Effects of the beta3-adrenoceptor (Adrb3) agonist SR58611A (amibegron) on serotonergic and noradrenergic transmission in the rodent: relevance to its antidepressant/anxiolytic-like profile.

SR58611A is a selective beta(3)-adrenoceptor (Adrb3) agonist which has demonstrated antidepressant and anxiolytic properties in rodents. The present study confirmed the detection of Adrb3 mRNA transcript in rodent brain sub-regions and evaluated the effect of SR58611A on serotonergic and noradrenergic transmission in rats and mice in an attempt to elucidate the mechanism(s) underlying these properties. SR58611A (3 and 10 mg/kg, p.

Effects of the vasopressin (V1b) receptor antagonist, SSR149415, and the corticotropin-releasing factor 1 receptor antagonist, SSR125543, on FG 7142-induced increase in acetylcholine and norepinephrine release in the rat.

Arginine vasopressin and corticotropin-releasing factor are two neuroactive peptides that regulate hypothalamic-pituitary-axis and associated stress response. While the potential antidepressant and anxiolytic profiles of corticotropin-releasing factor 1 antagonists have been well studied, the concept of blockade of vasopressin system as another approach for the treatment of emotional processes has only been made available recently by the synthesis of the first non-peptide antagonist at the V1b receptor, SSR149415. In the present study SSR149415 has been compared with the corticotropin-releasing factor 1 antagonist SSR125543 and with anxiolytic and antidepressant drugs on the response of hippocampal cholinergic and cortical noradrenergic systems to the anxiogenic benzodiazepine receptor inverse agonist FG 7142.

SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile.

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 monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.

SSR180575 (7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide), a peripheral benzodiazepine receptor ligand, promotes neuronal survival and repair.

In the present study, we have investigated the potential neuroprotective effects of a novel peripheral benzodiazepine binding site (PBR) ligand, 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575), in models of central and peripheral neurodegeneration in vivo and its effect on steroid concentrations in plasma and nervous tissue. SSR180575 shows high affinity (IC(50), 2.5-3.

The preclinical pharmacologic profile of tiapride.

Tiapride is a benzamide derivative that has been used successfully in the clinic for a number of years for the treatment of agitation and aggressiveness in elderly patients. Like many substituted benzamides, tiapride specifically blocks dopamine receptors in the brain. It has affinity for dopamine D(2) (IC(50) = 110-320 nM) and D(3) (IC(50) = 180 nM) receptors in vitro but lacks affinity for dopamine D(1) and D(4) receptors and for non-dopaminergic receptors including H(1), alpha(1), alpha(2)-adrenergic and serotonergic receptors.

Discriminative stimulus effects of drugs acting at GABA(A) receptors: differential profiles and receptor selectivity.

The GABA(A) receptor complex contains a number of binding sites at which a variety of psychotropic drugs, including benzodiazepines, barbiturates, and some neurosteroids, act to potentiate or inhibit the effect of the transmitter. Many studies have reported that these drugs can produce discriminative stimulus actions, but the cueing effects of compounds acting at different sites to enhance the effects of GABA are not identical. The discriminative stimulus effects of benzodiazepines have been analyzed in detail, and there is also a great deal of information available on the effects of nonbenzodiazepine compounds acting at BZ(omega) recognition sites, which form part of the GABA(A) receptor complex.

Amisulpride: from animal pharmacology to therapeutic action.

Amisulpride is a benzamide derivative with a unique neurochemical and psychopharmacological profile. This compound has selective affinity for human dopamine D3 and D2 receptor subtypes in vitro (binding constant, K approximately 3 nmol/l) and blocks functional responses mediated by these receptors. In ex vivo binding studies, amisulpride is twice as selective for D3 as for D2 receptors.

Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity.

The benzamide derivative amisulpride shows a unique therapeutic profile being antipsychotic, at high doses, and disinhibitory, at low doses, while giving rise to only a low incidence of extrapyramidal side effects. In vitro, amisulpride has high affinity and selectivity for the human dopamine D2 (Ki = 2.8 nM) and D3 (Ki = 3.

Activation of 5-HT1A receptors inhibits carbachol-stimulated inositol 1,4,5-trisphosphate mass accumulation in the rodent hippocampus.

We have previously demonstrated that 5-HT1A receptor agonists partially prevent the stimulation by carbachol of [3H]-phosphoinositide hydrolysis in immature rat hippocampal slices. This negative modulation has been investigated further by measuring, using a radioreceptor assay, the mass accumulation of IP3. In hippocampal slices from developing rats and in hippocampal neurons, carbachol enhanced the accumulation of IP3 and this response was partially inhibited by 8-OH-DPAT with a potency compatible with the affinity of this agonist for 5-HT1A receptors.

In vivo and in vitro interaction of the novel selective histamine H1 receptor antagonist mizolastine with H1 receptors in the rodent.

The interaction of mizolastine (CAS 108612-45-9, SL 85.0324) with histamine H1 receptors has been evaluated in the rodent. Mizolastine inhibited with high affinity (IC50 = 47 nmol/l) the binding of [3H]pyrilamine to histamine H1 receptors in guinea pig cerebellar membranes and sections.

Alpha 1-adrenoceptor antagonists differentially control serotonin release in the hippocampus and striatum: a microdialysis study.

Using the in vivo microdialysis technique, we have studied the effect of the systemic administration of several alpha 1-adrenoceptor antagonists on the extracellular levels of serotonin (5-HT) in the rat hippocampus. Prazosin, and to a lesser extent, terazosin, decreased these levels by 50-65% for 0.03-0.

Muscarinic receptor-mediated increase in extracellular inositol 1,4,5-trisphosphate levels in the rat hippocampus: an in vivo microdialysis study.

The extracellular concentration of inositol 1,4,5-trisphosphate (IP3) has been monitored in the ventral hippocampus of the anesthetized rat by using a microdialysis technique coupled to a radioreceptor assay. Three hours after the implantation of the cannula, basal extracellular concentration of IP3 (corrected for a 9% recovery) was 71 nM (0.39 pmol/60-microliters fraction) and remained stable for at least 5 h.

Effect of local injection of 8-OH-DPAT into the dorsal or median raphe nuclei on extracellular levels of serotonin in serotonergic projection areas in the rat brain.

Using in vivo microdialysis, we have examined the effects of local administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into either the dorsal (DRN) or the median (MRN) raphe nucleus on extracellular levels of serotonin (5-HT) in the corresponding projection fields, namely striatum and ventral hippocampus in the anaesthetized rat. Local injection of 8-OH-DPAT (0.5 microgram/0.

5-HT1C receptors mediate phosphoinositide turnover activation in the immature rat hippocampus.

The activation of phosphoinositide turnover in rat cerebral cortex and choroid plexus is triggered by the stimulation of 5-HT2 and 5-HT1C receptors, respectively. To characterize the 5-HT receptor subtype mediating the activation of phosphoinositide turnover in the hippocampus, the potency of several 5-HT agonists and antagonists on total [3H]inositol phosphate formation has been compared in the hippocampus, cerebral cortex and choroid plexus of immature rats. 5-HT, alpha-methyl-5-HT, quipazine, MK-212, mCPP (m-chlorophenylpiperazine) and TFMPP (m-trifluoromethylphenylpiperazine) are less potent and efficient in stimulating phosphoinositide turnover in the hippocampus and cerebral cortex than in the choroid plexus.

Effect of the putative 5-HT1A receptor antagonist NAN-190 on rat brain serotonergic transmission.

Based on the fact that 1-(2-methoxyphenyl)-4(4-(2-phtalimido)butyl)piperazine (NAN-190), a high-affinity ligand for 5-HT1A and alpha 1-adrenoceptors, antagonizes the behavioural effects of the 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), it has been suggested that this drug behaves as a 5-HT1A receptor antagonist. In the present study we examined the effects of this putative 5-HT1A receptor antagonist on rat brain serotonergic neurotransmission. In hippocampal slices of immature rats, NAN-190 but not prazosin potently antagonized (IC50 = 29 nM) the inhibitory effect of 8-OH-DPAT (1 microM) on carbachol-stimulated phosphoinositide turnover but (up to 1 microM) failed to alter the carbachol response.

L-glutamate increases internal free calcium levels in synaptoneurosomes from immature rat brain via quisqualate receptors.

Internal free calcium concentrations ([Ca2+]i) have been monitored in synaptoneurosomes from 8-d-old rat whole brain previously loaded with the calcium-sensitive fluorescent probe Fura 2. Under basal conditions, [Ca2+]i was around 200 nM, this concentration increasing only slowly during storage of the synaptoneurosomes at room temperature (40% increase 2 hr after loading). Opening of sodium channels with veratridine- (10 microM) or KCl- (30 mM) induced depolarization caused rapid increases in synaptoneurosomal [Ca2+]i.

5-HT1A receptor agonists inhibit carbachol-induced stimulation of phosphoinositide turnover in the rat hippocampus.

The selective 5-HT1A agonists, 8-hydroxy-2-(di-n-dipropylamino)tetralin (8-OH-DPAT) and ipsapirone, and the 5-HT1A/5-HT1B agonist, 1-(m-trifluoromethylphenyl)piperazine, partially inhibited the carbachol-stimulated [3H]inositol phosphate formation in rat hippocampal slices. The effect of 8-OH-DPAT was antagonized by cyanopindolol. Selective 5-HT1B, 5-HT2 and 5-HT3 agonists were inactive.

Pharmacological characterization of serotonin-stimulated phosphoinositide turnover in brain regions of the immature rat.

The effects of serotonin (5-HT) and related agonists and antagonists on phosphoinositide turnover have been investigated in several brain regions of the immature rat. In the presence of LiCl, 5-HT caused a marked increase in total [3H]inositol phosphate levels in cortical (maximal effect + 420%, EC50 = 7 microM) and to a lesser extent in hippocampal and striatal slices prepared from the immature (8-day-old) rat; the cortical 5-HT-induced phosphoinositide response was tetrodotoxin resistant. The magnitude of the increase in the cortical phosphoinositide response caused by 5-HT was maximal at 1 day postnatal and progressively declined to reach 6% of this maximal response in the adult.

Anorectic activities of serotonin uptake inhibitors: correlation with their potencies at inhibiting serotonin uptake in vivo and 3H-mazindol binding in vitro.

The mechanism of anorectic action of several serotonin uptake inhibitors was investigated by comparing their anorectic potencies with several biochemical and pharmacological properties and in reference to the novel compound SL 81.0385. The anorectic effect of the potent serotonin uptake inhibitor SL 81.

Fengabine, a novel antidepressant GABAergic agent. II. Effect on cerebral noradrenergic, serotonergic and GABAergic transmission in the rat.

The effects of fengabine (a novel benzylidene derivative possessing clinically demonstrated antidepressant action) on neurochemical parameters related to norepinephrine, serotonin and gamma-aminobutyric acid (GABA) neurons have been investigated in the rat and mouse brain. When given acutely, fengabine (50-1000 mg/kg i.p.

Pharmacological studies on stress-induced increase in frontal cortical dopamine metabolism in the rat.

The effects of a variety of minor tranquilizers and of benzodiazepine inverse agonists on the stress-induced increase in frontal cortical dopamine metabolism have been studied in the rat. Electric footshock stress increased 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the frontal (but not parietal) cortex and in the nucleus accumbens but not in the striatum or ventral tegmental area. Similar stress-induced alterations of frontal cortical DOPAC levels were observed after DSP4-induced noradrenergic denervation or after adrenalectomy.

Zolpidem, a novel nonbenzodiazepine hypnotic. II. Effects on cerebellar cyclic GMP levels and cerebral monoamines.

The effect of zolpidem, a novel nonbenzodiazepine short-acting hypnotic, on cerebellar cyclic GMP (cGMP) and biochemical indices of cerebral norepinephrine, serotonin and dopamine metabolism has been investigated in the rat and mouse. Zolpidem diminished the levels of cerebellar cGMP in the rat markedly (ED50 = 0.7 mg/kg i.

Characterization of [3H]paroxetine binding to rat cortical membranes.

Paroxetine is a selective and potent inhibitor of 5-hydroxytryptamine uptake into serotonergic neurons. The specific binding of [3H]paroxetine to rat cortical membranes at 22 degrees C was examined in this study. Our results indicate the presence of a single saturable high affinity binding component for [3H]paroxetine.

Relative selectivity of 6,7-dihydroxy-2-dimethylaminotetralin, N-n-propyl-3-(3-hydroxyphenyl)piperidine, N-n-propylnorapomorphine and pergolide as agonists at striatal dopamine autoreceptors and postsynaptic dopamine receptors.

6,7-Dihydroxy-2-dimethylaminotetralin (TL-99), N-n-propyl-3-(3-hydroxyphenylpiperidine [(+/-)-3-PPP], N-n-propylnorapomorphine and pergolide were evaluated for activity on a number of biochemical parameters that are presumed to indicate an agonist effect at dopamine (DA) autoreceptors (antagonism of the gamma-hydroxybutyrate-induced increase in dopa formation), at postsynaptic DA receptors (elevation of acetylcholine levels) or at both types of DA receptors (diminution of DA synthesis and homovanillic acid levels) in rat striatum. All four agents decreased striatal dopa accumulation (in the presence and in the absence of gamma-hydroxybutyrate). N-propylnorapomorphine, pergolide and TL-99 also reduced homovanillic acid levels and increased acetylcholine concentrations in striatum whereas (+/-)-3-PPP was inactive.