Current Neuropharmacology - Volume 1, Issue 2, 2003

Depression and schizophrenia are major psychiatric disorders. Recently it has been documented that these diseases are characterized by deficits and / or loss of neurons in specific brain regions. Nerve growth factor and brainderived neurotrophic factor are endogenous biological mediators involved in neuronal survival and plasticity of dopaminergic, cholinergic, and serotonergic neurons in the central nervous system. Structural, biochemical, and molecular findings led to the hypothesis that these molecules play a role in the pathophysiology of psychiatric disorders and suggested that alterations in expression of neurotrophic factors could be responsible for neural maldevelopment and disturbed neural plasticity both in young, adult and aged subjects. Studies aimed at understanding the mechanisms regulating these events might be an important line of research for analyzing the etiopathogenesis of psychiatric disorders and eventually identifying new methods for diagnosis and new therapeutic strategies.

Lipid peroxidation is one of the major outcomes of free radical-mediated injury to tissue that directly damages membranes and generates a number of secondary biologically active products. This occurs through fragmentation and rearrangement of oxygenated fatty acids that act via modification of macromolecules and activation of cell surface receptors. Numerous studies have demonstrated regionally increased brain lipid peroxidation in patients who have suffered acute brain injury from trauma or cerebrovascular disease as well as patients with protracted neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and human immunodeficiency virus-associated dementia. Recent studies have progressed from determining biomarkers of lipid peroxidation in tissue obtained post mortem to measuring levels in body fluids from living patients early in the course of disease. Elevated biomarkers of lipid peroxidation early in disease establish it as a potential therapeutic target and provide a novel method for following disease progression and response to therapy. Strategies for limiting the deleterious effects of lipid peroxidation include pharmacologic intervention at several points. We will present recent results from our laboratory on some of these therapeutic targets. Continuing development of pharmacologic targets and therapeutic interventions in experimental models of neurodegenerative diseases that include oxidative damage to brain may lead to effective interventions for this facet of neurodegeneration.

Stroke is the third leading cause of death after cancer and heart disease. Although great strides have been made in our understanding of the mechanisms that contribute to stroke pathology, effective pharmacological interventions for the millions of people annually affected by this disease is minimal. The only available treatment is tissue plasminogen activator (tPA) which promotes reperfusion of the ischaemic area, but the high associated risk of bleeding and short effective window have severely limited its use. Historically, much research to identify new therapeutics for the treatment of stroke has focussed on the mechanisms that promote cell death within the brain during and immediately after the traumatic event. Drugs that disrupt these mechanisms and thereby prevent cellular damage in animal stroke models have, unfortunately, proven disappointing in the clinic. A potentially more effective way of managing patients would be to target events that contribute both to the cellular damage and the tissue repair that occurs some time after the initial trauma. This review describes our current understanding of the mechanisms involved in later stage damage and, particularly, those processes that contribute to cellular and, therefore, functional recovery within injured areas of the brain. Potential strategies for exploiting these processes to achieve better and faster recovery of the patient will then be discussed.

Central serotonergic, and dopaminergic systems play a critical role in the regulation of normal and abnormal behaviors. Recent evidence suggests that a dysfunction of dopamine (DA) and serotonin (5-HT) neurotransmitter systems contribute to various pathological conditions. Among the multiple classes of 5-HT receptors described in the central nervous system, much attention has been devoted to the role of 5-HT2 receptor family in the control of central dopaminergic activity, because of the moderate to dense localization of both transcript and protein for 5-HT2A and 5-HT2C receptors in the substantia nigra (SN) and ventral tegmental area (VTA), as well as their terminal regions. Moreover, modulation of 5-HT2 receptor functions by various drugs has been shown to influence DA function in these brain areas, and is thought to be important in motor activation, motivation, and reward. Indeed, a number of electrophysiological and biochemical data have shown that 5-HT2C receptor agonists decrease, while 5-HT2C receptor antagonists enhance mesocorticolimbic DA function. In this article, the most relevant data regarding the role of these receptors in the control of brain DA function are reviewed, and the importance of this subject in the search of new therapies for neuropsychiatric disorders, such as depression, schizophrenia, drug addiction, and Parkinson's disease is also discussed.

Drug addiction is characterized by loss of control over drug consumption, with compulsive drug seeking and taking, despite obvious adverse consequences. It is a chronic brain disorder since the increased risk of relapse to active drug use remains high even after years of abstinence. Current research attempts to identify the cellular and molecular basis for the neuronal modifications underlying these complex behavioural alterations. Strong evidence indicates that the extracellular signal-regulated kinase (ERK) pathway is a conserved intracellular signalling module, critical for various types of learning and synaptic plasticity. Recent results show that drugs of abuse activate this pathway in the brain regions important for reward-controlled learning and addiction. Moreover, pharmacological and genetic approaches support a role of the ERK pathway in some of the long-term effects of addictive drugs. We suggest that drug-induced stimulation of the ERK pathway by dopamine in specific brain areas may be an exaggeration of its normal role in learning controlled by reward, and may contribute significantly to the acquisition of specific behaviours characteristic of drug addiction.

Behavioral studies in animals are an important part of neuropharmacological research, because they integrate findings from in vitro pharmacology, chemical neuroanatomy and electrophysiology at the system's level, thereby bridging the gap between basic research on one hand, and the development of pharmacological treatment with clinical trials on the other hand. Animal behavioral models of neuropsychiatric diseases (such as fear/anxiety disorders, depression, addiction, or schizophrenia) are, therefore, an eminent part of preclinical neuropharmacology. We review here recent neuropharmacological findings on prepulse inhibition (PPI) and fear-potentiation of the startle response (FPS) as behavioral models for sensorimotor gating deficits in neuropsychiatric disorders and fear/anxiety-related disorders, respectively.