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PubMed1989

Beta-N-oxalylamino-L-alanine action on glutamate receptors.

beta-N-Oxalylamino-L-alanine (L-BOAA) is a non-protein excitatory amino acid present in the seed of Lathyrus sativus L. This excitotoxin has been characterized as the causative agent of human neurolathyrism, an upper motor neuron disease producing corticospinal dysfunction from excessive consumption of the lathyrus pea. Previous behavioral, tissue-culture, and in vitro receptor binding investigations revealed that L-BOAA might mediate acute neurotoxicity through quisqualate (QA)-preferring glutamate receptors. The present study demonstrates the stereospecific action of L-BOAA on glutamate receptor binding in whole mouse brain synaptic membranes. L-BOAA was most active in displacing thiocyanate (KSCN)-sensitive specific tritiated (RS)-alpha-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) binding (i.e., QA receptor) (Ki = 0.76 microM) with a rank-order potency of QA greater than kainate greater than N-methyl-D-aspartate (NMDA). By contrast, the nonneurotoxic D-BOAA isomer (100 microM) was essentially inactive in displacing radioligands for glutamate receptors, except the NMDA site, where it was equipotent with L-BOAA. Scatchard analysis of L-BOAA displacement of specific [3H]AMPA binding indicated competitive antagonism (KD: control, 135 nM; L-BOAA, 265 nM) without a significant change in QA-receptor density, and Hill plots yielded coefficients approaching unity. Differential L-BOAA concentration-dependent decreases in specific [3H]AMPA binding were observed in synaptic membranes, indicating that the neurotoxin was more potent in displacing specific binding from frontal cortex membranes, followed by that for corpus striatum, hippocampus, cerebellum, and spinal cord. (ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗

PubMed1992

Cholinergic modulation of cortical associative memory function.

1. The effect of cholinergic modulation on associative memory function was studied in a computational model based on the physiology and anatomic structure of piriform cortex. Both the cholinergic suppression of intrinsic fiber synaptic transmission and the cholinergic changes in postsynaptic excitability described in the companion paper were examined. 2. Distributed input patterns representing odors were stored in the model with the use of a synaptic modification rule dependent on pre- and postsynaptic activity (i.e., Hebbian). Associative recall of these patterns was tested by presenting the model with degraded versions of the learned patterns and testing whether these degraded patterns evoked the same network response as the full learned input pattern. Storage was evaluated with the use of a performance measure designed to reflect how well degraded input patterns could be recognized as a particular learned input pattern. 3. When memory function was evaluated with a selective cholinergic suppression of intrinsic fiber synaptic transmission during learning, associative memory performance was greatly enhanced. Cholinergic suppression during learning prevents previously stored patterns from interfering with the storage of new patterns. 4. When memory function was evaluated with a cholinergic mediated enhancement in cell excitability during learning, the speed of learning increased, but so did the decay in performance due to interference during learning. 5. When suppression of intrinsic fiber synaptic transmission was coupled with an increase in cell excitability, the best memory performance was obtained. 6. These results provide a possible theoretical framework for linking the neuropharmacological effects of acetylcholine to behavioral evidence for a role of acetylcholine in memory function. This could help describe how memory deficits might arise from cholinergic dysfunction in diseases such as Alzheimer's dementia.

Association↗

PubMed1984

Scientific approaches to Huntington's disease.

Huntington's Disease (HD) is a progressive neurologic disorder transmitted as autosomal dominant. The symptoms of HD, which typically appear in midlife, include disturbances in movement, psychiatric symptoms, and a progressive dementia. Neuropathologic studies indicate a distinct pattern of neuronal degeneration in HD that affects many areas of the brain but consistently and severely involves the basal ganglia including the caudate, putamen, and globus pallidus. The basal ganglia undergo a progressive atrophy due to degeneration of intrinsic neurons that results in ventricular enlargement. Over the last decade, detailed neurochemical analyses have been carried out on the brains of patients who have died with HD. These studies have demonstrated the selective degeneration of chemically defined neuronal systems including the striatal cholinergic intrinsic neurons, the striatal nigral GABAergic pathway, and striatal peptidergic neurons with the relative sparing of other systems such as the nigrostriatal pathway. These findings have resulted in a better understanding of the pathophysiologic basis for the movement disorder of HD and have led to the development of pharmacologic strategies to correct the synaptic neurochemical imbalances. Recent studies have begun to focus on mechanisms responsible for the selective neuronal degeneration in HD. One promising hypothesis evolved from the finding that intrastriatal injections of excitatory amino acid analogues reproduces the neurochemical and histologic pathology of HD in experimental animals; as a consequence, it has been hypothesized that dysfunction of excitatory amino acid neurotransmission may cause the selective neuronal degeneration of HD. Another hypothesis involves an abnormality of the plasma membrane based upon observations of differences in membrane characteristics in fibroblasts and red blood cells from HD patients as compared to suitable controls. The ultimate goals of these studies are to develop methods for identifying presymptomatic carriers of the HD gene as well as strategies for preventing the neuronal degeneration associated with expression of the gene.

Autoantibodies↗

PubMed1994

Transmission electron microscope study of human hydrocephalic cerebral cortex.

Cortical biopsies of 17 patients with diagnosis of hydrocephalus and associated pathology were examined under the transmission electron microscope to study alterations of neurons, neuroglial cells, extracellular space and capillary wall. Nerve cells showed moderate and severe swelling as well as dilation of endoplasmic reticulum canaliculi and perinuclear cistern, edema and degenerative changes of Golgi apparatus, variable degrees of mitochondrial swelling and fragmentation of plasma membrane. The neighbouring neuropil showed notable enlargement of extracellular space and signs of synaptic degeneration characterized by swollen pre- and postsynaptic endings, clumping of spheroidal synaptic vesicles and detachment of glial synaptic ensheathment. The astrocytes exhibited edematous changes and phagocytic activity. Oligodendroglial cells appeared normal in certain cases and in others showed moderate hydropic changes. Evidences of oligodendrocyte mitotic divisions were not found. Numerous myelin figures were observed in some undifferentiated nerve cells. The capillary wall showed evident signs of blood-brain barrier dysfunction featured by increased endothelial vesicular and vacuolar transport, open interendothelial junctions and focal capillary basement membrane thickenings.

Adult↗

PubMed2003

Altered transcript expression of NMDA receptor-associated postsynaptic proteins in the thalamus of subjects with schizophrenia.

OBJECTIVE: NMDA receptor dysfunction has been implicated in the pathophysiology of schizophrenia. The NMDA receptor is a multimeric ligand-gated ion channel, and the obligate NR(1) subunit is expressed as one of eight isoforms due to the alternative splicing of exons 5, 21, and 22. Alternative splicing of NR(1) subunits modulates receptor function by influencing the association of NR(1) with other NMDA receptor subunits and myriad intracellular molecules, such as the postsynaptic density family of proteins that target NMDA receptors to the synaptic membrane and couple it to numerous signal transduction enzymes. Recently, the authors reported that the NMDA receptor subunits NR(1) and NR(2C) are abnormally expressed in the thalamus in schizophrenia. They hypothesized that this reduction is associated with specific NR(1) isoforms and that NMDA receptor-related postsynaptic density proteins are abnormally expressed. METHOD: Using in situ hybridization, the authors examined expression of the transcripts encoding NR(1) isoforms containing exons 5, 21, or 22, and the NMDA receptor-related postsynaptic density proteins NF-L, PSD93, PSD95, and SAP102. RESULTS: Reduced NR(1) subunit transcript expression was restricted to exon 22-containing isoforms. Increased expression of the NMDA receptor-associated postsynaptic density proteins NF-L, PSD95, and SAP102 was also detected in the thalamus of subjects with schizophrenia. CONCLUSIONS: These data support the hypothesis of glutamatergic abnormalities in schizophrenia and suggest that glutamatergic dysfunction may occur not only at the level of receptor expression but also within intracellular pathways associated with glutamate receptor-associated signal transduction.

Aged↗

PubMed1985

Disturbed GABAergic transmission in mutant Han-Wistar rats: further evidence for basal ganglia dysfunction.

A mutant strain of Wistar rats which carries an autosomal gene defect is characterized by a progressively developing hyperexcitability, tremor, olfactory and gustatory movements, bradykinesia, ataxia and a pathologically increased muscle tone of hindlimbs which can be measured by recording tonic activity in the electromyogram (EMG) of the gastrocnemius-soleus muscle. The activity of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) and the receptor binding of GABA as estimated by [3H]GABA binding to synaptic membranes were examined in olfactory bulbs, frontal cerebral cortex, corpus striatum, hippocampus, thalamus, hypothalamus, tectum, substantia nigra, medulla oblongata, cerebellum, and pons of mutant rats. Mutant rats exhibit a lower activity of GAD in synaptosomal fractions of olfactory bulbs and substantia nigra whereas GAD activity within the pons was increased. The changes in the activity of GAD were accompanied by alterations in [3H]GABA binding to synaptic membranes: GABA binding was significantly elevated in the olfactory bulbs and the substantia nigra, but it was markedly reduced in the pons. The functional importance of impaired nigral GABAergic transmission in mutant rats was demonstrated by the fact that intranigral injection of the GABA agonist muscimol reduced the tonic extension of the hindlimbs as indicated by reduced tonic EMG activity of the gastrocnemius-soleus muscle, while intranigral injection of the GABA antagonist bicuculline increased the disturbance.

Animals↗

PubMed1993

The neurological complications of sepsis.

Encephalopathy and polyneuropathy occur in 70% of septic patients. The encephalopathy is diffuse, appears early, is often severe, but reverses quickly with successful treatment of the sepsis. The electroencephalogram is a sensitive indicator of the incidence and severity of the encephalopathy, but computed tomograms of the brain and cerebrospinal fluid findings are unremarkable. Critical-illness polyneuropathy develops later and in association with multiple-organ failure. Recovery is more gradual. Difficulty in weaning from the ventilator is an important early manifestation. Electromyography should be routinely performed to establish the diagnosis. The polyneuropathy is a primary axonal degeneration, predominantly of distal motor fibers. A persistent deficit may eventuate in severe cases. Whether muscle is affected as consistently as brain and peripheral nerve, and by the same process, has not been determined. Medications used in critical care units, notably sedatives and neuromuscular blocking agents, often confuse the clinical picture. The neurological pathophysiology is unknown but current evidence suggests that nervous system dysfunction arises through the same mechanisms as for systemic organs in the septic syndrome.

Brain Diseases↗

PubMed1979

Interneuron circuits in the lateral geniculate nucleus of monocularly deprived cats.

This work investigated the function of interneurons and other types of cells in the lateral geniculate nucleus (LGN) in cats raised to adulthood with one eye sutured closed. In order to understand the basis of the commonly found deficit of Y-type relay cells in the deprived layers of the LGN, we looked for reduced or defective activity in other cells which also receive an afferent projection from Y-type ganglion cells in the visually deprived retina. Monocular deprivation did not produce a deficit in the activity of a class of interneurons which receive direct optic inputs from the same ganglion cells in the deprived eye that also drive the Y-type relay cells. Likewise, the Y-type afferent input from the deprived eye to XY-type relay cells was normal. The XY-type cells have mixed or hybrid receptive field properties and both X and Y excitatory inputs; although the Y-inputs to these cells are often much weaker than the X-inputs. The normal properties of Y-type interneurons and XY-type relay cells in the deprived LGN suggest that neither a retinal dysfunction nor an inherent inability of the Y-type optic tract axons to form adequate synapses onto LGN neurons are factors which would readily account for the reduction of Y-type relay cells in monocularly deprived cats. The hypothesis that the deprived Y-type relay cells may have difficulty in forming synaptic connections onto postsynaptic, binocular neurons was supported by observations of responses of cells in the perigeniculate region. Normally, perigeniculate neurons receive a strong binocular input from Y-type relay cells as well as an X-input in at least some cases. In binocular perigeniculate cells of the sutured cats, no inputs from deprived Y-type relay cells could be identified although a longer latency input, typical of that from X-type relay cells, was present.

Animals↗

PubMed2004

Screening for mutations in synaptotagmin XI in Parkinson's disease.

Parkinson's disease (PD) is characterized by selective degeneration of neurons in the substantia nigra and subsequent dysfunction of dopaminergic neurotransmission. Genes identified in familial forms of PD encode proteins that are linked to the ubiquitin-proteasome system indicating the pathogenic relevance of disturbed protein degradation in PD. Some of them, i.e. alpha-synuclein, parkin and synphilin-1, have been implicated in presynaptic neurotransmission based on their localization in synaptic vesicles. Synaptotagmin XI is linked to the pathogenesis of PD based on its identification as a substrate of the ubiquitin-E3-ligase parkin. Moreover synaptotagmin XI is involved in the maintainance of synaptic function and represents a component of Lewy bodies (LB) in brains of PD patients. Therefore, we performed a detailed mutation analysis of the synaptotagmin XI gene in a large sample of 393 familial and sporadic PD patients. We did not find any disease causing mutations arguing against a major role of mutations in the synaptotagmin XI gene in the pathogenesis of PD.

Aged↗

PubMed1995

Na+,K(+)-ATPase activities are increased in brain in both congenital and acquired hyperammonemic syndromes.

Activities of Na+,K(+)-ATPase were measured in brain regions of experimental animals with either congenital or acquired hyperammonemia. In the sparse-fur (spf) mutant mouse, with a genetic X-linked deficiency of ornithine transcarbamylase, an animal model of congenital hyperammonemia, Na+,K(+)-ATPase was increased in frontal cortex (by 57%, P < 0.001), cerebellum (by 61%, P < 0.001), brainstem (by 71%, P < 0.001) and striatum (by 48%, P < 0.01). Four weeks following portacaval anastomosis in the rat, Na+,K(+)-ATPase activities were increased in cerebellum and striatum (by 19%, P < 0.01) and in brainstem (by 28%, P < 0.01). Stimulation of Na+,K(+)-ATPase and the subsequent alteration of neuronal excitability could contribute to the CNS dysfunction characteristic of chronic hyperammonemic syndromes.

Ammonia↗

PubMed1997

Modulation of synaptosomal plasma membrane-bound enzyme activity through the perturbation of plasma membrane lipid structure by bupivacaine.

UNLABELLED: We investigated modulations of lipid dynamics and lipid-protein interactions of rat brain synaptosomal plasma membrane (SPM) as one of the possible mechanisms by which the local anesthetic bupivacaine (BPV) has an adverse effect on nerve cell function, with SPM-bound enzyme activity used as a functional probe. The kinetics of BPV impact on the activity of the endoenzymes Ca2+/Mg2+-stimulated ATPase and Na+/K+-stimulated ATPase and the active concentrations of the drug were relevant to those that produce biphasic systemic toxicity. Arrhenius plots of these enzymes showed a transition temperature of 26.6 +/- 1.8 degrees C and 24.5 +/- 1.2 degrees C (mean +/- SD), respectively, in control SPM, which shifted to 17.1 +/- 0.95 degrees C (P < 0.01) and 18.2 +/- 0.85 degrees C (P < 0.05) in SPM treated with 10(-5) M BPV. The Hill coefficients for the allosteric inhibition of Ca2+/Mg2+-stimulated ATPase by Na+ and Na+/K+-stimulated ATPase by fluoride decreased from 1.73 +/- 0.20 and 1.95 +/- 0.25, respectively, in controls to 0.92 +/- 0.09 (P < 0.001) and 1.09 +/- 0.11 (P < 0.001) in the presence of 10(-5) M BPV. The fluidity perturbation in the microenvironment of the ectoenzyme acetylcholinesterase was observed only at 5 x 10(-3) M BPV, as confirmed by the disparity in transition temperature between the controls (22.3 +/- 1.2 degrees C) and the BPV-treated SPM (17.5 +/- 0.8 degrees C, P < 0.01) and that in the Hill coefficient in the two groups: 2.15 +/- 0.24 and 0.97 +/- 0.12 (P < 0.001), respectively. IMPLICATIONS: We propose that under physiological conditions, the neutral and protonated forms of local anesthetics can affect nerve cell function through the asymmetric perturbation of the membrane lipid structure, accompanied by synaptosomal plasma membrane-bound enzyme dysfunction.

5'-Nucleotidase↗

PubMed1982

Hair follicle discrimination dysfunction in multiple sclerosis patients.

A method was developed of assessing somatosensory deficits quantitatively using hair follicle displacement as a stimulus within a psychophysical signal detection task paradigm. Multiple sclerosis patients with and without somatosensory disturbances could be differentiated and compared with normal subjects. This method may distinguish patients with somatosensory dysfunction, and dorsal funiculus neuropathology may underlie this distinction.

Adult↗

PubMed1996

Incubation with IgE increases cholinergic neurotransmission in human airways in vitro.

Airway cholinergic hyperresponsiveness is frequently observed in asthmatic patients. Recent reports suggest the possible involvement of IgE in hyperresponsiveness, although the exact mechanism is still uncertain. In this study, we examined whether incubation with IgE could facilitate the cholinergic function in human airways. Bronchi were obtained from 20 patients undergoing lung resection. Cholinergic contractile responses were induced by electrical field stimulation (EFS) or exogenous acetylcholine (ACh), and they were assessed by isometric tension measurement. EFS-induced ACh release from cholinergic nerves was also measured by high performance liquid chromatography. Incubation with IgE significantly enhanced EFS-induced bronchial contraction and ACh release as compared with the values of the bronchi incubated with heat inactivated IgE (control) (p < 0.05, respectively), but it did not alter the contractile responses induced by exogenous ACh. Pretreatment with the muscarinic M2-receptor agonist pilocarpine reduced the EFS-induced ACh release in the control tissues (p < 0.05), but not in the tissues incubated with IgE. The M2-receptor antagonist methoctramine significantly enhanced the EFS-induced contraction in control bronchi (p < 0.05), but this augmentation was not observed in the tissues incubated with IgE. These results suggest that IgE itself can enhance cholinergic bronchial contraction via facilitation of ACh release from cholinergic nerves and that this augmentation is related to autoreceptor M2 dysfunction at nerve endings.

Acetylcholine↗

PubMed2005

Glutamatergic neurotransmission modulators as emerging new drugs for schizophrenia.

Schizophrenia is a neurodevelopmental mental disorder whose aetiology includes genetic and environmental factors. Because of its early onset, chronicity and characteristic interference with education, employment and socialisation, this illness represents a tremendous human and economic burden to those who suffer from it, their families and society as a whole. Conventional and atypical antipsychotics, which mainly affect dopaminergic and serotonergic neurotransmission, are currently the cornerstone of schizophrenia treatment. Although the introduction of atypical antipsychotics represents a major development and, overall, antipsychotics are efficacious against psychotic symptoms, there remains a critical unmet need for innovative medications with improved efficacy and tolerability for the negative symptoms and cognitive deficits associated with schizophrenia. These dysfunction domains are reliable predictors of long-term disability and treatment outcome and are presently viewed as crucial targets for new pharmacological treatments of schizophrenia. Within this medication development framework, the modulation of glutamatergic neurotransmission has become the focus of intense research. Glutamate (GLU)-mediated neuronal processes are critical throughout the brain and glutamatergic neurotransmission dysfunctions have been hypothesised to play a crucial role in schizophrenia pathophysiology. Glutamatergic neurotransmission may be modulated at multiple levels, with GLU receptor families and their subtypes representing a modulatory site-rich environment for drug research. Numerous types of neurotransmission modulators, acting at the NMDA, AMPA and metabotropic GLU receptors, and/or affecting GLU synaptic release, are hypothesised to be beneficial for schizophrenia treatment, and are presently in various stages of development. For some of these compounds, preliminary studies have furnished encouraging clinical data. Ongoing and planned research is expected to provide, in the near future, critical information regarding the practical utility and tolerability of glutamatergic approaches for schizophrenia pharmacotherapy.

Animals↗

PubMed2006

Development of a novel high-throughput assay for the investigation of GlyT-1b neurotransmitter transporter function.

The glycine transporter (GlyT-1b) is a Na(+)/Cl(-)-dependent electrogenic transporter which mediates the rapid re-uptake of glycine from the synaptic cleft. Based on its tissue distribution, GlyT-1 has been suggested to co-localise with the NMDA receptor where it may modulate the concentration of glycine at its co-agonist binding site. This data has led to GlyT-1 inhibitors being proposed as targets for disorders such as schizophrenia and cognitive dysfunction. Radiolabelled uptake assays (e.g. [(3)H]glycine) have been traditionally used in compound screening to identify glycine transporter inhibitors. While such an assay format is useful for testing limited numbers of compounds, the identification of novel glycine uptake inhibitors requires a functional assay compatible with high-throughput screening (HTS) of large compound libraries. Here, the authors present the development of a novel homogenous cell-based assay using the FLIPR membrane potential blue dye (Molecular Devices) and FLEXstation. Pharmacological data for the GlyT-1 inhibitors Org 24598 and ALX 5407 obtained using this novel electrogenic assay correlated well with the conventional [(3)H]-glycine uptake assay format. Furthermore, the assay has been successfully miniaturised using FLIPR(3) and therefore has the potential to be used for high-throughput screening.

Animals↗

PubMed2007

Brain nitric oxide synthases and mitochondrial function.

Nitric oxide is a small signaling molecule, which may act as a neurotransmitter and neuromodulator, exerting a regulatory effect on neuronal function. It can diffuse from its site of synthesis to different intra and extracellular compartments, being therefore present in the pre-synaptic, synaptic and post-synaptic spaces. Recently, a NOS located in the mitochondria (mtNOS) has been observed in different brain regions, responsible for the production of NO in these organelles and identified as nNOS. A regulatory effect of NO on mitochondrial function was described in brain mitochondria, where NO acts mainly by inhibiting cytochrome oxidase activity. Hippocampal mitochondrial dysfunction and decreased mtNOS activity and expression were reported in association with ultrastructural damage in an experimental model of hepatic encephalopathy. Enriched environment exposure preserved the aged animals from spatial cognition impairment; also environment and training modulated neuronal plasticity in pre-pubertal rats through NO-dependent mechanisms. In addition, brain cortical mitochondrial respiration and mtNOS activity and expression were analyzed as function of age. Mitochondrial NO production showed a decreasing tendency as a function of age. These results are in accordance with the protein expression analyzed by Western Blot of mitochondrial fractions which was 6.5 times higher in 1 month aged rats as compared with 14 old animals. Concomitant with these results, a clear increasing oxygen uptake tendency in state 3 respiration was observed, meanwhile only a slight increase was observed in state 4. All these results seems to be clearly related with the reversible and concentration-dependent attenuation of the respiratory chain by NO.

Aging↗

PubMed1986

Role of noradrenergic ascending system in extinction of epileptic phenomena.

This chapter reviews results which show that in electroshock-induced and chemically induced convulsions, audiogenic seizures of genetic epilepsy-prone rats and mice, in the kindling focus and the cobalt lesion seizure, susceptibility is modulated by a noradrenergic mechanism. In general, mechanisms that increase or decrease norepinephrine activities decrease or increase seizures, respectively, in these models. In the kindling phenomenon, since the seizure itself provokes an increase in norepinephrine (NE) turnover, with decreased beta-adrenoceptor binding and hyposensitivity to ionophoretic catecholamine application, down regulation could be the cause of hyperexcitability or a consequence of it. In the cobalt focus, supersensitivity to NE appeared when NE-containing terminal density decreased (denervation supersensitivity) and beta-receptor sites increased greater than 50%. Perfusion experiments with NE support the hypothesis that the cortical NE system inhibits the spread of chronic epileptogenic activities in the cobalt focus. In the quaking mouse and in the tottering mouse, noradrenergic dysfunction underlying epileptogenesis may be expressed as a hyperinnervation.

Afferent Pathways↗

PubMed1983

The state of research in anorexia nervosa and bulimia.

Recent studies suggest that some of the DSM III criteria for anorexia nervosa require revision. In particular exclusion for onset beyond 25, and a requirement for 25 per cent weight loss appear inappropriate, whereas amenorrhoea correlates better with anorectic psychology than weight. Although an increased incidence of affective disturbance among the relatives of anorectics and bulimics has been shown, the precise relationship with affective disorder remains unclear. Cortisol non-suppression and low MHPG excretion are related to weight loss. However, some areas of hypothalamic dysfunction cannot be explained by emaciation or diet. Pre-pubertal LH secretion patterns, absence of estrogen positive feedback on LH, and failure of LH response to clomiphene can persist despite normalisation of weight. Furthermore 1-dopa fails to induce the normal growth hormone response in weight restored anorectics, suggesting impairment at post-synaptic dopamine receptors. Body image studies have been varied, suggesting heterogeneity of body image distortion among anorectic subgroups. The role of family environment in the pathogenesis of anorexia nervosa has not been fully elucidated, although such a role in the relationship between bulimic symptomatology and personality disturbance have been suggested. Of the behavioral therapies, operant positive reinforcement that restores weight in a hospital setting has had the best results. Successful pharmacological approaches have included cyproheptadine (a serotonin antagonist), chlorpromazine and metoclopramide.

Adolescent↗