Contents

Glutamate-regulated Behavior, Transmitter Release, Gene Expression and Addictive Plasticity in the Striatum: Roles of  Metabotropic Glutamate Receptors Pp. 1-20

John Q. Wang, Limin Mao, Nikhil K. Parelkar, Qingsong Tang, Zhenguo Liu, Shazia Sarwar and Eun Sang Choe

[Abstract] [Full text article]

The Abuse Liability and Therapeutic Potential of Drugs Evaluated for Cocaine Addiction as Predicted by Animal Models Pp. 21-46

Joshua A. Lile and Michael A. Nader

[Abstract] [Full text article]     

Filtering Disturbances in Schizophrenic Patients. Gating of Auditory Evoked Potentials and Prepulse Inhibition of the Acoustic Startle Response Compared. Emphasis on the Role of Dopamine Pp. 47-87

N.M.W.J. de Bruin, E.L.J.M. van Luijtelaar, A.R. Cools, B.A. Ellenbroek

[Abstract] [Full text article]     

Pharmacological Studies of the Molecular Basis of Memory Extinction Pp. 89-98

Monica R.M. Vianna, Martín P. Cammarota, Adriana S. Coitinho, Jorge H. Medina, and Ivan Izquierdo

[Abstract] [Full text article]     

Microglial Proteases: Strategic Targets for Neuroprotective Agents Pp. 99-108

Hiroshi Nakanishi

[Abstract] [Full text article]     

Abstracts

[Back to top] Glutamate-regulated Behavior, Transmitter Release, Gene Expression and Addictive Plasticity in the Striatum: Roles of  Metabotropic Glutamate Receptors

John Q. Wang, Limin Mao, Nikhil K. Parelkar, Qingsong Tang, Zhenguo Liu, Shazia Sarwar and Eun Sang Choe
[Full text article]

Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors and are densely expressed in medium spiny projection neurons of striatum. Emerging evidence demonstrates a significant role of mGluRs in the regulation of striatal functions. Activation of mGluRs alters local transmitter release and behaviors of experimental animals. In particular, mGluRs regulate phosphorylation of several key signaling proteins (protein kinases and transcription factors) resulting in significant changes in immediate early gene and neuropeptide gene expression in striatal neurons. The prominent involvement of mGluRs in genomic responses to synaptic stimulation is considered to play a pivotal role in the development of synaptic/neuronal plasticity underlying long-term adaptive changes in cellular physiology related to a variety of neurologic disorders. Available data indicate that the eight subtypes of mGluRs have distinct effects on gene expression. The group I subtypes (mGluR1/5) facilitate, whereas group II (mGluR2/3) and III (mGluR4/6/7/8) subtypes inhibit, gene expression. Due to their significance in regulating drug action, mGluRs have been considered as promising targets for the development of novel therapeutic drugs for the treatment of drug addiction. The present review summarizes the roles of mGluRs in the regulation of behavior, transmitter release and particularly genomic responses in striatal neurons to dopamine stimulation, following a description of anatomical organization of mGluRs in the striatum. The possible pre- and postsynaptic mechanisms that process mGluR modulatory effects are also discussed in detail. Finally, potential of mGluRs as targets for the development of therapeutic drugs for addictive and other mental illnesses concludes this review.

[Back to top] The Abuse Liability and Therapeutic Potential of Drugs Evaluated for Cocaine Addiction as Predicted by Animal Models

Joshua A. Lile and Michael A. Nader
[Full text article]

One strategy in the search for a pharmacotherapy for cocaine abuse and dependence has been to use drugs with a similar mechanism of action as cocaine, or agonist substitution therapy. Research has indicated that cocaine’s behavioral effects are primarily a result of its blockade of the dopamine (DA), serotonin (5-HT) and norepinephrine (NE) transporters. Therefore, drugs that act either directly or indirectly at these monoamine systems have been investigated for their potential as replacement medications for cocaine addiction. The intent of this review was to present data from animal models that assessed the reinforcing effects of these monoamine agonists using drug self-administration, and the rewarding effects, using the conditioned place preference paradigm. Those data were then compared to the abuse liability of the selected drugs in humans and to their efficacy as therapeutics for treating cocaine addiction to determine if animal models of reinforcing and rewarding effects were predictive of these drugs’ effects in humans. Fourteen drugs with a primary mechanism of action at either the DA, 5-HT or NE systems were identified that had been tested as potential treatments for cocaine addiction and had also been evaluated in either the self-administration or conditioned place preference paradigms in animals. From these comparisons, it was concluded that the animal models were, in general, predictive of the abuse liability of these monoamine agonists in humans. However, monoamine agonists with reinforcing or rewarding effects did not affect the desired treatment outcomes for cocaine addiction.

[Back to top] Filtering Disturbances in Schizophrenic Patients. Gating of Auditory Evoked Potentials and Prepulse Inhibition of the Acoustic  Startle Response Compared. Emphasis on the Role of Dopamine

N.M.W.J. de Bruin, E.L.J.M. van Luijtelaar, A.R. Cools, B.A. Ellenbroek
[Full text article] 

Two different paradigms have been used to assess auditory gating in human subjects, namely prepulse inhibition (PPI) of the acoustic startle response (ASR or sensorimotor gating) and gating of auditory evoked potentials (AEPs or sensory gating). PPI is the reduction in the ASR that occurs when a weak stimulus (prepulse) precedes a startling stimulus with interstimulus intervals between 30 and 500 ms. PPI has been found to be disturbed in schizophrenic patients. In the sensory gating paradigm, an auditory click (S1) is presented to a subject, eliciting a positive deflection at 50 ms after stimulus onset in the electroencephalogram (EEG). This deflection is referred to as the P50 component. After a brief interval, about 500 ms, a second click (S2) elicits a much smaller P50 in normal control subjects, who are said to show normal gating. The reduction in P50 amplitude to the second click has been found to be less pronounced in schizophrenic subjects.

This review discusses the similarities and differences between the AEP gating and PPI paradigms. Emphasis in the discussion is placed on the role of dopamine. Growing evidence from both human an animal studies supports the suggestion that AEP gating and PPI underlie different inhibitory systems. Therefore, it is concluded that PPI and AEP gating have neural substrates that only partly overlap each other and that both paradigms measure distinct types of gating mechanisms.

[Back to top]  Pharmacological Studies of the Molecular Basis of Memory Extinction

Monica R.M. Vianna, Martín P. Cammarota, Adriana S. Coitinho, Jorge H. Medina, and Ivan Izquierdo
[Full text article] 

Retrieval procedures, if carried out without reinforcement, initiate memory extinction. The extinction of onetrial avoidance learning requires glutamate NMDA receptors, calcium-calmodulin dependent protein kinase II, cAMPdependent protein kinase and mitogen-activated protein kinases, and, importantly, protein synthesis and gene expression in the hippocampus. The extinction of fear-potentiated startle requires NMDA receptors and mitogen-activated protein kinases in the basolateral amygdala. The extinction of conditioned taste aversion requires protein synthesis in the insular cortex. Thus, extinction is an active process that involves a variety of molecular events and –at least for the one task in which it was studied— both gene expression and protein synthesis. Insofar as in each of the tasks mentioned, the treatments were studied in a different brain region, therefore, it is still not known whether extinction in general uses those brain areas in parallel, or whether the extinction of each task is metabolically different. A role of endogenous cannabinoids in extinction has been postulated; some evidence indicate that they act on the amygdala, but indirect findings suggest that they may also exert their action in the hippocampus. When carried out using methods that enhance perception that the reinforcement is absent, extinction can be quite profound, and the animals require “de novo” gene expression and protein synthesis in the hippocampus in order to reinstall the original learning. This might be of value in the design of “exposure” therapies for the treatment of phobias and of post-traumatic stress disorders.

[Back to top] Microglial Proteases: Strategic Targets for Neuroprotective Agents

Hiroshi Nakanishi
^{[Full text article]}

There is growing evidence that proteolytic systems of microglia are closely associated with both their protective and cytotoxic roles in the central nervous system (CNS). Cathepsin E and cathepsin S have been shown to play important roles in the major histocompatibility complex (MHC) class II-mediated antigen presentation of microglia. On the other hand, proteasome is required for MHC class-I-mediated antigen presentation of microglia during viral and bacterial infections in the CNS. Several recent studies have suggested an involvement of cathepsin D and insulin-degrading enzyme in the clearance of amyloid-b peptides by microglia. Furthermore, attention has been also paid to the deleterious effects of proteases secreted from microglia. Besides having roles in the endosomal/lysosomal system, cathepsin S and cathepsin B secreted from microglia are also found to be responsible for microglia-induced tissue damage and neuronal death. Tissue-type plasminogen activator secreted from microglia also participates in neuronal death, an enhancement of N-methyl-D-aspartate receptor-mediated synaptic transmission, and an activation of microglia. Calpain has been demonstrated to play a pivotal role in the pathogenesis of multiple sclerosis by degrading myelin proteins extracellulary. Furthermore, matrix metalloproteases secreted from microglia contribute to the cerebrovascular diseases by degrading components of the basal lamina around the cerebral blood vessels.

In this review, I have focused on the proteolytic systems that are associated with the protective and cytotoxic roles of microglia in the CNS. The understanding of proteolytic events mediated by microglial proteases may also aid in the development of protease inhibitors as the novel neuroprotective agents.