A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight.

Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger serious side effects that precipitate treatment discontinuation. Here, we show that activation of the trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds, the full agonist RO5256390 and the partial agonist RO5263397, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 agonists do not induce catalepsy or weight gain; RO5263397 even reduced haloperidol-induced catalepsy and prevented olanzapine from increasing body weight and fat accumulation. Finally, TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. These data suggest that TAAR1 agonists may provide a novel and differentiated treatment of schizophrenia as compared with current medication standards: TAAR1 agonists may improve not only the positive symptoms but also the negative symptoms and cognitive deficits, without causing adverse effects such as motor impairments or weight gain.

Fast synaptic transmission mediated by alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors in lamina X neurones of neonatal rat spinal cord.

Using patch clamp recordings on neonatal rat spinal cord slices, we have looked for the presence of alpha-bungarotoxin-sensitive nicotinic ACh receptors (nAChRs) on sympathetic preganglionic neurones (SPNs) surrounding the central canal of the spinal cord (lamina X) and examined whether they were implicated in a fast cholinergic synaptic transmission. SPNs were identified either by their morphology using biocytin in the recording electrode and/or by antidromic stimulation of the ventral rootlets. The selective alpha7-containing nAChR (alpha7*nAChR) agonist choline (10 mM) induced a fast, rapidly desensitizing inward current, which was fully blocked by alpha-bungarotoxin (alpha-BgT; 50 nM) and strychnine (1 microM), two antagonists of alpha7*nAChRs. The I-V relationship of the choline-induced current showed a strong inward-going rectification. Electrically evoked excitatory postsynaptic currents (eEPSCs) could be recorded. At -60 mV, eEPSCs peaked at -26.2 pA and decayed monoexponentially with a mean time constant of 8.5 ms. The current-voltage relationship for eEPSCs exhibited a strong inward rectification and a reversal potential close to 0 mV, compatible with a non-selective cationic current. The appearance of eEPSCs was entirely suppressed by the application of 100 microM ACh or nicotine. Choline (10 mM) and 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP; 100 microM) both reduced the amplitude of eEPSCs, whereas cytisine (100 microM) had no effect. Strychnine (1 microM) and alpha-BgT (50 nM) both suppressed the eEPSCs. Blocking the P2X purinergic and 5-HT(3) receptors had no effect on eEPSCs. DMPP induced four types of current, which differed in their onset and desensitization rate. The most frequently encountered responses were insensitive to the action of strychnine and alpha-BgT, and were reproduced by ACh and nicotine but not by cytisine. We conclude that SPNs of the lamina X express several classes of nAChRs and in particular alpha-BgT-sensitive nAChRs. This is the first demonstration in a mammalian spinal cord preparation of a fast cholinergic neurotransmission in which alpha-BgT-sensitive nicotinic receptors are involved.

Nicotinic receptors regulate the release of glycine onto lamina X neurones of the rat spinal cord.

Whole-cell patch clamp recordings were performed on neurones in the lamina X of rat spinal cord slices in order to characterize glycinergic synaptic currents and their modulation by nicotinic acetylcholine receptors. In the presence of TTX, bicuculline and kynurenic acid, glycine-induced currents and miniature glycinergic postsynaptic currents (mIPSCs) were recorded. These currents reversed near the chloride ion equilibrium potential and were blocked by strychnine (1 microM). A selective nicotinic acetylcholine receptor (nAChR) agonist 1,1-dimethyl-4-phenyl-piperazinium (DMPP), increased the frequency of glycinergic mIPSCs without altering significantly their amplitude distributions or their kinetic properties. The effects of DMPP were mimicked by different nAChRs agonists with the following apparent order of potency: ACh > DMPP > nicotine > cytisine. The effect of DMPP on mIPSCs was blocked by both d-tubocurarine and hexamethonium, and was reduced by dihydro-beta-erythroidine and methyllycaconitine (MLA), antagonists of non alpha7- and alpha7-containing nAChRs, respectively. In the absence of TTX, strychnine-sensitive glycinergic electrically evoked postsynaptic currents (eIPSCs) could be recorded. DMPP blocked the appearance of electrically evoked IPSCs while still inducing the appearance of spontaneous glycine IPSCs. These data demonstrate that neurones surrounding the central canal of the spinal cord present a glycinergic synaptic transmission which is modulated by terminal nAChRs.

Perturbation by geraniol of cell membrane permeability and signal transduction pathways in human colon cancer cells.

Geraniol, a natural component of plant essential oils, has antiproliferative effects on human colon cancer cells. To obtain more insight into its mechanism of action, we studied its effect on the resting membrane potential and on the expression of proteins involved in cell signaling pathways. Since geraniol is a well known inhibitor of mevalonate metabolism, the effect of mevalonate supplementation on geraniol-triggered growth inhibition was also determined. Geraniol (400 microM) induced membrane depolarization with a decrease of membrane resistance due to local perforation of the cell membrane. Incubation of Caco-2 cells with geraniol (400 microM) for 6 h caused a 60% reduction of protein kinase C (PKC) activity. After 16 h of incubation, geraniol decreased by 50% the amount of active forms of p44/p42 extracellular signal-regulated protein kinases (ERK). Mevalonate supplementation did not reverse inhibition of cell growth by geraniol. These results indicate that the antiproliferative effect of geraniol on Caco-2 cells was not related to a limitation of the mevalonate pool but was directly linked to the perturbation of cell membrane function leading to the reduction of PKC activity and to the decreased expression of p44/p42 ERK active forms.