Current Neuropharmacology - Volume 4, Issue 1, 2006

The identification and cloning of the vanilloid receptor 1 (TRPV1) represented a significant step for the understanding of the molecular mechanisms underlying the transduction of noxious chemical and thermal stimuli by peripheral nociceptors. TRPV1 is a non-selective cation channel gated by noxious heat, vanilloids and extracellular protons. TRPV1 channel activity is remarkably potentiated by pro-inflammatory agents, a phenomenon that is thought to underlie the peripheral sensitisation of nociceptors that leads to thermal hyperalgesia. Cumulative evidence is building a strong case for the involvement of this receptor in the etiology of both peripheral and visceral inflammatory pain, such as inflammatory bowel disease, bladder inflammation and cancer pain. The validation of TRPV1 receptor as a key therapeutic target for pain management has thrust intensive drug discovery programs aimed at developing orally active antagonists of the receptor protein. Nonetheless, the real challenge of these drug discovery platforms is to develop antagonists that preserve the physiological activity of TRPV1 receptors while correcting over-active channels. This is a condition to ensure normal pro-prioceptive and nociceptive responses that represent a safety mechanism to prevent tissue injury. Recent and exciting advances in the function, dysfunction and modulation of this receptor will be the focus of this review.

Similar to patients with orbitofrontal cortex lesions, substance dependent individuals (SDI) show signs of impairments in decision-making, characterised by a tendency to choose the immediate reward at the expense of severe negative future consequences. The somatic-marker hypothesis proposes that decision-making depends in many important ways on neural substrates that regulate homeostasis, emotion and feeling. According to this model, there should be a link between abnormalities in experiencing emotions in SDI, and their severe impairments in decision-making in real-life. Growing evidence from neuroscientific studies suggests that core aspects of substance addiction may be explained in terms of abnormal emotional guidance of decision-making. Behavioural studies have revealed emotional processing and decision-making deficits in SDI. Combined neuropsychological and physiological assessment has demonstrated that the poorer decision-making of SDI is associated with altered reactions to reward and punishing events. Imaging studies have shown that impaired decision-making in addiction is associated with abnormal functioning of a distributed neural network critical for the processing of emotional information, including the ventromedial cortex, the amygdala, the striatum, the anterior cingulate cortex, and the insular/somato-sensory cortices, as well as non-specific neurotransmitter systems that modulate activities of neural processes involved in decision-making. The aim of this paper is to review this growing evidence, and to examine the extent of which these studies support a somatic-marker model of addiction.

Status epilepticus (SE) is a major medical emergency associated with significant morbidity and mortality. SE is best defined as a continuous, generalized, convulsive seizure lasting > 5 min, or two or more seizures during which the patient does not return to baseline consciousness. The relative efficacy and safety of different drugs in the treatment of human SE should be determined in a prospective, randomized, blinded study. However, complementary animal models of SE are required to answer important questions concerning the treatment of SE because of the obvious difficulties of setting up such studies in clinical emergency conditions. This review offers an overview of the implementation and characteristics of some of the most prevalent animal models of SE currently in use. A description is also provide about how animal models of SE may facilitate the use of neurobiological techniques to successfully address critical questions in the drug treatment of SE. In particular, the experience with recently introduced drugs such as intravenous valproate will be addressed. Finally, the importance of some animal models and pharmacological approaches is explained and we discuss their impact in the development of therapeutic strategies to improve pharmacological treatment for SE is discussed.

Prostaglandins, in particular PGE2 and prostacyclin PGI2, have diverse biological effects. Most importantly, they are involved in inflammation and pain. Prostaglandins in nano- and micromolar concentrations sensitize nerve cells, i.e. make them more sensitive to electrical or chemical stimuli. Sensitization arises from the effect of prostaglandins on ion channels and occurs both at the peripheral terminal of nociceptors at the site of tissue injury (peripheral sensitization) and at the synapses in the spinal cord (central sensitization). The first step is the binding of prostaglandins to receptors in the cell membrane, mainly EP and IP receptors. The receptors couple via G proteins to enzymes such as adenylate cyclase and phospholipase C (PLC). Activation of adenylate cyclase leads to increase of cAMP and subsequent activation of protein kinase A (PKA) or PKA-independent effects of cAMP, e.g. mediated by Epac (=exchange protein activated by cAMP). Activation of PLC causes increase of inositol phosphates and increase of cytosolic calcium. This article summarizes the effects of PGE2, PGE1, PGI2 and its stable analogues on non-selective cation channels and sodium, potassium, calcium and chloride channels. It describes the mechanism responsible for the facilitatory or inhibitory prostaglandin effects on ion channels. Understanding these mechanisms is essential for the development of useful new analgesics.

Schizophrenia has been associated with a dysfunction of brain dopamine (DA). This, so called, DA hypothesis has been refined as new insights into the pathophysiology of schizophrenia have emerged. Currently, dysfunction of prefrontocortical glutamatergic and GABAergic projections and dysfunction of serotonin (5-HT) systems are also thought to play a role in the pathophysiology of schizophrenia. Refinements of the DA hypothesis have lead to the emergence of new pharmacological targets for antipsychotic drug development. It was shown that effective antipsychotic drugs with a low liability for inducing extra-pyramidal side-effects have affinities for a range of neurotransmitter receptors in addition to DA receptors, suggesting that a combination of neurotransmitter receptor affinities may be favorable for treatment outcome. This review focuses on the interaction between DA and 5-HT, as most antipsychotics display affinity for 5-HT receptors. We will discuss DA/5-HT interactions at the level of receptors and G protein-coupled potassium channels and consequences for induction of depolarization blockade with specific attention to DA neurons in the ventral tegmental area (VTA) and the substantia nigra zona compacta (SN), neurons implicated in treatment efficacy and the side-effects of schizophrenia, respectively. Moreover, it has been reported that electrophysiological interactions between DA and 5-HT show subtle, but important, differences between the SN and the VTA which could explain (in part) the effectiveness and lower propensity to induce side-effects of the newer atypical antipsychotic drugs. In that respect the functional implications of DA/5-HT interactions for schizophrenia will be discussed.

Current knowledge of the pathogenesis of basal ganglia disorders, such as Huntington's disease (HD) and Parkinson's disease (PD) appoints a central role to a dysfunction in mitochondrial metabolism. The development of animal models, based upon the use of mitochondrial toxins has been successfully introduced to reproduce human disease, leading to important acquisitions. Most notably, experimental evidence supports the existence, within basal ganglia, of a peculiar regional vulnerability to distinct mitochondrial toxins. MPTP and rotenone, both selective inhibitors of mitochondrial complex I have been extensively used to mimic PD. Accordingly, in human PD, a specific dysfunction of complex I activity was found in vulnerable dopaminergic neurons of the substantia nigra. Conversely, in HD a selective impairment of mitochondrial succinate dehydrogenase, key enzyme in complex II activity was found in medium spiny neurons of the caudate-putamen. The relevance of such finding is further demonstrated by the evidence that toxins able to primarily target mitochondrial complex II, such as malonic acid and 3-nitropropionic acid (3-NP), strikingly reproduce the main phenotypic and pathological features of HD. Despite the advances obtained from these experimental models, a deeper understanding of the molecular and cellular mechanisms underlying such neuronal vulnerability is lacking. The present review provides a brief survey of currently utilized animal models of mitochondrial intoxication, in attempt to address the cellular mechanisms triggered by energy metabolism failure and to identify potential therapeutic targets.

The trafficking of ionotropic glutamate (AMPA, NMDA and kainate) and GABAA receptors in and out of, or laterally along, the postsynaptic membrane has recently emerged as an important mechanism in the regulation of synaptic function, both under physiological and pathological conditions, such as information processing, learning and memory formation, neuronal development, and neurodegenerative diseases. Non-ionotropic glutamate receptors, primarily group I metabotropic glutamate receptors (mGluRs), co-exist with the postsynaptic ionotropic glutamate and GABAA receptors. The ability of mGluRs to regulate postsynaptic phosphorylation and Ca2+ concentration, as well as their interactions with postsynaptic scaffolding/signaling proteins, makes them well suited to influence the trafficking of ionotropic glutamate and GABAA receptors. Recent studies have provided insights into how mGluRs may impose such an influence at central synapses, and thus how they may affect synaptic signaling and the maintenance of long-term synaptic plasticity. In this review we will discuss some of the recent progress in this area: i) long-term synaptic plasticity and the involvement of mGluRs; ii) ionotropic glutamate receptor trafficking and long-term synaptic plasticity; iii) the involvement of postsynaptic group I mGluRs in regulating ionotropic glutamate receptor trafficking; iv) involvement of postsynaptic group I mGluRs in regulating GABAA receptor trafficking; v) and the trafficking of postsynaptic group I mGluRs themselves.

Phospholipase A2 (PLA2), cyclooxygenase (COX) and prostaglandin (PG) synthase are enzymes involved in arachidonate cascade. PLA2 liberates arachidonic acid (AA) from cell membrane lipids. COX oxidizes AA to PGG2 followed by an endoperoxidase reaction that converts PGG2 into PGH2. PGs are generated from astrocytes, microglial cells and neurons in the central nervous system, and are altered in the brain of demented patients. Dementia is principally diagnosed into Alzheimer's disease (AD) and vascular dementia (VaD). In older patients, the brain lesions associated with each pathological process often occur together. Regional brain microvascular abnormalities appear before cognitive decline and neurodegeneration. The coexistence of AD and VaD pathology is often termed mixed dementia. AD and VaD brain lesions interact in important ways to decline cognition, suggesting common pathways of the two neurological diseases. Arachidonate cascade is one of the converged intracellular signal transductions between AD and VaD. PLA2 from mammalian sources are classified as secreted (sPLA2), Ca2+-dependent, cytosolic (cPLA2) and Ca2+-independent cytosolic PLA2 (iPLA2). PLA2 activity can be regulated by calcium, by phosphorylation, and by agonists binding to Gprotein- coupled receptors. cPLA2 is upregulalted in AD, but iPLA2 is downregulated. On the other hand, sPLA2 is increased in animal models for VaD. COX-2 is induced and PGD2 are elevated in both AD and VaD. This review presents evidences for central roles of PLA2s, COXs and PGs in the dementia.