Current Neuropharmacology - Volume 8, Issue 1, 2010

The GABAA receptor is a member of the Cys-loop family of transmitter-gated ion channels. GABAA receptors respond to synaptically-released or ambient transmitter with a conformational change, resulting in the opening of the gate that allows movement of small anions through the channel. Under most circumstances, GABAA receptor-mediated signaling leads to hyperpolarization in the mature brain. The normal functioning of the receptor is critical to cellular function, while errors in GABAA receptor activity can systemically manifest as seizures, anxiety disorders and others. The pharmacology of the GABAA receptor is remarkably rich. The receptor is a target for benzodiazepines, steroids, barbiturates, and a number of other classes of compounds, some of which are used clinically as anesthetics, anxiolytics, or anticonvulsants. The actions of the drugs are in many cases dependent on the subunit composition of the GABAA receptor. Thus, understanding how the existing therapeutics act can pave way to new drugs with improved specificity and reduced side effects. This Hot Topic Issue presents an overview of molecular pharmacology of the GABAA receptor focusing on three classes of positive modulators: general anesthetics, benzodiazepines, and neuroactive steroids. Paul Garcia, Scott Kolesky and Andrew Jenkins provide an introduction to GABAA receptors, and discuss the actions of major classes of volatile and intravenous anesthetics. The manuscript addresses the relationship between subunit composition of the receptor and modulation, and summarizes the data from work on mutated receptors on the location of the anesthetic binding cavity. Matt Bianchi presents a summary of the actions of benzodiazepines on the GABAA receptor. The major effect of benzodiazepines is to enhance the affinity of the receptor to the transmitter. The manuscript is aimed at comparing and contrasting the ability of benzodiazepines to modulate currents under conditions resembling synaptic conditions and tonic exposure to GABA. Finally, Gustav Akk and colleagues discuss the current knowledge about kinetic and structural features of GABAA receptor modulation by potentiating neuroactive steroids. This class of steroids acts by increasing channel open probability through a set of modifications in the channel open and closed time distributions. The review critically evaluates available experimental data discussing the possibility of a single vs. multiple interaction sites mediating the effects of potentiating steroids. This Hot Topics Issue provides an overview of the rapidly developing field of molecular pharmacology of the GABAA receptor. The manuscripts focus on several of the numerous positive modulators of the receptor summarizing the present state of knowledge and introducing new evidence and novel viewpoints about the kinetic and structural aspects of modulation. It is hoped that the presented material will provide an impetus for further research in this area.

General anesthetic drugs interact with many receptors in the nervous system, but only a handful of these interactions are critical for producing anesthesia. Over the last 20 years, neuropharmacologists have revealed that one of the most important target sites for general anesthetics is the GABAA receptor. In this review we will discuss what is known about anesthetic - GABAA receptor interactions.

The anxiolytic, hypnotic, and anti-convulsant properties of benzodiazepines (BDZs) require modulation of distinct GABAA receptor α-subtypes. BDZ modulation of GABAA receptors is often described in terms of increased opening frequency, and contrasted with the increased open durations occurring with barbiturate modulation. Several studies spanning single channel, rapid kinetic, and whole cell techniques have suggested that BDZs effect this observed change in frequency through increased affinity for GABA. BDZ-sensitive αβγ isoforms exist at extrasynaptic as well as synaptic locations, where they encounter markedly different concentration and time-course of GABA exposure. Interestingly, this affinity-based mechanism (specifically, decreasing the GABA unbinding rate) is only predicted to increase opening frequency under conditions that allow the unbinding and rebinding cycles typical of prolonged exposure to low GABA concentrations, which are more likely to occur at extrasynaptic GABAA receptors. In contrast, when rebinding is less likely, such as may occur in certain synaptic conditions, the number, but not the frequency, of channel openings increases in response to BDZ modulation. In conclusion, not only can multiple kinetic mechanisms alter channel opening frequency, but a single mechanism - increased affinity - impacts opening frequency differently under different contexts of GABAA receptor activation.

Endogenous neurosteroids and synthetic neuroactive steroid analogs are among the most potent and efficacious potentiators of the mammalian GABA-A receptor. The compounds interact with one or more sites on the receptor leading to an increase in the channel open probability through a set of changes in the open and closed time distributions. The endogenous neurosteroid allopregnanolone potentiates the α1β2γ2L GABA-A receptor by enhancing the mean duration and prevalence of the longest-lived open time component and by reducing the prevalence of the longest-lived intracluster closed time component. Thus the channel mean open time is increased and the mean closed time duration is decreased, resulting in potentiation of channel function. Some of the other previously characterized neurosteroids and steroid analogs act through similar mechanisms while others affect a subset of these parameters. The steroids modulate the GABA-A receptor through interactions with the membrane-spanning region of the receptor. However, the number of binding sites that mediate the actions of steroids is unclear. We discuss data supporting the notions of a single site vs. multiple sites mediating the potentiating actions of steroids.

This work reviews the neuropharmacology of the vestibular system, with an emphasis on the mechanism of action of drugs used in the treatment of vestibular disorders. Otolaryngologists are confronted with a rapidly changing field in which advances in the knowledge of ionic channel function and synaptic transmission mechanisms have led to the development of new scientific models for the understanding of vestibular dysfunction and its management. In particular, there have been recent advances in our knowledge of the fundamental mechanisms of vestibular system function and drug mechanisms of action. In this work, drugs acting on vestibular system have been grouped into two main categories according to their primary mechanisms of action: those with effects on neurotransmitters and neuromodulator receptors and those that act on voltage-gated ion channels. Particular attention is given in this review to drugs that may provide additional insight into the pathophysiology of vestibular diseases. A critical review of the pharmacology and highlights of the major advances are discussed in each case.

Cerebellar ataxias are a group of disabling neurological disorders. Patients exhibit a cerebellar syndrome and can also present with extra-cerebellar deficits, namely pigmentary retinopathy, extrapyramidal movement disorders, pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioural symptoms), and peripheral neuropathy. Recently, deficits in cognitive operations have been unraveled. Cerebellar ataxias are heterogeneous both at the phenotypic and genotypic point of view. Therapeutical trials performed during these last 4 decades have failed in most cases, in particular because drugs were not targeting a deleterious pathway, but were given to counteract putative defects in neurotransmission. The identification of the causative mutations of many hereditary ataxias, the development of relevant animal models and the recent identifications of the molecular mechanisms underlying ataxias are impacting on the development of new drugs. We provide an overview of the pharmacological treatments currently used in the clinical practice and we discuss the drugs under development.

Cyclooxygenase (COX) expression in the brain is associated with pro-inflammatory activities, which are instrumental in neurodegenerative processes such as Parkinson's disease (PD). It is discussed that drugs with the capacity to rescue dopaminergic neurons from microglia toxicity and neuroinflammatory processes may result in an amelioration of parkinsonian symptoms by delaying the onset or slowing progression. This article reviews the involvement of COX in neuroinflammation, specifically focussing at the role of selective COX-2 inhibition in neuroinflammation and neurodegeneration in Parkinson's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Worldwide prevalence of the disease is estimated at more than 24 million cases. With aging of populations, this number will likely increase to more than 80 million cases by the year 2040. The annual incidence worldwide is estimated at 4.6 million cases which is the equivalent of one new case every seven seconds! The pathophysiology of AD is complex and largely misunderstood. It is thought to start with the accumulation of beta-amyloid (Aβ) that leads to deposition of insoluble neuritic or senile plaques. Secondary events in this “amyloid cascade” include hyperphosphorylation of the protein tau into neurofibrillary tangles, inflammation, oxidation, and excitotoxicity that eventually cause activation of apoptotis, cell death and neurotransmitter deficits. This review will briefly summarize recent advances in the pathophysiology of AD and focus on the pharmacological treatment of the cognitive and functional symptoms of AD. It will discuss the roles of vascular prevention, cholinesterase inhibitors and an NMDA-antagonist in the management of AD. It will address the issues thought to be related to the lack of persistence or discontinuation of therapy with cholinesterase inhibitors shown in recent studies and some of the solutions proposed. These include setting realistic expectations in light of a neurodegenerative condition and available symptomatic treatments, slowly titrating medications, and using alternate routes of administration. Finally, it will introduce future therapeutic options currently under study.

This is with reference to the article entitled, “Adenosine, Ketogenic Diet and Epilepsy: The Emerging Therapeutic Relationship Between Metabolism and Brain Activity”, by, S.A. Masino, M. Kawamura Jr., C.D. Wasser, L.T. Pomeroy and D.N. Ruskin published in Current Neuropharmacology Journal, September 2009, Vol. 7, No. 3, pp. 257-268. Due to an oversight, author middle name was cited as Caleb A. Wasser and it should read as C.D. Wasser.

This is with reference to the article entitled, “Minimizing AED Adverse Effects: Improving Quality of Life in the Interictal State in Epilepsy Care.”, by Dr. St. Louis EK, published in Current Neuropharmacology, June 2009, Vol. 7, No. 2, pp. 106-114. Due to an oversight, First name author was cited as Louis EK and now it should read as St. Louis EK.