David H Farb

Boston University | BU · Department of Pharmacology and Experimental Therapeutics

The prevalence of hypertension increases with age and is the leading modifiable risk factor for cognitive impairment and dementia. At present, the neural mechanisms promoting hypertension across the lifespan are incompletely understood. Using the Sprague–Dawley (SD) rat as a model of normal aging, we hypothesized (1) blood brain barrier (BBB) disru...

Hypertension onset with aging is of widespread clinical significance, predominantly in males, yet the neural circuitry underpinnings for hypertension associated memory dysfunction remains unknown. Sprague Dawley (SD) male but not female rats develop age dependent increases in mean arterial blood pressure (MAP) by 16 months of age. We sought to inte...

Adverse effects of drugs on the human nervous system are rarely possible to anticipate based on preclinical neurotoxicity data, thus propagating the centuries long single most important obstacle to drug discovery and development for disorders of the nervous system. An emerging body of evidence indicates that in vivo electrophysiology using chronica...

A better understanding of the changes in neural activity that contribute to the prodromal progression and onset of overt symptoms of Alzheimer’s disease (AD) is essential to the discovery of e!ective therapeutics. These experiments explore prodromal neural network dysfunction in the hippocampal trisynaptic circuit by using an orally bioavailable es...

Hippocampal hyperactivity is a hallmark of amnestic mild cognitive impairment (aMCI) in aging and memory dysfunction in Alzheimer’s disease, leading to the hypothesis that hyperactivity in the hippocampal trisynaptic circuit impairs memory. As a test of this hypothesis, we sought to recapitulate hyperactivity in young adults by attenuating tonic in...

Inhibition α5GABAA-R Alzheimer's TgF344-AD A B S T R A C T Decades of research attempting to slow the onset of Alzheimer's disease (AD) indicates that a better understanding of memory will be key to the discovery of effective therapeutic approaches. Here, we ask whether prodromal neural network dysfunction might occur in the hippocampal trisynaptic...

Decades of research attempting to slow the onset of Alzheimer′s disease (AD) indicates that a better understanding of memory will be key to the discovery of effective therapeutic approaches. Here, we ask whether prodromal neural network dysfunction might occur in the hippocampal trisynaptic circuit by using α5IA as a selective negative modulator of...

Memory dysfunction is a symptomatic feature of many neurologic and neuropsychiatric disorders; however, the basic underlying mechanisms of memory and altered states of circuitry function associated with disorders of memory remain a vast unexplored territory. The initial discovery of endogenous neurosteroids triggered a quest to elucidate their role...

Learning and memory deficits associated with age-related mild cognitive impairment have long been attributed to impaired processing within the hippocampus. Hyperactivity within the hippocampal CA3 region that is associated with aging is mediated in part by a loss of functional inhibitory interneurons and thought to underlie impaired performance in...

An earlier age at onset of Parkinson’s disease (PD) has been reported to be associated with occupational exposures to manganese and hydrocarbon solvents suggesting that exposure to neurotoxic chemicals may hasten the progression of idiopathic PD. In this study the role of occupational exposure to metals and pesticides in the progression of idiopath...

The use of high density chronically implanted electrodes to monitor systems level in vivo electrophysiological responses to therapeutic agents is emerging as a powerful tool for the validation of targets and targeted drugs. In this study we sought to determine whether the spatial learning and memory enhancing effects of the α5GABAA receptor selecti...

Anxiety disorders are a major public health concern. Here, we examine the familiar area of anxiolysis in the context of a systems-level understanding that will hopefully lead to revealing an underlying pharmacological connectome. The introduction of benzodiazepines nearly half a century ago markedly improved the treatment of anxiety disorders. Thes...

The use-dependent regulation of the GABAA receptor occurs under physiological, pathological, and pharmacological conditions. Tolerance induced by prolonged administration of benzodiazepines is associated with changes in GABAA receptor function. Chronic exposure of neurons to GABA for 48 hr induces a downregulation of the GABAA receptor number and a...

Fast excitatory synaptic transmission that is contingent upon N-methyl D-aspartate (NMDA) receptor function contributes to core information flow in the central nervous system (CNS) and to the plasticity of neural circuits that underlie cognition. Hypoactivity of excitatory NMDA receptor-mediated neurotransmission is hypothesized to underlie the pat...

Rationale: The neurosteroid pregnenolone sulfate (PregS) acts as a cognitive enhancer and modulator of neurotransmission, yet aligning its pharmacological and physiological effects with reliable measurements of endogenous local concentrations and pharmacological and therapeutic targets has remained elusive for over 20 years. Objectives: New basi...

Memory deficits associated with normal aging have long been attributed to impaired processing within the hippocampus, perhaps due in part to a decrease in its ability to perform pattern separation- the creation of distinct representations for separate but overlapping experiences. Non-demented older adults and patients with amnestic mild cognitive i...

David H. Farb is Professor and Chair of the Department of Pharmacology & Experimental Therapeutics at Boston University School of Medicine. Dr. Farb is Principal Investigator and Director of the Laboratory of Molecular Neurobiology and Director of the university-wide NIGMS training program in Biomolecular Pharmacology. A renowned neuropharmacologis...

The gamma-aminobutyric acid (GABA) type A receptor (GABAAR) contains the recognition sites for a variety of agents used in the treatment of brain disorders, including anxiety and epilepsy. A better understanding of how receptor expression is regulated in individual neurons may provide novel opportunities for therapeutic intervention. Towards this g...

NMDA receptors (NMDARs) mediate fast excitatory synaptic transmission and play a critical role in synaptic plasticity associated with learning and memory. NMDAR hypoactivity has been implicated in the pathophysiology of schizophrenia, and clinical studies reveal reduced negative symptoms of schizophrenia with a dose of pregnenolone that elevates se...

Glutamate receptors play a major role in relapse of cocaine addiction. Effective treatments for prevention of relapse are still lacking. Previously, our laboratory has shown that pregnanolone hemisuccinate (3α5βHS or PAHS), the synthetic analogue of pregnanolone sulfate, inhibits reinstatement of cocaine seeking behavior in rats. In order to determ...

J. Neurochem. (2012) 120, 210–219. Regulation of gene expression via brain-derived neurotrophic factor (BDNF) is critical to the development of the nervous system and may well underlie cognitive performance throughout life. We now describe a mechanism by which BDNF can exert its effects on postsynaptic receptor populations that may have relevance t...

J. Neurochem. (2011) 119, 486–496. NMDA receptor (NMDAR)-mediated excitatory synaptic transmission plays a critical role in synaptic plasticity and memory formation, whereas its dysfunction may underlie neuropsychiatric and neurodegenerative diseases. The neuroactive steroid pregnenolone sulfate (PS) acts as a cognitive enhancer in impaired animals...

Disruption of the GABAergic system has been implicated in multiple developmental disorders, including epilepsy, autism spectrum disorder and schizophrenia. The human gene encoding uPAR (PLAUR) has been shown recently to be associated with the risk of autism. The uPAR(-/-) mouse exhibits a regionally-selective reduction in GABAergic interneurons in...

In this chapter, we will provide a brief overview of some current therapeutic agents, including their weaknesses, and highlight selected opportunities for continued drug discovery efforts in certain disease areas. We will then focus our attention on different strategies used to identify new therapeutic agents, comparing target - based discovery (TB...

The discovery of a nonaddictive therapeutic that diminishes relapse of cocaine-seeking behavior would be a major advance in the treatment of cocaine addiction. Glutamate receptor activation mediates reinstatement of cocaine-seeking behavior in rats. Here, we asked whether pregnanolone hemisuccinate (3α5βHS), a synthetic negatively charged neuroacti...

Positive allosteric modulation of the GABA(A) receptor (GABA(A)R) via the benzodiazepine recognition site is the mechanism whereby diverse chemical classes of therapeutic agents act to reduce anxiety, induce and maintain sleep, reduce seizures, and induce conscious sedation. The binding of such therapeutic agents to this allosteric modulatory site...

The balance between GABA-mediated inhibitory and glutamate-mediated excitatory synaptic transmission represents a fundamental mechanism for controlling nervous system function, and modulators that can alter this balance may participate in the pathophysiology of neuropsychiatric disorders. Pregnenolone sulfate (PS) is a neuroactive steroid that can...

Neuromodulators that alter the balance between lower-frequency glutamate-mediated excitatory and higher-frequency GABA-mediated inhibitory synaptic transmission are likely to participate in core mechanisms for CNS function and may contribute to the pathophysiology of neurological disorders such as schizophrenia and Alzheimer's disease. Pregnenolone...

Compounds targeting the benzodiazepine binding site of the GABAA-R are widely prescribed for the treatment of anxiety disorders, epilepsy, and insomnia as well as for pre-anesthetic sedation and muscle relaxation. It has been hypothesized that these various pharmacological effects are mediated by different GABAA-R subtypes. If this hypothesis is co...

The regulated expression of type A gamma-aminobutyric acid (GABA) receptor (GABA(A)R) subunit genes plays a critical role in neuronal maturation and synaptogenesis. It is also associated with a variety of neurological diseases. Changes in GABA(A) receptor alpha1 subunit gene (GABRA1) expression have been reported in animal models of epilepsy, alcoh...

The γ-aminobutyric acid (GABA) neurotransmitter acting through ionotropic and metabotropic receptor classes exerts the major inhibitory control in the central nervous system. Therapeutic agents targeting GABA receptors (GABA-R), such as benzodiazepines and baclofen, are used to treat many nervous system conditions, including anxiety and spasticity....

GABA mediates most inhibitory synaptic transmission in the adult vertebrate CNS by activating type-A GABA receptors that contain an integral ion channel and type-B GABA receptors that are G-protein coupled. GABAA receptors have been a rich target for the development of therapeutics for treatment of anxiety disorders, convulsive disorders, sleep dis...

Studies using mice with point mutations of GABA(A) receptor alpha subunits suggest that the sedative and anxiolytic properties of 1,4-benzodiazepines are mediated, respectively, by GABA(A) receptors bearing the alpha(1) and alpha(2) subunits. This hypothesis predicts that a compound with high efficacy at GABA(A) receptors containing the alpha(1) su...

The prevention of relapse is among the greatest challenges in the treatment of cocaine addiction. Research has shown that activation of glutamate receptors in the nucleus accumbens is involved in reinstatement of cocaine seeking behavior in rats (Cornish and Kalivas, 2000). While inhibition of NMDA receptors has been shown to induce reinstatement (...

Central nervous system function is critically dependent upon an exquisitely tuned balance between excitatory synaptic transmission, mediated primarily by glutamate, and inhibitory synaptic transmission, mediated primarily by GABA. Modulation of either excitation or inhibition would be expected to result in altered functionality of finely tuned syna...

Benzodiazepines (BZDs) have been used extensively for more than 40 years because of their high therapeutic index and low toxicity. Although BZDs are understood to act primarily as allosteric modulators of GABA A receptors, the mechanism of modulation is not well understood. The applicability of an allosteric model with two binding sites for γ ‐amin...

Changes in the function of type A gamma-aminobutyric acid receptors (GABA(A)Rs) are associated with neuronal development and tolerance to the sedative-hypnotic effects of GABA(A)R positive modulators. Persistent activation of GABA(A)Rs by millimolar concentrations of GABA occurs under physiological conditions as GABAergic fast-spiking neurons in ne...

Benzodiazepines remain widely used for the treatment of anxiety disorders despite prominent, often limiting side effects including sedation, muscle relaxation, and ataxia. A compound producing a robust anxiolytic action comparable to benzodiazepines, but lacking these limiting side effects at therapeutic doses (an anxioselective agent), would repre...

Expression of metabotropic GABA(B) receptors is essential for slow inhibitory synaptic transmission in the CNS, and disruption of GABA(B) receptor-mediated responses has been associated with several disorders, including neuropathic pain and epilepsy. The location of GABA(B) receptors in neurons determines their specific role in synaptic transmissio...

N-methyl-D-aspartate (NMDA) receptor function is modulated by several endogenous molecules, including zinc, polyamines, protons, and sulfated neurosteroids. Zinc, polyamines, and phenylethanolamines exert their respective modulatory effects by exacerbating or relieving tonic proton inhibition. Here, we report that pregnenolone sulfate (PS) uses a u...

gamma-Aminobutyric acid type B receptors (GABA(B)Rs) mediate both slow inhibitory synaptic activity in the adult nervous system and motility signals for migrating embryonic cortical cells. Previous papers have described the expression of GABA(B)Rs in the adult brain, but the expression and functional significance of these gene products in the embry...

Exposure of pregnant rats to protein malnutrition throughout pregnancy alters the developing hippocampus, leading to increased inhibition and selective changes in hippocampal-mediated behaviors. Given that GABA mediates most inhibitory neurotransmission, we asked whether selective changes in the levels of GABA receptor subunit mRNAs might result. Q...

Exposure of pregnant rats to protein malnutrition throughout pregnancy alters the developing hippocampus, leading to increased inhibition and selective changes in hippocampal-mediated behaviors. Given that GABA mediates most inhibitory neurotransmission, we asked whether selective changes in the levels of GABA receptor subunit mRNAs might result. Q...

Our laboratory has previously shown that the synthetic neuroactive steroid 3alpha-hydroxy-5beta-pregnan-20-one hemisuccinate (3alpha5betaHS) is a negative modulator of NMDA receptors in vitro. Similarly, 3alpha5betaHS exhibits rapid sedative, analgesic, anticonvulsive, and neuroprotective effects in vivo. Here we report a study designed to investig...

Benzodiazepines (BZDs), barbiturates, ethanol, and general anesthetics potentiate the action of γ-aminobutyric acid (GABA) at the type A GABA receptor (GABAAR) and have profound effects on mood, arousal, and susceptibility to seizures. GABAAR number and subunit mRNA levels change in animal models of epilepsy and anxiety and following exposure to GA...

Neuroactive steroids can produce rapid effects on central nervous system (CNS) function by acting directly on a variety of neurotransmitter receptors, including GABAA, glycine, and glutamate receptors. Although GABAA and NMDA receptors are structurally distinct, both exhibit bidirectional modulation by neuroactive steroids, with some steroids enhan...

Rats exposed to prenatal protein malnutrition are less sensitive to the amnestic effects of chlordiazepoxide when administered directly into the medial septum. Here we report that prenatal malnutrition selectively decreases gamma-aminobutyric acid A (GABA(A)) receptor gamma(2L) mRNA levels in the medial septum, consistent with malnutrition-induced...

Rats exposed to prenatal protein malnutrition are less sensitive to the amnestic effects of chlordiazepoxide when administered directly into the medial septum. Here we report that prenatal malnutrition selectively decreases γ-aminobutyric acid A (GABAA) receptor γ2L mRNA levels in the medial septum, consistent with malnutrition-induced decreases in...

The neurosteroid pregnenolone sulphate (PS) potentiates N-methyl-D-aspartate (NMDA) receptor mediated responses in various neuronal preparations. The NR1 subunit can combine with NR2A, NR2B, NR2C, or NR2D subunits to form functional receptors. Differential NR2 subunit expression in brain and during development raises the question of how the NR2 sub...

The type B gamma-aminobutryic acid receptor (GABA(B)R) is a G protein coupled receptor that mediates slow pre- and post-synaptic inhibition in the nervous system. We find that the human GABA(B)R2 gene spans greater than 350 kb and contains 2.8 kb of coding region in 19 exons. The overall similarity in genomic structure with regard to conservation o...

Changes in GABA receptor (GABA(A)R) gene expression are detected in animal models of epilepsy, anxiety and in post-mortem schizophrenic brain, suggesting a role for GABA(A)R regulation in neurological disorders. Persistent (48 h) exposure of brain neurons in culture to GABA results in down-regulation of GABA(A)R number and uncoupling of GABA and be...

Neurosteroids can be positive or negative regulators of neurotransmitter receptor action, depending on the receptor and the chemical structure of the neurosteroid. This Perspective by Gibbs and Farb is one of two on the subject of neurosteroids. The authors address the possible role of sigma receptors in mediating neurosteroid action and describe h...

The regulated expression of type A gamma-aminobutyric acid receptor (GABA(A)R) subunit genes is postulated to play a role in neuronal maturation, synaptogenesis, and predisposition to neurological disease. Increases in GABA levels and changes in GABA(A)R subunit gene expression, including decreased beta1 mRNA levels, have been observed in animal mo...

The regulated expression of type A gamma-aminobutyric acid receptor (GABA(A)R) subunit genes is postulated to play a role in neuronal maturation, synaptogenesis, and predisposition to neurological disease. Increases in GABA levels and changes in GABA(A)R subunit gene expression, including decreased beta1 mRNA levels, have been observed in animal mo...