Annick Vassout

The selective nicotinic acetylcholine receptor α7 agonist JN403 is active in animal models of cognition, sensory gating, epilepsy and pain

Several lines of evidence suggest that the nicotinic acetylcholine receptor alpha7 (nAChR alpha7) is involved in central nervous system disorders like schizophrenia and Alzheimers disease as well as in inflammatory disorders like sepsis and pancreatitis. The present article describes the in vivo effects of JN403, a compound recently characterized to be a potent and selective partial nAChR alpha7 agonist. JN403 rapidly penetrates into the brain after i.v. and after p.o. administration in mice and rats. In the social recognition test in mice JN403 facilitates learning/memory performance over a broad dose range. JN403 shows anxiolytic-like properties in the social exploration model in rats and the effects are retained after a 6h pre-treatment period and after subchronic administration. The effect on sensory inhibition was investigated in DBA/2 mice, a strain with reduced sensory inhibition under standard experimental conditions. Systemic administration of JN403 restores sensory gating in DBA/2 mice, both in anaesthetized and awake animals. Furthermore, JN403 shows anticonvulsant potential in the audiogenic seizure paradigm in DBA/2 mice. In the two models of permanent pain tested, JN403 produces a significant reversal of mechanical hyperalgesia. The onset was fast and the duration lasted for about 6h. Altogether, the present set of data suggests that nAChR alpha7 agonists, like JN403 may be beneficial for improving learning/memory performance, restoring sensory gating deficits, and alleviating pain, epileptic seizures and conditions of anxiety.

The NK1-receptor antagonist NKP608 has an antidepressant-like effect in the chronic mild stress model of depression in rats

The chronic mild stress (CMS) model of depression was used to study the potential antidepressant-like activity of NKP608, a non-peptidic, specific, potent and orally active NK1 receptor antagonist. In this model, a substantial decrease in consumption of a 1% sucrose solution is observed in rats continously subjected to a variety of mild stressors. This effect can be reversed by chronic administration of various classes of antidepressant drugs. Chronic, oral treatment with NKP608 (once daily for 5 weeks) gradually reversed CMS-induced reductions in sucrose consumption and, the magnitude of this effect was comparable to that observed following administration of imipramine (10 mg/kg). The time-course of action of NKP608 in the CMS model was dose-dependent. At the dose of 0.03 mg/kg, NKP608 caused a full reversal of the CMS-induced deficit in sucrose consumption after 4 weeks of treatment (comparable to 5 weeks required for imipramine), while only 1 week of treatment was required in the group receiving the dose of 0.1 mg/kg NKP608. Lower (0.003 mg/kg) and higher (1.0 mg/kg) doses of the compound were ineffective. These results suggest that NKP608 has antidepressant-like properties in the CMS model in rats; the effect was comparable to conventional drugs, but the onset of action was faster than with the representative tricyclic antidepressant imipramine.

Modulation of dopamine-mediated behavioural responses by antidepressants: Effects of single and repeated treatment

The study concerned the effects of maprotiline, imipramine, clomipramine and amitriptyline on the stereotyped and turning behaviour induced by apomorphine in rats. At either single or repeated doses of 25 mg/kg i.p. neither maprotiline nor imipramine changed the stereotyped responses induced by apomorphine. Clomipramine showed in contrast an inhibitory effect which increased after 7 daily injections of the drug. Moderate suppression of stereotypies was also observed after repeated administration of amitriptyline. In rats with unilateral 6-OHDA lesions of the s.nigra apomorphine-induced contralateral turning was markedly suppressed (70%) after a single 25 mg/kg i.p. injection of maprotiline. A tolerance to this effect developed after 7 daily injections of the drug. Clomipramine and amitriptyline caused an inhibition of turning which was markedly increased after repeated treatment. These results suggest that antidepressants do not uniformly affect the behavioural responses mediated by dopamine. Clomipramine and amitriptyline appear to possess dopamine receptor blocking properties which may become more pronounced after chronic treatment. In contrast, the dopamine receptor blockade by maprotiline diminished and disappeared under such conditions. Among the drugs investigated imipramine was the one which seemed to have the weakest influence on dopaminergic receptors.

NKP608: a selective NK-1 receptor antagonist with anxiolytic-like effects in the social interaction and social exploration test in rats.

NKP608 is a non-peptidic derivative of 4-aminopiperidine which acts as a selective, specific and potent antagonist at the neurokinin-1 (NK-1) receptor both in vitro and in vivo. In vitro, the binding of NKP608 to bovine retina was characterized by an IC50 of 2.6+/-0.4 nM, whereas the compounds affinity to other receptor binding sites, including NK-2 and NK-3, was much lower. Species differences in IC(50) values with NKP608 were less pronounced than with previously described NK-1 receptor antagonists, being 13+/-2 and 27+/-2 nM in gerbil midbrain and rat striatum, respectively. In vivo, using the hind foot thumping model in gerbils, NKP608 exhibited a potent NK-1 antagonistic activity following oral administration (ID(50)=0.23 mg/kg; 2 h pretreatment), supporting a central activity of NKP608. The compound had a long duration of action with an ID(50) value of 0. 15 mg/kg p.o. and 0.38 mg/kg p.o. following a pretreatment of 5 and 24 h, respectively. Following a subchronic administration for 7 consecutive days (once daily) there was no evidence for the development of tolerance or accumulation. In the social interaction test performed in a highly illuminated, unfamiliar test arena, NKP608 specifically increased the time the two rats spent in social contact, and there was no concomitant increase in parameters reflecting general activity, i.e. ambulation (number of square entries) or the number of rearings. Active social time was maximally increased at a dose range of 0.01-1 mg/kg p.o. NKP608, the effect being weaker or absent at both lower (0.001 mg/kg p.o.) and higher (10 mg/kg p.o.) doses. A comparable bell-shaped dose-response relation was seen in the social exploration test in rats. In this modified resident/intruder paradigm, maximal increase in social contact of the intruder rat directed towards the resident rat was seen at a similar dose range (0.03-3 mg/kg p.o.) The effects observed following an acute oral administration of NKP608 were comparable to those seen following a treatment with the well-known benzodiazepine, chlordiazepoxide, in both these tests. These findings indicate that NKP608 exhibits an anxiolytic-like effect and that this effect, as concluded from the observed antagonism of the hind foot thumping induced by i.c.v. administration of the NK-1 receptor agonist SPOMe, is centrally mediated. This makes this compound a potentially promising candidate for treating anxiety-related disorders in humans.

Anxiolytic effect of NKP608, a NK1-receptor antagonist, in the social investigation test in gerbils.

NKP608 is a potent, selective and orally active non-peptidic neurokinin-1 (NK1)-receptor antagonist for which anxiolytic- and antidepressant-like effects have been described in various animal models in rats. Since species differences have been reported for some NK1-receptor antagonists, NKP608 was tested here in the social investigation test in gerbils, in a species in which the NK1-receptor is close to the human receptor. NKP608 (0.01 to> or =0.3 mg/kg p.o.) increased the time investigating the partner comparable to that seen following treatment with chlordiazepoxid (7 mg/kg p.o.), thus clearly indicating that NKP608 also has a robust anxiolytic effect in the social investigation test in gerbils. Such findings are in line with previous data obtained in rats, extend them to gerbils and corroborate the potential of NKP608 (and other representatives of the class of NK1-receptor antagonists) as new therapeutic agents beneficial in psychiatric disorders such as anxiety and/or depression.

Regulation of Dopamine Receptors by Bupropion: Comparison with Antidepressants and CNS Stimulants

Acute treatment of rats with the antidepressant bupropion increased [3H]spiperone binding to D2 receptors in vivo. This dose- and time-dependent effect was greatest in striatum and minimal in cerebellum and pituitary. A parallel behavioral stimulation occurred in the same rats. Among 21 antidepressants and CNS stimulants tested, only those that activate dopamine (DA) transmission had similar effects: nomifensine, amineptine, methylphenidate, D-amphetamine, amfonelic acid, cocaine, benztropine and GBR 12909. Decreasing DA transmission with reserpine plus alpha-methyl-p-tyrosine prevented the action of bupropion. Finally, bupropion was inactive in vitro and ex-vivo. Therefore, we propose that bupropion and other DA-enhancing agents modify the characteristics of [3H]spiperone binding through the intervention of a dynamic regulation of the D2 receptors by the neurotransmitter itself.

SAR of 2-benzyl-4-aminopiperidines: CGP 49823, an orally and centrally active non-peptide NK1 antagonist

Abstract Novel 2-benzyl-4-aminopiperidines have been shown to be potent and selective antagonists at the NK 1 receptor. Some compounds of this series, e.g. CGP 49823 ( 2 ), show CNS activity after oral administration.

Blockade of hippocampal dopamine (da) receptors: A tool for antipsychotics with low extrapyramidal side effects

1. 32 neuroleptics (NL) and a Ciba-Geigy antipsychotic (savoxepine, CGP 19 486 A) were tested on adult male rats and mice. 2. Interaction with D2 DA receptors was assessed using in vivo (3H)spiperone (SPI) binding in rat hippocampus and striatum. 3. Antipsychotic efficacy of NL was checked by their ability to antagonize apomorphine-induced climbing behavior in mice. 4. We found a good correlation between blockade of DA receptors in hippocampus and antagonism of climbing with both classical and atypical NL. 5. No correlation was found between blockade of DA receptors in striatum and climbing with the atypical NL. 6. It is suggested that NL exerting preferential blockade of hippocampal as compared to striatal DA receptors may show a better dissociation between antipsychotic efficacy and induction of extrapyramidal side effects (EPS) in the clinic. The antipsychotic agent savoxepine, displayed such a favourable profile of action.

Affinity changes of rat striatal dopamine receptors in vivo after acute bupropion treatment

The effect of bupropion (Wellbutrin) was studied on in vivo [3H]spiperone binding in rat striatum and cerebellum. The compound increased binding dose dependently in striatum whereas no effect was observed in cerebellum. Saturation analyses of in vivo binding in the striatum revealed an increased affinity of the receptors rather than changes in the number of binding sites. These results are the first demonstration of an increased sensitivity of central dopamine receptors after acute bupropion treatment.

Differences in pre- and post-synaptic sensitivity to apomorphine between saline and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated C57BL/6 mice as reflected in climbing activity

The climbing behaviour after low doses (0.05, 0.1 and 0.2 mg/kg) or a high dose (1.5 mg/kg) of apomorphine was studied in saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57BL/6 mice. Following a 3-week recovery from two injections of saline or MPTP (50 mg/kg inter-injection period: 72 h), mice were randomly selected for determinations of contents of neurotransmitters and metabolites (dopamine, homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA)) or the apomorphine-induced climbing paradigm. For the climbing experiment, the animals were habituated for 60 min to metal climbing cylinders after which they received a subcutaneous injection of apomorphine or its solvent. Subsequently, the animals were placed back in the cylinders and their climbing scores were recorded every 5 min for 60 min. The biochemical data indicated that striatal levels of dopamine, DOPAC and HVA were significantly reduced following MPTP-treatment whereas striatal 5-HT and 5-HIAA levels were unaffected. In the climbing paradigm saline and MPTP-treated C57BL/6 mice responded diametrically opposite to low doses of apomorphine: 0.1 and 0.2 mg/kg apomorphine reduced the climbing score in saline-treated mice as compared to saline injections whereas 0.2 mg/kg apomorphine increased the climbing score in MPTP-treated mice. A relatively high dose of apomorphine (1.5 mg/kg) increased the climbing score in both saline- and MPTP-treated mice. However, the climbing score was significantly higher in MPTP-treated mice than in saline-treated mice. These data suggest that MPTP-treated mice lack pre-synaptic dopamine receptors and have an increased post-synaptic sensitivity for apomorphine which is in agreement with the fact that MPTP selectively affects the dopaminergic nigro-striatal pathway which then results in an up-regulation of post-synaptic receptors.