Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC 50 ¼ 18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID 50 : 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 mM) and intrastriatal glycine-induced rotations in mice (MED: 1 mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB 1 receptors): it reversed the decrease in electrically evoked [3 H]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.
In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective a7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human a7 n-AChRs (K i of 2274 and 1471 nM, respectively). Ex vivo 3 [H]a-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID 50 ¼ 8 mg/kg p.o.). In functional studies performed with human a7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity ¼ 51 and 36%, EC 50 ¼ 4.4 and 0.9 mM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small a-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic a7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 mM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the a7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3-10 mg/kg i.p.) dosedependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse a7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.
Sodium-activated potassium (K Na ) channels have been suggested to set the resting potential, to modulate slow afterhyperpolarizations, and to control bursting behavior or spike frequency adaptation (Trends Neurosci 28:422-428, 2005). One of the genes that encodes K Na channels is called Slack (Kcnt1, Slo2.2). Studies found that Slack channels were highly expressed in nociceptive dorsal root ganglion neurons and modulated their firing frequency (J Neurosci 30:14165-14172, 2010). Therefore, Slack channel openers are of significant interest as putative analgesic drugs. We screened the library of pharmacologically active compounds with recombinant human Slack channels expressed in Chinese hamster ovary cells, by using rubidium efflux measurements with atomic absorption spectrometry. Riluzole at 500 M was used as a reference agonist. The antipsychotic drug loxapine and the anthelmintic drug niclosamide were both found to activate Slack channels, which was confirmed by using manual patch-clamp analyses (EC 50 ϭ 4.4 M and EC 50 ϭ 2.9 M, respectively). Psychotropic drugs structurally related to loxapine were also evaluated in patch-clamp experiments, but none was found to be as active as loxapine. Loxapine properties were confirmed at the singlechannel level with recombinant rat Slack channels. In dorsal root ganglion neurons, loxapine was found to behave as an opener of native K Na channels and to increase the rheobase of action potential. This study identifies new K Na channel pharmacological tools, which will be useful for further Slack channel investigations.
Hypophysiotropic somatostatin (SRIF) and growth hormone-releasing hormone (GHRH) neurons are primarily involved in the neurohormonal control of growth hormone (GH) secretion. They are located in periventricular (PEV) and arcuate (ARC) hypothalamic nuclei, respectively, but their connectivity is not well defined. To better understand the neuronal network involved in the control of GH secretion, connections from PEV to ARC neurons were reconstructed in vitro and neuronal phenotypes assessed by single-cell multiplex RT-PCR. Of 814 stimulated PEV neurons, monosynaptic responses were detected in only 45 ARC neurons. Monosynaptic excitatory currents were detected in 29 ARC neurons and inhibitory currents in 16, indicating a 2/1 ratio for excitatory versus inhibitory connections. Galanin (GAL), NPY, pro-opiomelanocortin (POMC), and SRIF mRNAs were detected in neurons from both nuclei but GHRH mRNA almost exclusively in ARC. Among the five SRIF receptors, only sst1 and sst2 were expressed, in 94% of ARC and 59% of PEV neurons, respectively. Of 128 theoritical combinations between neuropeptides and sst receptors, only 22 were represented in PEV and 25 in ARC. For PEV neurons, neuropeptide phenotypes did not influence excitatory connections. However, the occurrence of presynaptic sst receptors on GAL and SRIF PEV neurons significantly increased their probability of connection to ARC neurons. GHRH ARC neurons expressing sst2, but not sst1, receptors were always connected with PEV neurons. Physiological responses to sst1 (CH-275) or sst2 (Octreotide) agonists were always correlated with the detection of respective sst mRNAs. In conclusion, 1) SRIF-modulated excitatory transmission develops in vitro from PEV to ARC neurons, 2) ARC GHRH neurons bearing sst2 receptors appears directly controlled by fast glutamatergic transmission from PEV neurons simultaneously expressing one to four neuropeptides, 3) GHRH neurons bearing sst1 receptors lack this control, and 4) these results suggest that fast excitatory neurotransmission and neuropeptide modulation can derive from a small subset of PEV hypothalamic neurons targeted at ARC neuronal subpopulations.
Cell death mechanisms frequently involve the influx of extracellular calcium through voltage- and ligand-gated ion channels, e.g., the NMDA receptor (Greene, 1999). The vanilloid receptor (VR1) is present in regions of the brain (Mezey et al., 2000) that are highly susceptible to neurodegenerative insults, suggesting that this ion channel might contribute to the cellular processes involved in neuronal death. We tested the effects of VR1 ligands in the oxygen glucose deprivation (OGD) model of cell death in organotypic hippocampal slice cultures. The VR1 agonist capsaicin at concentrations that are selective for VR1 did not affect cell viability per se or the extent of neurodegeneration induced by the OGD insult. In contrast, the VR1 antagonist capsazepine (0.1-10 microm) significantly reduced the amount of OGD-induced cell death. However, capsazepine was still neuroprotective in slices prepared from VR1 knock-out mice, which exhibited the same degree of neurodegeneration to that observed in slices prepared from wild-type mice, excluding the possibility that it afforded neuroprotection through inhibition of VR1. Instead, capsazepine inhibited the hyperpolarization-activated nonspecific cation channel generated current I(h) in a concentration range similar to that which was neuroprotective. Furthermore, the specific I(h) blocker ZD-7288 was also neuroprotective, mirroring the effects of capsazepine, in that it was effective at preventing cell death when applied either during or after the OGD insult. These results demonstrate that capsazepine affords neuroprotection through inhibition of I(h) rather than inhibition of VR1.
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