Differential respiratory control of the upper airway and diaphragm muscles induced by 5-HT1A receptor ligands.

BACKGROUND: Serotonin (5-HT) has a role in respiratory function and dysfunction. Although 5-HT affects respiratory drive to both phrenic and cranial motoneurons, relatively little is known about the role of 5-HT receptor subtypes in the control of upper airway muscle (UAM) respiratory activity. MATERIALS AND METHODS: Here, we performed central injections of 5-HT1A agonist (8-OHDPAT) or antagonist (WAY100635) in anesthetized rats and analyzed changes in the electromyographic activity of several UAM and other cardiorespiratory parameters. We also compared the pattern of Fos expression induced after central injection of a control solution or 8-OHDPAT. RESULTS: Results showed that 8-OHDPAT induced a robust increase in UAM activity, associated with either tachypnea under volatile anesthesia or bradypnea under liquid anesthesia. Injection of WAY100635 switched off UAM respiratory activity and led to bradypnea, suggesting a tonic excitatory role of endogenous 5-HT1A receptor activation. Co-injection of the agonist and the antagonist blocked the effects produced by each drug alone. Besides drug-induced changes in respiratory frequency, only slight increases in surface of diaphragm bursts were observed. Significant increases in Fos expression after 5-HT1A receptor activation were seen in the nucleus tractus solitarius, nucleus raphe pallidus, parapyramidal region, retrotrapezoid nucleus, lateral parabrachial, and Kölliker-Fuse nuclei. This restricted pattern of Fos expression likely identified the neural substrate responsible for the enhancement of UAM respiratory activity observed after 8-OHDPAT injection. CONCLUSIONS: These findings suggest an important role for the 5-HT1A receptors in the neural control of upper airway patency and may be relevant to counteract pharyngeal atonia during obstructive sleep apneas.

Anxiolytic-like effects of DOI microinjections into the hippocampus (but not the amygdala nor the PAG) in the mice four plates test.

Anxiolytic-like effects of DOI, a 5-HT(2A/2C) agonist have been observed in the four plates test (FPT) after intra-peritoneal administrations. In the present study, DOI (1 microg, 2 microg or 5 microg per mice) was directly injected to three brain structures, the hippocampus, the amygdala and the periaqueductal gray matter (PAG). Tests were carried out immediately after injections. In amygdala and PAG, DOI exerted an anxiogenic-like effect. In the hippocampus, a strong anxiolytic-like effect was found only when injecting 5 microg DOI/mice in the FPT, with a size effect comparable to the anxiolytic-like effect of diazepam 1mg/kg injected intra-peritoneally. DOI or vehicle injections did not affect locomotor activity. These results help us to understand mechanisms of action of DOI in animal models of anxiety, probably through an interaction with other neurotransmitter system, which may take place in the hippocampus.

Anxiolytic-like effect of 5-HT(2) ligands and benzodiazepines co-administration: comparison of two animal models of anxiety (the four-plate test and the elevated plus maze).

Animal models of anxiety remain a useful tool for evaluating the anxiolytic-like effect of new treatments. Even though many tests are similarly based on exploration tasks, using more than one animal model is all the more recommended since there are qualitative differences between such tests. Furthermore, although many tests are excellent tool for detecting benzodiazepines/GABA compounds, inconsistent results have been reported for 5-HT ligands. Here, two animal models have been chosen, the elevated plus maze (EPM) based on the natural aversion of rodents for open spaces and the four-plates test (FPT) a models involving the animal's conditioned response to stressful events. In a recent study, we have demonstrated that the 5-HT(2A/2C) agonist DOI and the 5-HT(2B) agonist BW 723C86 were shown to produce an anxiolytic-like effect in both tests. This study aimed to evaluate a putative interaction between benzodiazepine and 5-HT(2) ligands in the FPT and the EPM. Indeed, close distribution of GABA(A) and 5-HT(2) receptors was found in brain structures leading to functional interrelation. In the FPT, sub-active doses of alprazolam and diazepam were strongly potentiated by DOI. BW 723C86, also potentiated the anxiolytic-like effect of the two benzodiazepines with a weaker effect. In the same way, DOI and benzodiazepines administration induced an increase in the anxiolytic-like parameters in the EPM with a strongest effect observed with alprazolam. Regardless of anxiety models used in this study, 5-HT(2A) ligands exerted facilitatory influence upon GABAergic system. Therefore, the FPT and the EPM might implicate the same kind of anxiety.

Effect of GABAergic ligands on the anxiolytic-like activity of DOI (a 5-HT(2A/2C) agonist) in the four-plate test in mice.

5-HTergic and GABAergic systems are involved in neurobiology of anxiety. Precedent studies have demonstrated that SSRIs possessed an anxiolytic-like effect in the four-plate test (FPT) at doses that did not modify spontaneous locomotor activity. This effect seems to be mediated through the activation of 5-HT(2A) postsynaptic receptors. The purpose of the present study was to examine the implication of GABA system in the anxiolytic-like activity of DOI in the FPT. To achieve this, the co-administration of DOI (5-HT(2A/2C) receptor agonists) with GABA(A) and GABA(B) receptor ligands was evaluated in the FPT. Alprazolam, diazepam and muscimol (for higher dose) potentiated the anxiolytic-like effect of DOI. Bicuculline, picrotoxin and baclofen inhibited the anxiolytic-like effect of DOI. Flumazenil and CGP 35348 had no effect on the anxiolytic-like activity of DOI. These results suggest that the GABA system seems to be strongly implicated in the anxiolytic-like activity of DOI in the FPT.

Effect of noradrenergic system on the anxiolytic-like effect of DOI (5-HT2A/2C agonists) in the four-plate test.

RATIONALE: Selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors demonstrated an anxiolytic-like effect in the four-plate test (FPT). (+/-)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI; a 5-HT2A receptor agonist) also possessed strong anxiolytic-like effect in the same test. A 5-HT2A mechanism seems to be implicated in the mechanism of action of both antidepressants and DOI in this test. On the other hand, the alpha-adrenergic ligands have also demonstrated an activity in other models of anxiety. A previous study demonstrated that the alpha2-adrenoceptor agonists abolished the anxiolytic-like effect of antidepressants. OBJECTIVES: The aim of the present study was to evaluate the role of noradrenergic system on the regulation of 5-HT2 receptors implicated in the DOI anxiolytic-like activity in the FPT. METHODS: First, the effect of noradrenergic and serotonergic lesions on DOI anxiolytic-like activity was studied in the FPT. Second, the effect of co-administration of alpha-adrenoceptor ligands and DOI was evaluated in the same test. RESULTS: The noradrenergic and serotonergic lesions had no effect on DOI (1 mg/kg) anti-punishment activity in the FPT. Adrafinil 0.25 and 4 mg/kg (an alpha1-adrenoceptor agonist), prazosin 0.5 and 2 mg/kg (an alpha1-adrenoceptor antagonist) and idazoxan 1 and 4 mg/kg (an alpha2-adrenoceptor antagonist) did not modify the activity of DOI. Clonidine 0.06 mg/kg, guanabenz 0.125 and 0.5 mg/kg (two alpha2-adrenoceptor agonists) and guanfacine 0.06 and 0.125 mg/kg (a specific alpha2A-adrenoceptor agonist) completely abolished DOI-induced increase in punished passages. CONCLUSION: These results indicate that the DOI seems to act on the 5-HT2 receptors post-synaptically located. The effect of DOI is regulated by the alpha2-adrenoceptors.

alpha2-Adrenergic agonists antagonise the anxiolytic-like effect of antidepressants in the four-plate test in mice.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline reuptake inhibitors (SNRIs) has been reported to be efficient in anxiety disorders. Some animal models have demonstrated an anxiolytic-like effect following acute administration, however, it is not yet known how noradrenergic receptors are implicated in the therapeutic effects of antidepressants (ADs) in anxiety. The effects of two alpha(2)-adrenoceptor agonists (clonidine, guanabenz) on anxiolytic-like effect of two SSRIs (paroxetine and citalopram) and two SNRIs (venlafaxine and milnacipran) were evaluated in the four-plate test (FPT) in mice. Paroxetine (4 mg/kg), citalopram (8 mg/kg), venlafaxine (8 mg/kg), and milnacipran (8 mg/kg) administered intraperitoneally (i.p.) increased the number of punishments accepted by mice in the FPT. Clonidine (0.0039-0.5 mg/kg) and guanabenz (0.03-0.5mg/kg) had no effect on the number of punishments accepted by mice. Clonidine (0.03 and 0.06 mg/kg) and guanabenz (0.125 and 0.5 mg/kg) (i.p. -45 min) reversed the anti-punishment effect of paroxetine, citalopram, venlafaxine and milnacipran (i.p. -30 min). But if the antidepressants are administered 45 min before the test and alpha(2)-adrenoceptor agonists 30 min before the test, alpha(2)-adrenoceptor agonists failed to alter the anti-punishment effect of antidepressants. The results of this present study indicate that alpha(2)-adrenoceptor agonists antagonise the anxiolytic-like effect of antidepressants in mice when they are administered 15 min before the administration of antidepressant suggesting a close inter-regulation between noradrenergic and serotoninergic system in the mechanism of SSRIs and SNRIs in anxiety-like behaviour.

Anxiolytic-like effect of milnacipran in the four-plate test in mice: mechanism of action.

Milnacipran is a serotonin/noradrenaline reuptake inhibitor (SNRI) which has not yet been systematically studied preclinically or clinically for the treatment of anxiety disorders. In the four-plate test (FPT) which is known to predict anxiolytic-like activity in mice, milnacipran (4, 8, 16 and 32 mg/kg) demonstrated strong anti-punishment effects following acute administration. The anxiolytic-like effect of milnacipran was not reversed by the selective GABA(A) receptor antagonist, flumazenil (2 and 4 mg/kg), the selective alpha1-adrenoceptor antagonist, prazosin (0.5 and 2 mg/kg), the selective alpha2-adrenoceptor antagonist, idazoxan (1 and 4 mg/kg) or the selective 5-HT2B receptor antagonist, SB 206553 (0.1 and 1 mg/kg). In contrast, the selective 5-HT2A receptor antagonist, SR 46349B (0.1 and 1 mg/kg), and the non-selective 5-HT2 receptor antagonist, ketanserin (0.125 and 0.5 mg/kg), completely abolished the anxiolytic-like effect of milnacipran in FPT. Neurochemical depletion of NA or 5-HT completely abolished the activity of milnacipran. These results strongly suggest that activation of 5-HT2A receptors is critically involved in the anxiolytic activity of milnacipran. On the other hand the lack of activity of milnacipran after depletion of NA or 5-HT is consistent with milnacipran acting on the locus coeruleus to induce 5-HT release. The present data suggest a strong connection between 5-HT2A receptors and NA neurotransmission.

D-amphetamine improves attention performance in adolescent Wistar, but not in SHR rats, in a two-choice visual discrimination task.

The validity of spontaneous hypertensive rat (SHR) as a model of attention deficit hyperactivity disorder (ADHD) has been explored by comparing SHR with Wistar rats in a test of attention, the two-choice visual discrimination task (2-CVDT). Animals were 4-5 weeks old during the training phase of the experiment and 6-7 weeks old during the testing phase in which they were tested with D-amphetamine, a stimulant drug used for the treatment of ADHD. As compared to Wistar, SHR showed a slightly better attention performance, a slightly lower impulsivity level, and a lower general activity during the training phase, but these differences disappeared or lessened thereafter, during the testing phase. D-amphetamine (0.5, 1 mg/kg) improved attention performance in Wistar, but not in SHR, and did not modify impulsivity and activity in the two strains. In conclusion, the present study did not demonstrate that SHR represents a valid model of ADHD, since it did not show face validity regarding the behavioral symptoms of ADHD and predictive validity regarding the effect of a compound used for the treatment of ADHD. On the other hand, this study showed that the 2-CVDT may represent a suitable tool for evaluating in adolescent Wistar rats the effect on attention of compounds intended for the treatment of ADHD.

Brain structures implicated in the four-plate test in naïve and experienced Swiss mice using injection of diazepam and the 5-HT2A agonist DOI.

Four-plate test-retest (FPT-R) is a useful tool to study aversive memory and abolishment of benzodiazepine effects in experienced mice to four-plate test (FPT), namely one-trial tolerance. In the present study, we have used local injections paradigm, in order to localize structures implied in anxiolytic-like effects of two drugs in naïve and experienced mice: a benzodiazepine, diazepam that is only active in naïve mice; and a 5-HT(2A/2C) agonist, DOI that exert its anxiolytic-like effect both in naïve and experienced mice. Periacqueductal grey substance, three sub-regions of hippocampus (CA1, CA2 and CA3) and two nuclei of amygdala (BLA and LA) have been studied. Local injections did not cause any modifications of ambulatory activity. DOI injections elicit anxiolytic-like effects only when injected into CA2, in naïve and experienced mice. Diazepam had an anxiolytic-like effect in naïve mice, only when injected into lateral nucleus of amygdala; and in experienced mice when injected into PAG. These results help us to better understand the way of action of these two compounds and the structures functionally involved in their effects and in one-trial tolerance (OTT).

Evidence for the activity of lamotrigine at 5-HT(1A) receptors in the mouse forced swimming test.

BACKGROUND: The antiepileptic drug lamotrigine is effective in the treatment of focal epilepsies. It is thought to act by inhibition of glutamate release through blockade of voltage-sensitive sodium channels and stabilization of the neuronal membrane. Lamotrigine is also effective in the treatment of mood disorders such as bipolar disorder. However, its exact mechanism of action in these conditions remains unclear. The aim of the present study was to evaluate the antidepressant-like effect of lamotrigine in a mouse model of depression, namely the forced swimming test (FST). Association studies using specific and nonspecific ligands acting on serotonin (5-hydroxytryptamine; 5-HT1) receptor subtypes were undertaken to evaluate the potential role of these receptors in the anti-immobility effect of lamotrigine. METHODS: The mouse FST was performed after single administration of lamotrigine. Subactive doses of lamotrigine were administered in association with subactive doses of the following 5-HT1 receptor agonists or antagonists: 8-hydroxy-2-(di-n-propilamino)-tetralin (8-OH-DPAT, a standard 5-HT(1A) receptor selective agonist), pindolol (a presynaptic and postsynaptic 5-HT(1A/1B) receptor antagonist), NAN-190 (a 5-HT(1A) receptor antagonist), RU 24969 (a 5-HT(1A/1B) receptor agonist) and anpirtoline (5-HT(1B) agonist). RESULTS: Lamotrigine impaired spontaneous locomotor activity at doses of 4 mg/kg or greater, and activity decreased by more than 50% at the 16 mg/kg dose. When administered alone, lamotrigine (8 and 16 mg/kg) decreased immobility time in the FST. Only 8-OH-DPAT (1 mg/kg), pindolol (32 mg/kg) and RU 24969 (0.5 mg/kg) enhanced the antidepressant-like effect of lamotrigine in the FST. CONCLUSIONS: These results suggest that postsynaptic 5-HT(1A) receptors might be involved in the activity of lamotrigine. Furthermore, they demonstrate that lamotrigine more closely resembles valproate and carbamazepine than lithium, with the advantage of an anti-immobility effect in the mouse FST when administered on its own.