Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Baclofen therapy resulted in improvement of dyskinesias only in patients with trunkal tardive dyskinesia. However, the appearance of undesirable side effects did not warrant continuation of treatment with this drug. Baclofen did not have any therapeutic effect in schizophrenia and moreover a trend towards a worsening of the psychiatric conditions with irritability, assaultiveness and prominent auditory hallucinations was observed. The effects of baclofen on tardive dyskinesia and schizophrenia can be explained in terms of its phenylethylamine-like properties.
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PMID:Phenylethylamine-like properties of baclofen. 664 93

We have previously demonstrated that pallidotegmental GABAergic neurons play a crucial role in prepulse inhibition (PPI) of the startle reflex in mice through the activation of GABA(B) receptors in pedunculopontine tegmental neurons. In this study, we investigated whether PPI disruption induced by methamphetamine (METH) or MK-801 is associated with the dysfunction of pallidotegmental neurons. Furthermore, we examined the effects of baclofen, a GABA(B) receptor agonist, on METH- and MK-801-induced PPI impairment. Acute treatment with METH (3 mg/kg, subcutaneouly (s.c.)) and MK-801 (>0.3 mg/kg, s.c.) significantly disrupted PPI, accompanied by the suppression of c-Fos expression in lateral globus pallidus induced by PPI. Furthermore, acute treatment with METH and MK-801 stimulated c-Fos expression in the caudal pontine reticular nucleus (PnC) in mice subjected to the PPT test, although PPI alone had no effect on c-Fos expression. Repeated treatment with 1 mg/kg METH for 7 days, which did not affect PPI acutely, showed similar effects on PPI and c-Fos expression to acute treatment with METH (3 mg/kg). Baclofen dose-dependently ameliorated PPI impairment induced by acute treatment with METH (3 mg/kg) and MK-801 (1 mg/kg), and decreased METH- and MK-801-stimulated c-Fos expression in PnC to the basal level. These results suggest that dysfunction of pallidotegmental neurons is involved in PPI disruption caused by METH and MK-801 in mice. GABA(B) receptor may constitute a putative target in treating neuropsychiatric disorders with sensorimotor gating deficits, such as schizophrenia and METH psychosis.
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PMID:Involvement of pallidotegmental neurons in methamphetamine- and MK-801-induced impairment of prepulse inhibition of the acoustic startle reflex in mice: reversal by GABAB receptor agonist baclofen. 1835 84

In this study, we investigated the effects of GABA(A) and GABA(B) receptor agonists on the methamphetamine-induced impairment of recognition memory in mice. Repeated treatment with methamphetamine at a dose of 1 mg/kg for 7 days induced an impairment of recognition memory. Baclofen, a GABA(B) receptor agonist, ameliorated the repeated methamphetamine-induced cognitive impairment, although gaboxadol, a GABA(A) receptor agonist, had no significant effect. GABA(B) receptors may constitute a putative new target in treating cognitive deficits in patients suffering from schizophrenia, as well as methamphetamine psychosis.
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PMID:GABAB receptor agonist baclofen improves methamphetamine-induced cognitive deficit in mice. 1902 88

Although the presence of prostaglandin PGF(2?) has been demonstrated in the central nervous system in the mid sixties, it has taken a rather long time to pinpoint a role of certain metabolites of arachidonic acid in the regulation of neural activity. The modern family of bioactive compounds known as "prostanoids" or "eicosanoids" includes the classical end-products of the cyclooxygenase pathway (prostaglandins, prostacyclin and thromboxane), as well as the molecules formed after the activation of 5- and/or 15-lipoxygenases (leucotrienes and lipoxines), 12-lipoxygenase (hepoxilins) or of epoxygenase (epoxides). Although the brain levels of arachidonic acid-the precursor generating prostaglandins from the series 2-are very low, a plethora of stimuli appears to trigger its release from membrane phospholipids mainly by activation of phospholipase A(2) or subordinately phospholipase C; furthermore, its reesterification can also be subtly regulated by endogenous metabolic processes. Numerous prostanoids have now been detected in the nervous system, namely in neurons, astrocytes, cerebrospinal fluid and cerebral vascular endothelium. Efforts have been oriented at the elucidation of the roles of prostanoids in some physiological conditions (for example sleep regulation) or pathological situations (fever, migraine, epilepsy, schizophrenia). Moreover, several investigators have examined the localization of neuronal membrane receptors for prostanoids and searched for the mechanisms of signal transduction or the identity of second messengers. Those embody cyclic nucleotides (cAMP and cGMP) and calcium. There is also compelling evidence for a modulation by prostanoids of the release of noradrenaline, serotonin and vasoactive intestinal peptide (VIP) as well as of several hormones of the hypothalamic-hypophyseal tract. In addition, neurotransmitters can influence prostanoid synthesis; this has been demonstrated in particular for noradrenaline and more recently for acetylcholine. Prostanoids can also amplify neurotransmitter-mediated signals. Thus, ?(1)-adrenergic agonists, H(1)-histaminergic agonists as well as adenosine potentiate cAMP formation elicited by the VIP, through a concomitant generation of prostaglandins mediated by a direct coupling with phospholipase A(2). Baclofen (a GABA(B)-receptor agonist) exerts a similar potentiation mediated in part by the increased activity of 5-lipoxygenase. Furthermore, eicosanoids generated by 12-lipoxygenase are involved in the histamine- or FMRFamide-induced hyperpolarization (opening of K(+) channels) that has been demonstrated in identified sensory neurons of Aplysia. Finally, the stimulation of N- methyl - d - aspartate receptors (a subclass of glutamate receptors) leads to a release of arachidonic acid as well as of 11- and 12-hydroxyeicosatetraenoic acids in cultured striatal neurons. Arachidonic acid and a large number of its classical or recently discovered metabolites therefore display various effects in the central nervous system, both at the level of integrated processes and of the fine synaptic circuitry, where they can act as intracellular or extracellular local messengers triggering new cascades of short term or long term cellular events.
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PMID:Prostanoids and their role in cell-cell interactions in the central nervous system. 2050 6

NMDA-receptor (NMDAR) hypofunction is strongly implicated in the pathophysiology of schizophrenia. Several convergent lines of evidence suggest that net excitation propagated by impaired NMDAR signaling on GABAergic interneurons may be of particular interest in mediating several aspects of schizophrenia. However, it is unclear which behavioral domains are governed by a net increase of excitation and whether modulating downstream GABAergic signaling can reverse neural and thus behavioral deficits. The current study determines the selective contributions of NMDAR dysfunction on PV-containing interneurons to electrophysiological, cognitive, and negative-symptom-related behavioral phenotypes of schizophrenia using mice with a PVcre-NR1flox-driven ablation of NR1 on PV-containing interneurons. In addition, we assessed the efficacy of one agent that directly modulates GABAergic signaling (baclofen) and one agent that indirectly modifies NMDAR-mediated signaling through antagonism of mGluR5 receptors (2-methyl-6-(phenylethynyl) pyridine (MPEP)). The data indicate that loss of NMDAR function on PV interneurons impairs self-care and sociability while increasing N1 latency and baseline gamma power, and reducing induction and maintenance of long-term potentiation. Baclofen normalized baseline gamma power without corresponding effects on behavior. MPEP further increased N1 latency and reduced social behavior in PVcre/NR1+/+ mice. These two indices were negatively correlated before and following MPEP such that as N1 latency increases, sociability decreases. This finding suggests a predictive role for N1 latency with respect to social function. Although previous data suggest that MPEP may be beneficial for core features of autism spectrum disorders, current data suggest that such effects require intact function of NMDAR on PV interneurons.
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PMID:Parvalbumin cell ablation of NMDA-R1 causes increased resting network excitability with associated social and self-care deficits. 2452 9

GABAB-receptor (GABABR) mediated inhibition is important in regulating neuronal excitability. The paired-pulse transcranial magnetic stimulation (TMS) protocol of long-interval intracortical inhibition (LICI) likely reflects this GABABergic inhibition. However, this view is based on indirect evidence from electromyographic (EMG) studies. Here we combined paired-pulse TMS with simultaneous electroencephalography (paired-pulse TMS-EEG) and pharmacology to directly investigate mechanisms of LICI at the cortical level. We tested the effects of a conditioning stimulus (CS100) applied 100ms prior to a test stimulus (TS) over primary motor cortex on TS-evoked EEG-potentials (TEPs). Healthy subjects were given a single oral dose of baclofen, a GABABR agonist, or diazepam, a positive modulator at GABAARs, in a placebo-controlled, pseudo-randomized double-blinded crossover study. LICI was quantified as the difference between paired-pulse TEPs (corrected for long-lasting EEG responses by the conditioning pulse) minus single-pulse TEPs. LICI at baseline (i.e. pre-drug intake) was characterized by decreased P25, N45, N100 and P180 and increased P70 TEP components. Baclofen resulted in a trend towards the enhancement of LICI of the N45 and N100, and significantly enhanced LICI of the P180. In contrast, diazepam consistently suppressed LICI of late potentials (i.e. N100, P180), without having an effect on LICI of earlier (i.e. P25, N45 and P70) potentials. These findings demonstrate for the first time directly at the system level of the human cortex that GABABR-mediated cortical inhibition contributes to LICI, while GABAAR-mediated inhibition occludes LICI. Paired-pulse TMS-EEG allows investigating cortical GABABR-mediated inhibition more directly and specifically than hitherto possible, and may thus inform on network abnormalities caused by disordered inhibition, e.g. in patients with schizophrenia or epilepsy.
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PMID:Characterization of GABAB-receptor mediated neurotransmission in the human cortex by paired-pulse TMS-EEG. 2524 14

Clozapine is the gold-standard agent for treatment resistant schizophrenia but its mechanism of action remains unclear. There is emerging evidence of the potential role of the GABAB receptor in the pathogenesis of schizophrenia. It has been hypothesised that clozapine can mediate its actions via the GABAB receptor. Baclofen is currently recognised as the prototype GABAB receptor agonist. There are some potential clinical similarities between clozapine and baclofen. Indeed, baclofen has been previously proposed for use as an antipsychotic agent. Our analysis of the X-ray crystal structure of GABAB receptor along with molecular docking calculations, suggests that clozapine could directly bind to the GABAB receptor similar to that of baclofen. This finding could lead to a better understanding of the pharmacological uniqueness of clozapine, potential development of a biomarker for treatment resistant schizophrenia and the development of more targeted treatments leading to personalisation of treatment.
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PMID:Binding of clozapine to the GABAB receptor: clinical and structural insights. 3220 58