Peter J. West

University of Utah | UOU · Department of Pharmacology and Toxicology

The shift from drug abuse to addiction is considered to arise from the transition between goal-directed and habitual control over drug behavior. Habitual responding for appetitive and skill-based behaviors is mediated by potentiated glutamate signaling in the dorsolateral striatum (DLS), but the state of the DLS glutamate system in the context of h...

Ascorbic acid (AA; a.k.a. vitamin C) is well known for its cellular protection in environments of high oxidative stress. Even though physiological concentrations of AA in the brain are significant (0.2–10 mM), surprisingly little is known concerning the role of AA in synaptic neurotransmission under normal, non-disease state conditions. Here, we ex...

Rationale Methamphetamine (METH) exposure is associated with damage to central monoamine systems, particularly dopamine signaling. Rodent models of such damage have revealed a decrease in the amplitude of phasic dopamine signals and significant striatal dysfunction, including changes in the molecular, system, and behavioral functions of the striatu...

The discovery and development of novel antiseizure drugs (ASDs) that are effective in controlling pharmacoresistant spontaneous recurrent seizures (SRSs) continues to represent a significant unmet clinical need. The Epilepsy Therapy Screening Program (ETSP) has undertaken efforts to address this need by adopting animal models that represent the sal...

Objective: Infection with Theiler's Murine Encephalomyelitis Virus (TMEV) in C57Bl/6J mice results in handling-induced seizures and is useful for evaluating compounds effective against infection-induced seizures. However, to date only a few compounds have been evaluated in this model, and a comprehensive study of antiseizure medications (ASMs) has...

Dravet syndrome (DS) is a rare childhood epilepsy disorder resulting in spontaneous, recurrent seizures and behavioral co-morbidities. A successful drug screening model should recapitulate the phenotypes observed in a clinical setting. To facilitate the discovery and development of anti-seizure drugs for DS, the contract site of the NINDS Epilepsy...

Objective Dravet syndrome (DS) is a rare but catastrophic genetic epilepsy, with 80% of patients carrying a mutation in the SCN1A gene. Currently, no antiseizure drug (ASD) exists that adequately controls seizures. In the clinic, individuals with DS often present first with a febrile seizure and, subsequently, generalized tonic‐clonic seizures that...

The discovery and development of novel antiseizure drugs (ASDs) that are effective in controlling pharmacoresistant spontaneous recurrent seizures (SRSs) continues to represent a significant unmet clinical need. The Epilepsy Therapy Screening Program (ETSP) has undertaken efforts to address this need by adopting animal models that better represent...

Objective Dravet syndrome (DS) is a rare, but catastrophic genetic epilepsy, with 80% of patients with carrying a mutation in the SCN1A gene. Currently, no anti-seizure drug (ASD) exists that adequately controls seizures. Patients with DS often present clinically with a febrile seizure and generalized tonic-clonic seizures that continue throughout...

Objective Approximately 30% of patients with epilepsy do not experience full seizure control on their antiseizure drug (ASD) regimen. Historically, screening for novel ASDs has relied on evaluating efficacy following a single administration of a test compound in either acute electrical or chemical seizure induction. However, the use of animal model...

Despite the availability of more than 25 anti-seizure drugs on the market, approximately 30% of patients with epilepsy still suffer from seizures. Thus, the epilepsy therapy market has a great need for a breakthrough drug that will aid pharmacoresistant patients. In our previous study, we discovered a vitamin K analog, 2h, which displayed modest an...

Astrocyte expression of metabotropic glutamate receptor 5 (mGluR5) is consistently observed in resected tissue from patients with epilepsy and is equally prevalent in animal models of epilepsy. However, little is known about the functional signaling properties or downstream consequences of astrocyte mGluR5 activation during epilepsy development. In...

Objective Approximately 30% of patients with epilepsy are refractory to existing antiseizure drugs (ASDs). Given that the properties of the central nervous systems of these patients are likely to be altered due to their epilepsy, tissues from rodents that have undergone epileptogenesis might provide a therapeutically relevant disease substrate for...

Hoxb8 mutant mice exhibit compulsive grooming and hair removal dysfunction similar to humans with the obsessive-compulsive disorder (OCD)-spectrum disorder, trichotillomania. As, in the mouse brain, the only detectable cells that label with Hoxb8 cell lineage appear to be microglia, we suggested that defective microglia cause the neuropsychiatric d...

This corrects the article DOI: 10.1038/mp.2017.180.

Hippocampal CA3 neurons form synapses with CA1 neurons in two layers, stratum oriens (SO) and stratum radiatum (SR). Each layer develops unique synaptic properties but molecular mechanisms that mediate these differences are unknown. Here, we show that SO synapses normally have significantly more mushroom spines and higher-magnitude long-term potent...

The successful identification of promising investigational therapies for the treatment of epilepsy can be credited to the use of numerous animal models of seizure and epilepsy for over 80 years. In this time, the maximal electroshock test in mice and rats, the subcutaneous pentylenetetrazol test in mice and rats, and more recently the 6 Hz assay in...

Memory deficits have a significant impact on the quality of life of patients with epilepsy and currently no effective treatments exist to mitigate this comorbidity. While these cognitive comorbidities can be associated with varying degrees of hippocampal cell death and hippocampal sclerosis, more subtle changes in hippocampal physiology independent...

Example of a vEEG recording from a mouse implanted with an electrode in the dentate gyrus. The vEEG recording was obtained at 5 d after TMEV infection. It is noted that the behavioral aspects of the generalized tonic-clonic seizure in this mouse are preceded by an electrographic seizure activity in the hippocampus, and the electrographic seizure st...

Objective: The mouse 6 Hz model of psychomotor seizures is a well-established and commonly used preclinical model for antiseizure drug (ASD) discovery. Despite its widespread use both in the identification and differentiation of novel ASDs in mice, a corresponding assay in rats has not been developed. We established a method for 6 Hz seizure induc...

Central nervous system infection can induce epilepsy that is often refractory to established antiseizure drugs. Previous studies in the Theiler’s murine encephalomyelitis virus (TMEV)-induced mouse model of limbic epilepsy have demonstrated the importance of inflammation, especially that mediated by tumor necrosis factor-α (TNFα), in the developmen...

Chronic pain is a multifactorial disease comprised of both inflammatory and neuropathic components that affect ∼20% of the world’s population. sec-Butylpropylacetamide (SPD) is a novel amide analogue of valproic acid (VPA) previously shown to possess a broad spectrum of anticonvulsant activity. In this study we defined the pharmacokinetic parameter...

The endogenous neuropeptide galanin is ubiquitously expressed throughout the mammalian brain. Through the galanin receptors GalR1-3, galanin has been demonstrated to modulate both glutamatergic and GABAergic neurotransmission, and this appears to be important in epilepsy and seizure activity. Accordingly, galanin analogues are likely to provide a n...

Unlabelled: New strategies for introducing genetically encoded activity indicators into animal models facilitate the investigation of nervous system function. We have developed the PC::G5-tdT mouse line that expresses the GCaMP5G calcium indicator in a Cre-dependent fashion. Instead of targeting the ROSA26 locus, we inserted the reporter cassette...

Objective: Cognitive comorbidities are increasingly recognized as an equal (or even more disabling) aspect of epilepsy. In addition, the actions of some antiseizure drugs (ASDs) can impact learning and memory. Accordingly, the National Institute of Neurological Disorders and Stroke (NINDS) epilepsy research benchmarks call for the implementation o...

Viral infection of the CNS can result in encephalitis and acute seizures, increasing the risk for later-life epilepsy. We have previously characterized a novel animal model of temporal lobe epilepsy that recapitulates key sequela in the development of epilepsy following viral infection. C57BL/6J mice inoculated with the Daniel's strain of Theiler's...

The 5-HT(6) receptor is predominantly expressed in the CNS and has been implicated in the regulation of cognitive function. Antagonists of the 5-HT(6) receptor improve cognitive performance in a number of preclinical models and have recently been found to be effective in Alzheimer's disease patients. Systemic administration of 5-HT(6) antagonists i...

Although in situ hybridization studies have revealed the presence of kainate receptor (KAR) mRNA in neurons of the rat medial entorhinal cortex (mEC), the functional presence and roles of these receptors are only beginning to be examined. To address this deficiency, whole cell voltage clamp recordings of locally evoked excitatory postsynaptic curre...

delta-Conotoxins are a family of small, disulfide-rich peptides found in the venoms of predatory cone snails (Conus). We examined in detail the effects of delta-conotoxin PVIA from the fish hunting cone snail Conus purpurascens on sodium currents in dissociated sympathetic neurons from the leopard frog Rana pipiens. We also compared this toxin's ef...

The peptides isolated from venoms of predatory marine Conus snails ("conotoxins") are well-known to be highly potent and selective pharmacological agents for voltage-gated ion channels and receptors. We report the discovery of two novel TTX-resistant sodium channel blockers, mu-conotoxins SIIIA and KIIIA, from two species of cone snails. The two to...

SmIIIA is a new micro-conotoxin isolated recently from Conus stercusmuscarum. Although it shares several biochemical characteristics with other micro-conotoxins (the arrangement of cysteine residues and a conserved arginine believed to interact with residues near the channel pore), it has several distinctive features, including the absence of hydro...

Mu-conotoxins are a family of peptides from the venoms of predatory cone snails. Previously characterized mu-conotoxins preferentially block skeletal muscle voltage-gated sodium channels. We report here the discovery (via cloning), synthesis, and electrophysiological characterization of a new peptide in this family, mu-conotoxin SmIIIA from Conus s...

Delta-conotoxins are Conus peptides that inhibit inactivation of voltage-gated sodium channels. The suggestion that delta-conotoxins might be an essential component of the venoms of fish-hunting cone snails which rapidly immobilize their prey [Terlau, H., Shon, K., Grilley, M., Stocker, M., Stühmer, W., and Olivera, B. M. (1996) Nature 381, 148-151...

delta -Conotoxins are Conus peptides that inhibit inactivation of voltage-gated sodium channels. The suggestion that delta -conotoxins might be an essential component of the venoms of fish-hunting cone snails which rapidly immobilize their prey [Terlau, H., Shon, K., Grilley, M., Stocker, M., Stuhmer, W., and Olivera, B. M. (1996) Nature 381, 148-1...

We purified and characterized a novel peptide from the venom of the fish-hunting cone snail Conus striatus that inhibits voltage-gated K+ channels. The peptide, kappaA-conotoxin SIVA, causes characteristic spastic paralytic symptoms when injected into fish, and in frog nerve-muscle preparations exposed to the toxin, repetitive action potentials are...

Cone snails ( Conus ) are carnivorous marine gastropods that feed on such diverse prey as marine worms, molluscs, and most remarkably, fish. They have accomplished this by developing a vast number of specialized toxins that selectively target particular receptors and ion channels in the nervous systems of their prey. These Conus toxins, collectivel...