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Review Article

Functional Pharmacology in Human Brain

Dipartimento di Medicina Sperimentale, Sezione di Farmacologia e Tossicologia and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genoa, Italy

Abstract

I. Introduction

II. Cholinergic Receptors

A. Norepinephrine Release Regulation by Nicotinic Receptors

B. Nicotinic alpha7 Receptors and Glutamate Release

C. Nicotinic Autoreceptors

III. Adrenergic Receptors

A. Norepinephrine Release Regulation through Autoreceptors

IV. Dopamine Receptors and Transporters

A. Dopamine Autoreceptors

B. Drugs of Abuse and Dopamine Release

C. Drugs of Abuse and Dopamine Transporters

V. Serotoninergic Receptors

A. Release of Serotonin and Control by Human 5-Hydroxytryptamine 1B Autoreceptors

B. Glutamate Release and Modulation by Human 5-Hydroxytryptamine 1D Receptors

C. Pharmacological Diversity between Human 5-Hydroxytryptamine 1B and Human 5-Hydroxytryptamine 1D Receptors

D. GABA Release and Modulation by 5-Hydroxytryptamine

E. Serotonin Inhibition of the N-Methyl-D-aspartate Receptor/Nitric Oxide/Cyclic GMP Pathway

VI. GABA Receptors

A. GABAB Receptor Subtypes: Pharmacological Evidence

1. GABAB Autoreceptors.

2. GABAB Heteroreceptors Regulating Neuropeptide Release.

3. GABAB Heteroreceptors Regulating Glutamate Release.

4. The Mystery of GABAB Receptor Subtypes.

VII. Glutamatergic Receptors

A. Metabotropic Glutamate Receptors

1. Phosphatidylinositol Turnover.

2. Release of Acetylcholine.

B. N-Methyl-D-aspartate Glutamate Receptors

1. Release of Norepinephrine.

2. The ''Kynurenate Test.''

VIII. Neuropeptide Receptors

A. Release of Acetylcholine Mediated by Opioid Receptors

B. Release of Norepinephrine Mediated by Opioid Receptor-Like 1 Receptors

IX. Cannabinoids and Cannabinoid Receptors

A. Release of Norepinephrine

B. Release of GABA

C. Release of Acetylcholine

D. Release of Dopamine

X. Calcium Channels and Intraterminal Calcium Pools

A. Voltage-Sensitive Calcium Channels

1. Influx of Calcium and Norepinephrine Release.

2. Influx of Calcium and Nitric-Oxide Synthase Activity.

B. Calcium Pools and Dopamine Release

XI. Neurotransmitters in the Alzheimer's Brain

A. Functional Studies of Alzheimer's Brain Antemortem

1. The Cholinergic System.

2. The Monoaminergic Systems.

3. Somatostatin.

XII. Epilepsy: In Vitro and in Vivo Studies

A. The GABA and Glutamate Systems in Epilepsy

1. GABA and Glutamate Receptors: Electrophysiological Studies.

2. In Vivo Microdialysis in Epileptic Patients: Glutamate/GABA Release and GABA Transporters.

3. The Glutamate-Glutamine Cycling in Epilepsy.

B. Calcium Channels and Epilepsy

XIII. Brain Ischemia and Traumatic Injury

A. Glutamate Release during Ischemia

1. Mechanisms of Release.

2. Glutamate Release and Adenosine A2A Receptors.

3. Glutamate Release and 5-Hydroxytryptamine Receptors.

B. Glutamatergic Transmission following Brain Injury: In Vivo Microdialysis Studies

XIV. Effects of HIV-1 Proteins

A. Activation of Glutamate N-Methyl-D-aspartate Receptors by gp120

B. Activation of Glutamate Metabotropic Receptors by Tat

XV. Parkinson's Disease: In Vivo Microdialysis Studies

XVI. Conclusions

Most neurological and psychiatric disorders involve selective or preferential impairments of neurotransmitter systems. Therefore, studies of functional transmitter pathophysiology in human brain are of unique importance in view of the development of effective, mechanism-based, therapeutic modalities. It is well known that central nervous system functional proteins, including receptors, transporters, ion channels, and enzymes, can exhibit high heterogeneity in terms of structure, function, and pharmacological profile. If the existence of types and subtypes of functional proteins amplifies the possibility of developing selective drugs, such heterogeneity certainly increases the likelihood of interspecies differences. It is therefore essential, before choosing animal models to be used in preclinical pharmacology experimentation, to establish whether functionally corresponding proteins in men and animals also display identical pharmacological profiles. Because of evidence that scaffolding proteins, trafficking between plasma membrane and intracellular pools, phosphorylation and allosteric modulators can affect the function of receptors and transporters, experiments with human clones expressed in host cells where the environment of native receptors is rarely reproduced should be interpreted with caution. Thus, the use of neurosurgically removed fresh human brain tissue samples in which receptors, transporters, ion channels, and enzymes essentially retain their natural environment represents a unique experimental approach to enlarge our understanding of human brain processes and to help in the choice of appropriate animal models. Using this experimental approach, many human brain functional proteins, in particular transmitter receptors, have been characterized in terms of localization, function, and pharmacological properties.

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