The Efficacy of Sodium Channel Blockers to Prevent Phencyclidine-Induced Cognitive Dysfunction in the Rat: Potential for Novel Treatments for Schizophrenia

Large, Charles H.; Bison, Silvia; Sartori, Ilaria; Read, Kevin D.; Gozzi, Alessandro; Quarta, Davide; Antolini, Marinella; Hollands, Emma; Gill, Catherine H.; Gunthorpe, Martin J.; Idris, Nagi F.; Neill, Joanna C.; Alvaro, Giuseppe

doi:10.1124/jpet.110.178475

Cited by 18 publications

(13 citation statements)

References 41 publications

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“…With use of phMRI, drug action on rodent brain function has been evaluated for a range of compounds that include amphetamine (Chen et al, 2005), nicotine (Gozzi et al, 2006), remifentanil (Liu et al, 2007), and cocaine (Schwarz et al, 2004). Previous studies have also used phMRI as a means to characterize the effects of a pharmacological pretreatment (eg, 5HT-2A receptor antagonist) on a particular challenge (e.g., phencylidine) (Gozzi et al, 2008;Gozzi et al, 2010;Chin et al, 2011;Large et al, 2011;McKie et al, 2011;Baker et al, 2012). Such studies can be highly informative with regard to understanding the underlying neurobiology (receptor and brain circuit level) that drives a certain cognitive phenomenon.…”

Section: Discussionmentioning

confidence: 99%

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

Becerra

Upadhyay

Chang

et al. 2013

J Pharmacol Exp Ther

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Pharmacological magnetic resonance imaging (phMRI) is one method by which a drug's pharmacodynamic effects in the brain can be assessed. Although phMRI has been frequently used in preclinical and clinical settings, the extent to which a phMRI signature for a compound translates between rodents and humans has not been systematically examined. In the current investigation, we aimed to build on recent clinical work in which the functional response to 0.1 and 0.2 mg/70 kg i.v. buprenorphine (partial m-opioid receptor agonist) was measured in healthy humans. Here, we measured the phMRI response to 0.04 and 0.1 mg/kg i.v. buprenorphine in conscious, naive rats to establish the parallelism of the phMRI signature of buprenorphine across species. PhMRI of 0.04 and 0.1 mg/kg i.v. buprenorphine yielded dose-dependent activation in a brain network composed of the somatosensory cortex, cingulate, insula, striatum, thalamus, periaqueductal gray, and cerebellum. Similar dose-dependent phMRI activation was observed in the human phMRI studies. These observations indicate an overall preservation of pharmacodynamic responses to buprenorphine between conscious, naive rodents and healthy human subjects, particularly in brain regions implicated in pain and analgesia. This investigation further demonstrates the usefulness of phMRI as a translational tool in neuroscience research that can provide mechanistic insight and guide dose selection in drug development.

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Section: Discussionmentioning

confidence: 99%

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

Becerra

Upadhyay

Chang

et al. 2013

J Pharmacol Exp Ther

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“…Although not approved to treat schizophrenia, clinical studies have noted lamotrigine may improve some symptoms in a clozapine-resistant patient population (Goff, 2009; Tiihonen et al, 2009). Notably, lamotrigine and related voltage-gated sodium channel blockers attenuate cognitive deficits in methamphetamine- and PCP-treated rats and transgenic mice models used to investigate schizophrenia, including visual and spatial learning (Celikyurt et al, 2012), reversal learning (Large et al, 2011), and PPI deficits (Brody et al, 2003b; Nakato et al, 2010). The mechanisms underlying these pro-cognitive effects are unclear but could involve modulation of cortical glutamate release.…”

Section: Introductionmentioning

confidence: 99%

Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following Combined Neonatal Phencyclidine and Post-Weaning Social Isolation of Rats as a Neurodevelopmental Model for Schizophrenia

Gaskin

Toledo-Rodriguez

Alexander

et al. 2016

IJNPPY

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Background:Dysfunction of dopaminergic, GABAergic, and glutamatergic function underlies many core symptoms of schizophrenia. Combined neonatal injection of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP), and post-weaning social isolation of rats produces a behavioral syndrome with translational relevance to several core symptoms of schizophrenia. This study uses DNA microarray to characterize alterations in hippocampal neurotransmitter-related gene expression and examines the ability of the sodium channel blocker, lamotrigine, to reverse behavioral changes in this model.Methods:Fifty-four male Lister-hooded rat pups either received phencyclidine (PCP, 10mg/kg, s.c.) on post-natal days (PND) 7, 9, and 11 before being weaned on PND 23 into separate cages (isolation; PCP-SI; n = 31) or received vehicle injection and group-housing (2–4 per cage; V-GH; n = 23) from weaning. The effect of lamotrigine on locomotor activity, novel object recognition, and prepulse inhibition of acoustic startle was examined (PND 60–75) and drug-free hippocampal gene expression on PND 70.Results:Acute lamotrigine (10–15mg/kg i.p.) reversed the hyperactivity and novel object recognition impairment induced by PCP-SI but had no effect on the prepulse inhibition deficit. Microarray revealed small but significant down-regulation of hippocampal genes involved in glutamate metabolism, dopamine neurotransmission, and GABA receptor signaling and in specific schizophrenia-linked genes, including parvalbumin (PVALB) and GAD67, in PCP-SI rats, which resemble changes reported in schizophrenia.Conclusions:Findings indicate that alterations in dopamine neurotransmission, glutamate metabolism, and GABA signaling may contribute to some of the behavioral deficits observed following PCP-SI, and that lamotrigine may have some utility as an adjunctive therapy to improve certain cognitive deficits symptoms in schizophrenia.

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“…Similarly, other bases (DBU, t-BuOK, Cs 2 CO 3 ) and solvents (1,4-dioxane, toluene) resulted in lower stereocontrol and/or chemical yields. 7 We reasoned that an electron-releasing group such as para-methoxy (R=PMP, Once we determined these optimized reaction conditions to obtain exclusively adduct syn-4a, we extended these interrupted (3 + 2) cycloadditions to imines 1c,d and nitroalkenes 2b-f to obtain (2S,3R)−α−amino−γ−nitro esters syn-4b-h. The results are reported in Table 2 and indicate that in all cases both the diastereo-and the enentiocontrol were excellent.…”

Section: Resultsmentioning

confidence: 99%

“…Calcd. For C 24 H 22 N 2 O 4 : C,71.6;H,5.5;N,7.0;Found: C,71.4;H,5.6;N,7. 3,163.1,161.2,134.7,129.0,115.8,58.7,50.1,CDCl 3 ) δ = -114.92.…”

Section: Acs Paragon Plus Environmentmentioning

confidence: 96%

Enantiodivergent Synthesis of Bis-Spiropyrrolidines via Sequential Interrupted and Completed (3 + 2) Cycloadditions

et al. 2015

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Both (5R)- and (5S)-1,7-diazaspiro[4.4]nonan-6-ones are obtained via a sequence of interrupted and completed stepwise (3 + 2) cycloadditions between azomethine ylides and π-deficient alkenes. The only source of chirality along the whole process is an enantiopure ferrocenyl pyrrolidine catalytic ligand. When the starting imine incorporates two aryl groups or one aryl group with one electron-releasing substituent, the reaction between the azomethine ylide and the alkene stops at the first step, leading to the corresponding Michael adduct. When imines derived from p-methoxybenzaldehyde are used, the corresponding syn-α-amino-γ-nitro ester is obtained with almost complete enantiocontrol. In contrast, imines derived from benzophenone lead to the corresponding anti analogue. From this interrupted (3 + 2) cycloaddition, cis- and trans-α-amino-γ-lactams can be obtained via hydrogenation of the nitro group followed by in situ cyclization. Imines derived from these latter compounds are the precursors of N-metalated azomethine ylides from which up to four new chiral centers can be generated via completed (3 + 2) cycloaddition reactions with full regio- and diastereocontrol. Cis- and trans-γ-lactams lead to opposite bis-spiropyrrolidine enantiomers. Therefore, both enantiomeric series of spiro compounds can be obtained by means of the same catalytic system. The potential of these rigid, densely substituted homochiral compounds in medicinal chemistry is briefly described.

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The Efficacy of Sodium Channel Blockers to Prevent Phencyclidine-Induced Cognitive Dysfunction in the Rat: Potential for Novel Treatments for Schizophrenia

Cited by 18 publications

References 41 publications

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following Combined Neonatal Phencyclidine and Post-Weaning Social Isolation of Rats as a Neurodevelopmental Model for Schizophrenia

Enantiodivergent Synthesis of Bis-Spiropyrrolidines via Sequential Interrupted and Completed (3 + 2) Cycloadditions

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