Parkinson's disease (PD) is known to be a chronic and progressive neurodegenerative disease caused by a selective degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). A large body of experimental evidence indicates that the factors involved in the pathogenesis of this disease are several, occurring inside and outside the DAergic neuron. Recently, the role of the neuron-glia interaction and the inflammatory process, in particular, has been the object of intense study by the research community. It seems to represent a new therapeutic approach opportunity for this neurological disorder. Indeed, it has been demonstrated that the cyclooxygenase type 2 (COX-2) is upregulated in SNc DAergic neurons in both PD patients and animal models of PD and, furthermore, non-steroidal anti-inflammatory drugs (NSAIDs) pre-treatment protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6 hydroxydopamine (6-OHDA)-induced nigrostriatal dopamine degeneration. Moreover, recent epidemiological studies have revealed that the risk of developing PD is reduced in humans who make therapeutical use of NSAIDs. Consequently, it is hypothesized that they might delay or prevent the onset of PD. However, whether or not these common drugs may also be of benefit to those individuals who already have Parkinson's disease has not as yet been shown.In this paper, evidence relating to the protective effects of aspirin or other NSAIDs on DAergic neurons in animal models of Parkinson's disease will be discussed. In addition, the pharmacological mechanisms by which these molecules can exert their neuroprotective effects will be reviewed. Finally, epidemiological data exploring the effectiveness of NSAIDs in the prevention of PD and their possible use as adjuvants in the therapy of this neurodegenerative disease will also be examined.

A basic tenet in the realm of modern behavioral sciences is that behavior consists of patterns in time. For this reason, investigations of behavior deal with sequences that are not easily perceivable by the unaided observer. This problem calls for improved means of detection, data handling and analysis. This review focuses on the analysis of the temporal structure of behavior carried out by means of a multivariate approach known as T-pattern analysis. Using this technique, recurring sequences of behavioral events, usually hard to detect, can be unveiled and carefully described. T-pattern analysis has been successfully applied in the study of various aspects of human or animal behavior such as behavioral modifications in neuro-psychiatric diseases, route-tracing stereotypy in mice, interaction between human subjects and animal or artificial agents, hormonal–behavioral interactions, patterns of behavior associated with emesis and, in our laboratories, exploration and anxiety-related behaviors in rodents. After describing the theory and concepts of T-pattern analysis, this review will focus on the application of the analysis to the study of the temporal characteristics of behavior in different species from rodents to human beings. This work could represent a useful background for researchers who intend to employ such a refined multivariate approach to the study of behavior

Several recent studies have emphasized a crucial role for the interactions between serotonergic and dopaminergic systems in movement control and the pathophysiology of basal ganglia. These observations are supported by anatomical evidence demonstrating large serotonergic innervation of all the basal ganglia nuclei. In fact, serotonergic terminals have been reported to make synaptic contacts with both substantia nigra dopamine-containing neurons and their terminal areas such as the striatum, the globus pallidus and the subthalamus. These brain areas contain a high concentration of serotonin (5-HT), with the substantia nigra pars reticulata receiving the greatest input. In this chapter, the distribution of different 5-HT receptor subtypes in the basal ganglia nuclei will be described. Furthermore, evidence demonstrating the serotonergic control of basal ganglia activity will be reviewed and the contribution of the different 5-HT receptor subtypes examined. The new avenues that the increasing knowledge of 5-HT in motor control has opened for exploring the pathophysiology and pharmacology of Parkinson's disease and other movement disorders will be discussed. It is clear that these avenues will be fruitful, despite the disappointing results so far obtained by clinical studies with selective 5-HT ligands. Nevertheless, these studies have led to a great increase in the attention given to the neurotransmitters of the basal ganglia and their connections.

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Nicotine is one of the most addictive drugs of abuse. Tobacco smoking is a major cause of many health problems, and is the first preventable cause of death worldwide. Several findings show that nicotine exerts significant aversive as well as the well-known rewarding motivational effects. Less certain is the anatomical substrate that mediates or enables nicotine aversion. Here, we show that acute nicotine induces anxiogenic-like effects in rats at the doses investigated (0.1, 0.5, and 1.0 mg/kg, i.p.), as measured by the hole-board apparatus and manifested in behaviors such as decreased rearing and head-dipping and increased grooming. No changes in locomotor behavior were observed at any of the nicotine doses given. T-pattern analysis of the behavioral outcomes revealed a drastic reduction and disruption of complex behavioral patterns induced by all three nicotine doses, with the maximum effect for 1 mg/kg. Lesion of the lateral habenula (LHb) induced hyperlocomotion and, strikingly, reversed the nicotine-induced anxiety obtained at 1 mg/kg to an anxiolytic-like effect, as shown by T-pattern analysis. We suggest that the LHb is critically involved in emotional behavior states and in nicotine-induced anxiety, most likely through modulation of monoaminergic nuclei.

Since the 1950s, when serotonin (5-HT) was discovered in the mammalian central nervous system (CNS), an enormous amount of experimental evidence has revealed the pivotal role of this biogenic amine in a number of cognitive and behavioural functions. Although 5-HT is synthesized by a small group of neurons within the raphe nuclei of the brain stem, almost all parts of the CNS receive serotonergic projections. Furthermore, the importance of 5-HT modulation and the fine-tuning of its action is underlined by the large number of 5-HT binding sites found in the CNS. Hitherto, up to 15 different 5-HT receptors subtypes have been identified. This review was undertaken to summarize the work that has explored the pathophysiological role of one of these receptors, the 5-HT 2C receptor, that has been emerged as a prominent central serotonin receptor subtype. The physiology, pharmacology and anatomical distribution of the 5-HT 2C receptors in the CNS will be firstly reviewed. Finally, their potential involvement in the pathophysiology of depression, schizophrenia, Parkinson's disease and drug abuse will be also discussed.Keywords: Serotonergic receptors, Depression, Schizophrenia, Drug of abuse, selective 5-HT 2C drugs. BASIC ANATOMY OF 5-HT SYSTEMMore than fifty years have passed since Twarog and Page [1] isolated an indole, identified as serotonin (5-HT), in the mammalian brain. Subsequently, Brodie and colleagues [2] suggested that 5-HT might serve as a neurotransmitter in the central nervous system (CNS). The result was one of the most important discoveries in science, giving birth to a new branch of neuroscience [3]. Serotonin is one of the oldest biologically active compound on earth, found in a variety of plants and animals. In vertebrates, the majority of the neurons containing 5-HT are grouped in 9 nuclei named B1 to B9, located in the medial part of the brainstem, generically called the raphe nuclei [4] (Fig. 1). These midline clusters can be divided into two major groups. The caudal or inferior group, localized in the medulla, contains the three nuclei projecting essentially to the grey matter of the spinal cord: the nucleus raphe magnus (NRM, cell group B5), nucleus raphe obscurus (NRO, cell groups B1-B2-B3), and nucleus raphe pallidus (NRP, cell group B4). The rostral or superior group, situated in the pons/mesenchephalon, contains the dorsal raphe nucleus (DRN, cell groups B6 and B7) and the median raphe nucleus (MRN, cell group B8). These nuclei supply about 80% of the serotonergic innervation of the forebrain. Even if in many brain areas, the innervation coming from the two nuclei overlaps, in certain regions the innervation comes exclusively or prevalently from one nucleus only. For example, the dorsal hippocampus receives a serotonergic innervation only from MRN, other areas innervated preferentially from this nucleus are: the medial preoptic area, the suprachiasmatic nucleus, the olfactory bulb *Address correspondence to this author at the Istituto di Ricerche Farmacologiche "Mario Negri", Consor...

Nicotine, the major psychoactive agent present in tobacco, acts as a potent addictive drug both in humans and laboratory animals, whose locomotor activity is also stimulated. A large body of evidence indicates that the locomotor activation and the reinforcing effects of nicotine may be related to its stimulatory effects on the mesolimbic dopaminergic function. Thus, it is now well established that nicotine can increase in vivo DA outflow in the nucleus accumbens and the corpus striatum. The stimulatory effect of nicotine on DA release most probably results from its ability to excite the neuronal firing rate and to increase the bursting activity of DA neurons in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), and from its stimulatory action on DA terminals in the corpus striatum and the nucleus accumbens. The neurochemical data are consistent with neuroanatomical findings showing the presence of nicotinic acetylcholine receptors (nAChRs) in the SNc, the VTA, and in projection areas of the central dopaminergic system such as the corpus striatum and the nucleus accumbens. Several lines of evidence indicate that the reinforcing properties of drugs of abuse, including nicotine, can be affected by a number of transmitter systems which may act by modulating central dopaminergic function. In this paper, the neurobiological mechanisms underlying nicotine addiction will be reviewed, and the possible strategies for new pharmacological treatments of nicotine dependence will be examined.

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