors. Electrical and chemical stimulation of these structures elicits fear and escape behaviour, expressed by immobility (freezing) and wild running, followed by jumps and rapid rotations. There is evidence that the neural substrates responsible for defensive behavior in this level of the midbrain tectum (MT) may also be responsible for fear-induced analgesia. This study was aimed at examining the characteristics of the analgesia that follows the defense-oriented reactions induced by electrical midbrain tectum stimulation at freezing and escape thresholds. The animals were submitted to the tail-flick test, following the induction of the defensive behavioral responses. The obtained results show that the antinociception that follows the freezing and escape behaviours were not antagonized by MT microinjections of the opioid antagonist naltrexone. These results emphasize previous data showing the non-opioid nature of this analgesia. On the other hand, the fear-induced analgesia was inhibited by microinjections of the serotonergic blockers, methysergide and ketanserin in the MT. Since methysergide is a non-specific antagonist of 5-HT receptors and ketanserin acts with a high degree of specificity at 5-HT 2 receptors the present results suggest that activation of 5-HT 2 receptors may be implicated in the antinociception induced by midbrain tectum stimulation.
European Journal of Pharmacology, 1993
The neurochemical profile of the selective 5-HT1A receptor antagonist WAY100135 [N-tert-butyl 3-4-(2-methoxyphenyl) piperazin-l-yl-2-phenylpropanamide dihydrochloride] and its enantiomers at the somatodendritic 5°HT1A receptor was determined by studying the effects of these compounds on 5-HT (5-hydroxytryptamine, serotonin) release in the rat hippocampus using in vivo microdialysis. (+)-WAY100135, (+)-WAY100135 and (-)-WAY100135 (all at 10 mg/kg s.c.) had no significant effect on extracellular levels of 5-HT in the hippocampus demonstrating that these compounds are devoid of 5-HT1A receptor agonist properties. In contrast, the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (0.1 mg/kg s.c.) and the partial agonists BMY 7378 (1.0 mg/kg s.c.) and buspirone (5 mg/kg s.c.) significantly decreased hippocampal 5-HT. Pretreatment with (:i:)-WAY100135 (at 10 mg/kg s.c.) and (+)-WAY100135 (at 1.0-10 mg/kg s.c.) completely blocked the 8-OH-DPAT-induced decrease in 5-HT release demonstrating that these compounds are antagonists at the somatodendritic 5-HT1A autoreceptor. (-)-WAY100135 at a dose of 10 mg/kg s.c. had no significant effect on the 8-OH-DPAT-induced inhibition of 5-HT release. (_+)-WAY100135 had no significant effect on extracellular levels of dopamine in the rat hippocampus but significantly increased extracellular levels of noradrenaline. The mechanism underlying the increase in noradrenaline is unknown at present. These data suggest that WAY100135 is a silent and selective receptor antagonist at the somatodendritic 5-HT1A receptor with activity residing in. the (+)-enantiomer. In addition, these findings confirm that WAY100135 is likely to be a useful tool for further investigation of 5-HT1A receptor function.
Behavioural Brain Research, 1995
Although considerable progress has been made in characterising the 5-HT1A receptor using agonists, partial agonists or nonselective antagonists, further studies of 5-HT1.4 receptor function have been hindered by the lack of highly selective antagonists. The term 'silent' antagonist has been used for such compounds in order to distinguish them unequivocally from several 5-HT1A receptor partial agonists which were initially designated 'antagonists'. In this report we provide a comprehensive review of the biochemical, pharmacological and behavioural properties of the first potent, selective and silent 5-HT1A receptor antagonist, WAY-100635 (N-{2-[4-(2-meth•xypheny•)-•-piperaziny•]ethy•}-N-(2-pyridiny•)cyc••hexanecarb•xamide trihydrochloride). WAY-100635 had an ICs0 (displacement of specific [3H]8-OH-DPAT binding to 5-HT~a receptors in the rat hippocampus) of 1.35 nM and was > 100-fold selective for the 5-HT1A site relative to a range of other CNS receptors.
Effects of MDL 73005EF on central pre- and postsynaptic 5-HT1A receptor function in the rat in vivo
European Journal of Pharmacology, 1990
The effects of MDL 7300SEF (8-[2-(2,3-dihydro-1.4-benzodioxin-2-yi)methyiamino]-8-azaspiro[4,S]decan-7.9-dione methyl suiphonate), a novel selective S-HT,. receptor iigand with putative anxioiytic properties, were explored using models of central pre-and postsynaptic S-HT,, receptor function iii the male rat. MDL 73005EF dose dependently decreased :he hippocampai S-HT oatput measured by in vivo microdialysis in chiorai hydrate-anaesthetised rats and this response was antagonised by the S-HT,,,, receptor antagonist, pindoioi. Local administration of MDL 7300SEF had no effect on the hippocampai S-HT output. MDL 7300SEF failed to alter basal plasma adrenocorticotropin (ACTH) levels but, in common with pindpioi, attenuated the ACTH response to the S-HT,, receptor agonist. 8-hydroxy-2-(di-n-propyiamino)tetraiin (&OH-DPAT). In contrast to 8-OH-DPAT, MDL 7300SEF significantly increased plasma proiactin but apparently not through a 5-HT receptor-mediated mechanism. The results indicate that MDL 7300SEF possesses mixed S-HT,, receptor agonist/antagonist properties, acting as an agonist at presynaptic S-HT,, receptors controlling 5-HT release and as an antagonist at postsynaptic 5-HT,, receptors mediating ACTI-J release. MDL 7300SEF (8-~2-(2.3-dihydro-1,4-benzodioxin-2-yl)methyiamino]-8-azaspiro[4,S]decan-7,9-dione methyl sulphonate); S-HT,, receptors; 5-HT release; ACTH (adrenocorticotropin); Microdialysis (brain, in vivo): Radioimmunoassay