Littérature scientifique sur le sujet « Orexinergic system »

To know the processes involved in feeding, the dysregulation of hypothalamic neuropeptides promoting anorexigenic/orexigenic mechanisms must be investigated. Many neuropeptides are involved in this behavior and in overweight/obesity. Current pharmacological strategies for the treatment of obesity are unfortunately not very effective and, hence, new therapeutic strategies must be investigated and developed. Due to the crucial role played by orexins in feeding behavior, the aim of this review is to update the involvement of the orexinergic system in this behavior. The studies performed in experimental animal models and humans and the relationships between the orexinergic system and other substances are mentioned and discussed. Promising research lines on the orexinergic system are highlighted (signaling pathways, heterogeneity of the hypothalamic orexinergic neurons, receptor-receptor interaction, and sex differences). Each of the orexin 1 and 2 receptors plays a unique role in energy metabolism, exerting a differential function in obesity. Additional preclinical/clinical studies must be carried out to demonstrate the beneficial effects mediated by orexin receptor antagonists. Because therapies applied are in general ineffective when they are directed against a single target, the best option for successful anti-obesity treatments is the development of combination therapies as well as the development of new and more specific orexin receptor antagonists.

Orexin A and orexin B are hypothalamic peptides that act on their targets via two G protein-coupled receptors (OX1 and OX2 receptors). In the central nervous system, the cell bodies producing orexins are localized in a narrow region within the lateral hypothalamus and project mainly to regions involved in feeding, sleep, and autonomic functions. Via putative pre- and postsynaptic effects, orexins increase synaptic activity in these regions. In isolated neurons and cells expressing recombinant receptors orexins cause Ca2+ elevation, which is mainly dependent on influx. The activity of orexinergic cells appears to be controlled by feeding- and sleep-related signals via a variety of neurotransmitters/hormones from the brain and other tissues. Orexins and orexin receptors are also found outside the central nervous system, particularly in organs involved in feeding and energy metabolism, e.g., gastrointestinal tract, pancreas, and adrenal gland. In the present review we focus on the physiological properties of the cells that secrete or respond to orexins.

The present immunohistochemical study represents a detailed spatiotemporal analysis of the localization of orexin-immunoreactive (OX-ir) cells and fibers throughout development in the brain of the anuran amphibian Xenopus laevis, a model frequently used in developmental studies. Anurans undergo remarkable physiological changes during the early life stages, and very little is known about the ontogeny and the localization of the centers that control functions such as appetite and feed ingestion in the developing brain. We examined the onset of the orexinergic system, demonstrated to be involved in appetite regulation, using antibodies against mammalian orexin-A and orexin-B peptides. Simultaneous detection of orexins with other territorial markers was used to assess the precise location of the orexinergic cells in the hypothalamus, analyzed within a segmental paradigm. Double staining of orexins and tyrosine hydroxylase served to evaluate possible interactions with the catecholaminergic systems. At early embryonic stages, the first OX-ir cells were detected in the hypothalamus and, soon after, long descending projections were observed through the brainstem to the spinal cord. As brain development proceeded, the double-staining techniques demonstrated that this OX-ir cell group was located in the suprachiasmatic nucleus within the alar hypothalamus. Throughout larval development, the number of OX-ir cells increased notably and a widespread fiber network that innervated the main areas of the forebrain and brainstem was progressively formed, including innervation in the posterior tubercle and mesencephalon, the locus coeruleus, and the nucleus of the solitary tract where catecholaminergic cells are present. In addition, orexinergic cells were detected in the preoptic area and the tuberal hypothalamus only at late prometamorphic stages. The final distribution pattern, largely similar to that of the adult, was achieved through metamorphic climax. The early expression of orexins in Xenopus suggests important roles in brain development in the embryonic period before feeding, and the progression of the temporal and spatial complexity of the orexinergic system might be correlated to the maturation of appetite control regulation, among other functions.

Orexins, or hypocretins, are excitatory neuropeptides involved in the regulation of feeding behavior and the sleep and wakefulness states. Since their discovery, several lines of evidence have highlighted that orexin neurons regulate a great range of physiological functions, giving it the definition of a multitasking system. In the present review, we firstly describe the mechanisms underlining the orexin system and their interactions with the central nervous system (CNS). Then, the system’s involvement in goal-directed behaviors, sleep/wakefulness state regulation, feeding behavior and energy homeostasis, reward system, and aging and neurodegenerative diseases are described. Advanced evidence suggests that the orexin system is crucial for regulating many physiological functions and could represent a promising target for therapeutical approaches to obesity, drug addiction, and emotional stress.

Il sistema di regolazione ascendente è costituito da diversi nuclei situati nel tronco cerebrale, nel prosencefalo basale e nell'ipotalamo. Questi nuclei regolano l'eccitazione, gli stati attentivi e coscienti, nonché l’attivazione autonomica. Il sistema di regolazione ascendente agisce a tutte le scale temporali e questi livelli di controllo sono raggiunti attraverso una varietà di meccanismi d'azione dei neurotrasmettitori, con diversi tempi e durate. Qualsiasi alterazione del sistema modulatorio ascendente può influire sulla sua capacità di generare i ritmi e quindi influenzare la regolazione e la stabilità del sonno/veglia e gli stati comportamentali, così come la cognizione. Le due malattie che ho studiato sono: l'epilessia ipermotoria correlata al sonno autosomica dominante (ADSHE), spesso legata a disfunzione colinergica, e la narcolessia con cataplessia (NC), causata da carenza di oressina. Sia l'ADSHE che la narcolessia possono essere definite ritmopatie, poiché i loro sintomi distintivi sono disfunzioni del ritmo dell'attività cerebrale. In questa tesi, ho caratterizzato le alterazioni funzionali dei recettori nicotinici dell'acetilcolina (nAChR) contenenti subunità α2 mutanti legate all'ADSHE o all’epilessia del lobo temporale laterale autosomico dominante. Le mutazioni hanno causato una perdita di funzione del canale suggerendo che le mutazioni su CHRNA2 sono più comunemente legate a sindromi epilettiche di quanto si pensasse in precedenza. Abbiamo studiato le alterazioni morfo-funzionali nello strato V della corteccia prefrontale di topi che esprimono la subunità β2V287L legata all'ADSHE. La sua espressione era correlata ad alterazioni morfologiche nella ramificazione dendritica dei neuroni piramidali, nonché a una diminuzione del 10% circa dello spessore della corteccia. I topi mutanti hanno mostrato correnti nicotiniche somatiche più grandi negli interneuroni SOM+ regular spiking insensibili alla serotonina (in gran parte cellule di Martinotti). Ciò può spiegare perché le convulsioni possono essere facilitate dal basso tono colinergico tipico del sonno NREM e perché la somministrazione di nicotina può essere palliativa nei pazienti. Ho dimostrato l'efficace eliminazione di Ox2R nei topi Ox2R-Δ, creati da Anne Vassalli. Ho anche valutato se i topi Ox2R-flox avessero un Ox2R funzionalmente equivalente ai topi di controllo C57BL6/J. Le risposte agli agonisti Ox2R dei neuroni istaminergici del nucleo tuberomammillare dell'ipotalamo hanno confermato questo modello murino come uno strumento affidabile per sezionare la funzione specifica di Ox2R nei circuiti cerebrali. Abbiamo studiato la modulazione Orx del microcircuito in Fr2 e PFC mediale. Le EPSC sono stimolate da OrxA sui neuroni piramidali dello strato V. L'effetto è mediato da Ox1Rs e dipende da un meccanismo presinaptico che coinvolge meccanismi indipendenti e dipendenti dal canale CaV. OrxB esercita un effetto combinato su Ox2Rs e Ox1Rs, producendo un effetto inibitorio. Ox2R ha un distribuzione diffusa sui corpi cellulari e nel neuropilo, e l'analisi di colocalizzazione ha mostrato un'innervazione oressinergica più densa degli interneuroni SOM+ GABAergici, rispetto alle cellule PV+ e una maggiore espressione di Ox2R sui neuroni SOM+. Questi interneuroni contribuiscono alla generazione del ritmo θ nella neocorteccia e nell'ippocampo, quindi le oressine potrebbero regolare la ritmogenesi θ nella PFC. Infine, abbiamo studiato le ragioni dell'aumentata eccitabilità della via VTA-septo-ippocampale mostrata dai topi Ox2RDat-CKO. Ciò potrebbe essere dovuto a una specifica regolazione Ox2R-dipendente dei neuroni VTADA, probabilmente a valle di quelli VTADA: quando la sensibilità all'oressina Ox2R-dipendente dei neuroni VTADA è compromessa, le cellule VTADABA non sono più in grado di bloccare l’attività θ intrinseca in ippocampo, sia attraverso l'attivazione di VTADA che attraverso un altro meccanismo sconosciuto.
The brain ascending regulatory system is a complex of interconnected neuronal nuclei of different neurochemical nature, located in the brainstem, basal forebrain and hypothalamus. These nuclei regulate arousal, attentive and conscious states as well as in the autonomic state regulation. The brain ascending regulatory system acts at all scales in the brain and these levels of control are achieved through a variety of neurotransmitters’ mechanisms of action, having different time lags and durations. Any defect or alteration of the brain ascending modulatory system may impact on its ability to generate and sustain rhythms and thus affect the regulation and stability of sleep/wake and behavioural states, as well as cognition. The two diseases I have studied are of this kind: Autosomal Dominant Sleep-related Hypermotor Epilepsy (ADSHE), often linked to cholinergic dysfunction, and narcolepsy with cataplexy (NC), caused by orexin deficiency. Both ADSHE and narcolepsy can be defined as rhythmopaties, since their defining symptoms are dysfunctions of brain activity rhythm. In this thesis, I characterized the functional alterations of nicotinic acetylcholine receptors (nAChRs) containing mutant α2 subunits linked to ADSHE or Autosomal Dominant Lateral Temporal Lobe Epilepsy. The mutations caused a loss-of-function of the channel suggesting that CHRNA2-affecting mutations are more commonly linked to epileptic syndromes than previously thought, especially loss-of-function ones. We also studied the morpho-functional alterations in the prefrontal cortex layer V of mice conditionally expressing the ADSHE-linked β2V287L subunit. Its expression was correlated to minor morphological alterations in pyramidal neurons’ dendritic ramification, as well as to a ~10% decrease of prefrontal cortex thickness. Mutant mice showed larger somatic nicotinic currents in regular spiking SOM+ interneurons insensitive to serotonin (largely Martinotti cells). These results may explain why seizures may be facilitated by the low cholinergic tone typical of NREM sleep and why nicotine administration can be palliative in patients. I demonstrated the effective deletion of Ox2R in the Ox2R-Δ mice, created by Dr. Anne Vassalli. I also assessed if the Ox2R-flox mice had functionally equivalent Ox2R as C57BL6/J control mice. The responses to Ox2R agonists of the classical Ox2R-expressing neuronal type – the histaminergic neurons of the ventral tuberomammillary nucleus of the hypothalamus – confirmed this mouse model as a reliable tool to dissect the specific function of Ox2R in the cerebral circuits. We studied the Orx modulation of pyramidal and interneuronal microcircuits of Fr2 and medial PFC. OrxA stimulated EPSCs on layer V pyramidal neurons. The effect is mainly mediated by Ox1Rs and depends on a presynaptic mechanism involving CaV channel-dependent and independent mechanisms. OrxB exerts a combined effect on Ox2Rs and Ox1Rs, producing an inhibitory effect that is reverse compared to that of the activation of Ox2Rs or Ox1Rs alone. Immunocytochemistry showed a diffuse Ox2R distribution on both cell bodies and neuropil and colocalization analysis showed a denser orexinergic innervation of SOM+ GABAergic interneurons, as compared to PV+ cells; a higher expression of Ox2R on SOM+ neurons. These interneurons have been shown to contribute to the generation of θ band rhythm in the neocortex and hippocampus, so orexins could regulate θ rhytmogenesis in the PFC. Finally, we investigated the reasons of the increased excitability of the VTA-septo-hippocampal pathway shown by Ox2RDat-CKO mice. Our data suggest that it may be due to a specific Ox2R-dependent regulation of VTADA neurons, probably downstream of VTAGABA ones: when the Ox2R-dependent orexin sensitivity of VTADA neurons is impaired, the VTAGABA cells are no longer able to block the intrinsic θ-resonant hippocampal activity, either through VTADA activation or via another unknow mechanism.

Neurons which release the orexins (OX)/hypocretins peptides and are located in the lateral hypothalamus (LH) are key regulators of energy metabolism, arousal and sleep-wake stability, motivated behaviors. This thesis presents three data sets focused on the synaptic wiring of OX-A cell bodies in relation to state-dependent behavior in mice. The first study (Chapter 2; Laperchia et al. 2017) tested the hypothesis of synaptic plasticity phenomena of OX soma innervation in basal conditions. Adult mice were sacrificed during day or night periods in which sleep or wake predominance, respectively, were assessed by electroencephalography in matched mice. Excitatory and inhibitory terminals on OX somata were evaluated with multiple immunofluorescence. The total number of these terminals did not vary between day and night, but glutamatergic terminals prevailed at night and GABAergic ones at daytime. The findings thus revealed a striking daily fluctuation in the axosomatic wiring of OX neurons, with a switch from prevalent excitatory innervation during wake to prevalent inhibitory innervation during sleep. An addendum to Chapter 2 presents methodological approaches to the analysis of astrocytes surrounding OX neurons, at day and night time points in antiphase as above, and preliminary observations. The second study (Chapter 3) tested the hypotheses that the above diurnal fluctuation could be altered during aging and in the pathology that characterizes Alzheimer's disease (AD). The same paradigm and approaches of the first study were applied to 3 month-old and 20 month-old TASTPM mice, which provide a model of AD and in which main pathological features were investigated, and to matched wild-type (WT) mice. The day/night fluctuation in the inhibitory/excitatory wiring of OX somata was replicated in young WT and TASTPM mice, but was lost in aged WT mice and TASTPM mice. In addition, an overall decrease of presynaptic terminals on OX cell bodies was found in aged WT and TASTPM mice vs young ones, and in TASTPM mice vs WT ones (all sampled during daytime). In 15 month-old TASTPM mice stereological OX cell counts revealed significant loss (34% decrease), and densitometric evaluation showed a significant enhancement OX immunosignal intensity, suggesting a potential compensatory increase of peptide synthesis. The third study (Chapter 4) tested the hypothesis that extracellular matrix (ECM) components, reported to be among the players regulating neural plasticity, could be involved in the daily reorganization of OX cell body wiring. The study was conducted in healthy mice and in a murine model of the parasitic encephalitis African trypanosomiasis or sleeping sickness. The ECM was labelled by Wisteria floribunda agglutinin (WFA) immunofluorescence. Marked day/night variations were observed in confocal microscopy, with a diffuse ECM distribution at daytime, and a more compact organization and condensation around OX cell bodies at night. Furthermore, WFA expression in the LH, evaluated with Western blotting, was significantly enhanced at night compared to day. This diurnal variation of ECM organization was not found in other brain areas (suprachiasmatic nucleus, neocortex, hippocampus), and was lost in the LH after African trypanosome infection. These findings indicate regional day/night fluctuation of the ECM in the LH, and its disruption in a chronic neuroinflammatory pathology which leads to sleep-wake dysregulation.

Alterazioni acute o croniche dello stato energetico provocano cambiamenti negli equilibri tra trasmissione sinaptica eccitatoria ed inibitoria e nella plasticità sinaptica ad essi associata, favorendo l'adattamento del metabolismo energetico alle nuove esigenze omeostatiche. L'impatto di tali cambiamenti, in particolare durante l'obesità, sul segnale degli endocannabinoidi sui recettori CB1, uno dei principali modulatori della trasmissione sinaptica, e uno dei target per i farmaci anti-obesità, non è ben compreso. Gli endocannabinoidi stimolano l'assunzione di cibo e la loro sintesi e rilascio aumentano dopo deprivazione di cibo, inducendo così l'attivazione dei recettori CB1. In particolare i livelli di endocannabinoidi aumentano nell'ipotalamo e nel sangue durante brevi periodi di digiuno (1, 2) e diminuiscono in seguito a somministrazione di leptina e dopo assunzione di cibo (3, 4). Topi con riduzione dei segnali della leptina (topi db/db che esprimono un recettore difettoso della leptina), con carenza di leptina (ob/ob), e con resistenza alla leptina (resistenza acquisita a causa dell’ obesità indotta da dieta, topi HFD) presentano elevati livelli di endocannabinoidi nell'ipotalamo e nel tessuto adiposo (5). Lavori recenti mostrano che la leptina modula anche la crescita degli assoni e la plasticità sinaptica nell'ipotalamo (6,7). In particolare, la leptina incrementa l’estensione degli assoni nel Nucleo Arcuato durante lo sviluppo perinatale del topo, svolgendo così un ruolo trofico all'interno di quei circuiti che saranno oggetto delle azioni fisiologiche della leptina nella vita adulta (6). La leptina può anche agire sui neuroni sintetizzanti Orexina (OX) dell'ipotalamo laterale, i quali inviano proiezioni diffuse al cervello (8) svolgendo un ruolo integrativo strategico nell'alimentazione. La leptina sopprime l'attività dei neuroni OX, la loro biosintesi o entrambi. Inoltre, un antagonista selettivo del recettore OX1R riduce l’assunzione di cibo e diminuisce l’obesità in topi ob/ob (9), suggerendo che la carenza di leptina, almeno in parte, attiva il patway dell’orexina per aumentare l'assunzione di cibo. D'altra parte, il pretrattamento con dosi sub-efficaci di rimonabant, un antagonista selettivo del CB1, attenua l’azione oressigenica dell’OX (10), mentre dati elettrofisiologici sostengono un ruolo inibitorio dei cannabinoidi sui neuroni orexinergici in condizioni fisiologiche (11). Partendo da queste basi, abbiamo studiato se un rimodellamento del wiring neuronale orexinergico si verifica nell’LH nel corso di una prolungata perturbazione nutrizionale causata da, o risultante in, carenza di segnalazione della leptina, come in topi ob/ob e topi HFD, rispettivamente, ed il suo impatto sulla funzione neuromodulatoria del sistema endocannabinoide, dato che un’ alta plasticità neuronale si verifica in questo circuito per un’ adeguata regolazione del bilancio energetico (12).
Acute or chronic alterations in energy status lead to changes in the balance between excitatory and inhibitory synaptic transmission and associated synaptic plasticity, facilitating adaptation of energy metabolism to new homeostatic requirements. The impact of such changes, especially during obesity, on endocannabinoid signalling at CB1 receptors, a master modulator of synaptic transmission and strength, and a target for anti-obesity drugs, is not well understood. Endocannabinoids stimulate food intake and their synthesis and release increase after food-deprivation thus inducing activation of CB1 receptors. In particular, endocannabinoid levels increase in the hypothalamus and blood during short-term fasting (1, 2) and decrease after leptin administration and feeding (3, 4). Impairment of leptin signaling (db/db mice expressing a defective leptin receptor), leptin deficiency (ob/ob), and leptin resistance (acquired resistance due to diet-induced obesity, HFD mice) in mice showed elevated levels of Endocannabinoids in the hypothalamus and in adipose tissue (5). Recent papers show that leptin modulates also the axonal growth and synaptic plasticity within the hypothalamus (6,7). In particular, leptin increases neurite extension in the Arcuate Nucleus during mouse perinatal development, thus playing an early trophic role within those circuits that will be the target of leptin physiological actions in adult life (6). Leptin also may act on the Orexinergic-synthesizing (OX) neurons of the lateral hypothalamus, which send widespread projections to the brain (8) playing a strategic integrative role in the feeding. Leptin suppress the activity of OX neurons, the biosynthesis of OX or both. Moreover, an OX1R-selective antagonist reduced food intake and ameliorated obesity of leptin-deficient ob/ob mice (9), suggesting that leptin deficiency at least partly activates the orexin pathway to increase food intake. On the other hand, pretreatment with subeffective doses of rimonabant, a selective CB1 antagonist, attenuates the orexigenic actions of OX (10), whereas electrophysiological data support the inhibitory role of cannabinoids on orexinergic neurons in physiological conditions (11). Staring from these bases, we investigated if a remodeling of orexinergic neuronal wiring occurs in the LH during a prolonged nutritional perturbation caused by, or resulting in, leptin signalling deficiency, as in ob/ob and HFD mice, respectively, and its impact on neuromodulatory function of the endocannabinoid system, since high neural plasticity occurs in this circuitry for adequate regulation of energy balance (12).

One of the few remaining mysteries in mammalian phylogeny is the issue of Chiropteran phylogeny. In order to further investigate the diphyletic hypothesis that states that Megachiroptera evolved from primate-like gliders and that Microchiroptera evolved from insectivores, the cholinergic, catecholaminergic, serotonergic and orexinergic systems were analyzed in, not only five insectivores (Crocidura cyanea, Crocidura olivieri, Sylvisorex ollula, Paraechinus aethiopicus and Atelerix frontalis) and three prosimian primates (Galagoides demidoff, Perodicticus potto and Lemur catta), but in species from other orders of interest including the Afrotheria (Potamogale velox, Amblysomus hottentotus and Petrodromus tetradactylus), Lagomorpha (Lepus capensis) and Scandentia (Tupaia belangeri). Brains of the mammals were coronally sectioned and immunohistochemically stained with antibodies against cholineacetyltransferase, tyrosine hydroxylase, serotonin and orexin-A. The presence or absence of 93 nuclei within these neuromodulatory systems was entered into modern cladistics software for analysis of the 13 studied species, as well as an additional 40 previously studied mammals. The majority of nuclei revealed in the current study were similar among the species investigated and to mammals generally, but certain differences in the nuclear complement highlighted potential phylogenetic interrelationships. The Afrotherian, A. hottentotus, presented unusual cholinergic interneurons in the cerebral cortex, hippocampus, olfactory bulb and amygdala, and exhibited an unusual foreshortening of the brain, such that a major mesencephalic flexure in the brainstem was evident. The Afrotherian, P. tetradactylus, lacked the catecholaminergic A15d nucleus as in a previously studied member of Macroscelididae. The three Insectivoran shrews lacked the cholinergic parabigeminal and Edinger-Westphal nuclei, had a mediodorsal arch of the cholinergic laterodorsal tegmental nucleus, lacked the catecholaminergic A4 and A15d nuclei and presented an incipient ventral division of the substantia nigra which is identical to previously studied Microchiroptera. All three prosimians presented a central compact division of catecholaminergic locus coeruleus (A6c) surrounded by a shell of less densely packed (A6d) tyrosine hydroxylase immunopositive neurons. This combination of compact and diffuse divisions of the locus coeruleus complex is only found in primates and Megachiropterans of all the mammalian species studied to date. T. belangeri of the Scandentia contained ChAT+ neurons within the nucleus of the trapezoid body as well as the superior olivary nuclear complex, which has not been described in any mammal studied to date. L. capensis of the Lagomorpha presented vi the rodent specific rostral dorsal midline medullary nucleus (C3), while T. belangeri was lacking both the ventral and dorsal divisions of the anterior hypothalamic group (A15v and A15d), and both species were lacking the primate/Megachiropteran specific compact portion of the locus coeruleus. Our neuroanatomical analysis suggests a phylogenetic relationship between the Soricidae (shrews) and the Microchiropterans, supports the phylogenetic grouping of primates with Megachiropterans, confirms previous molecular evidence of the relationship between lagomorphs and rodents within the super-order Glires, and suggests that primates are phylogenetically closer to Megachiroptera than to any members of the Euarchontoglires. The cladistic analysis confirmed the neuroanatomical analysis with the most parsimonious tree placing Megachiroptera into the Euarchontoglires as a sister group to primates and the Microchiroptera next to Soricidae within the Laurasiatheria.

Stimulants are typically prescribed for their positive effects on mood, motivation, alertness, arousal, and energy. They are believed to exert their pharmacologic effects by increasing synaptic release of endogenous catecholamines (norepinephrine and dopamine) while simultaneously blocking catecholamine reuptake at the nerve terminals. Themost commonly used ‘‘traditional’’ agents are methylphenidate and dextroamphetamine. Methylphenidate reaches peak blood levels in 1 to 3 hours and has an elimination half-life of 2 to 3 hours. Dextroamphetamine reaches peak levels in 2 to 4 hours and has an elimination half-life of 3 to 6 hours. Controlled-release formulations are available, allowing for dosing once daily. Dextroamphetamine is excreted primarily in the urine in unchanged form, whereas methylphenidate is excreted mainly as ritalinic acid. The newer generation stimulant modafinil has been marketed in the United States since 1998. Initially used in the treatment of narcolepsy, it is now prescribed for a wider range of conditions because of its positive effects on wakefulness, vigilance, cognitive performance, and mood. Its pharmacologic effects are thought to result primarily from the stimulation of wakefulness-promoting orexinergic neurons in the anterior hypothalamus. Inhibition of norepinephrine reuptake in the ventrolateral preoptic nucleus and of dopamine reuptake (by binding to the transporter) may contribute to its action. Modafinil is administered orally, achieves peak plasma concentrations in 2 to 4 hours, and has an elimination half-life of 12 to 15 hours. It is 90% metabolized in the liver, and its metabolites are excreted in the urine. The ergot alkaloids bromocriptine and pergolide are familiar to most neurologists in their use in the treatment of Parkinson’s disease (PD) and migraine headache. These dopamine receptor agonists are also used in neuropsychiatry in the treatment of apathetic states in patients recovering from brain trauma, cerebral anoxia, and strokes. Amantadine is another familiar agent used in the treatment of PD and drug-induced parkinsonism. In addition to other effects in the central nervous system (CNS), amantadine facilitates dopamine release and inhibits its reuptake. It thus has modest ‘‘stimulant-like’’ effects useful in the treatment of executive dysfunction syndromes, particularly in patients with dementia. Bupropion is a dopamine and norepinephrine reuptake inhibitor. It usually is prescribed as a ‘‘nonsedating’’ antidepressant, but its potentiation of catecholamine neurotransmission results in modest stimulant-like clinical effects.