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By M. Khabir. Stonehill College.

Neuroleptics alone would cheap 5 mg eldepryl overnight delivery medicine numbers, by virtue of being DA antagonists generic 5 mg eldepryl free shipping symptoms zoloft, produce the equivalent of denervation supersensitivity and automatically increase DA receptor number. PET studies on newly diagnosed untreated patients were disappointingly inconclusive, possibly due to the lack of specificity of the ligands used. Generally it is felt that there might be a slight increase in striatal D2 receptors in schizophrenia which is independent of neuroleptic treatment. If this was so and DA release remained normal, then increased DA function would follow. It should be borne in mind, however, that an increase in receptor number is normally the response to a defect in NT release (transmission). Possibly increased DA function is not the actual cause of schizophrenia and its symptoms are just mediated by normally functioning DA systems that appear overactive because of the loss of some counteracting function or other NT(s). To date there is no evidence to fully implicate any other NT but there is growing interest in 5-HT and glutamate (see below). BLOCKADE OF DA PATHWAYS IN SCHIZOPHRENIA There are three main ascending DA pathways in the brain (Fig. It is not clear which pathway is responsible for which schizophrenic symptom. The VTA (A10) neurons innervating the cortex certainly show features that distin- guish them from those in A9. There is no doubt that the nigrostriatal pathway is concerned with motor function and blocking DA transmission in it with most neuroleptics would certainly produce signs of Parkinsonism (see Chapter 15). The nucleus accumbens (and some other sub- cortical regions) are generally assumed to be concerned with psychotic effects although its core is also regarded as part of the basal ganglia. In rats it is involved in motor 356 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION function since the locomotor activity caused by low doses of amphetamine is abolished by 6-OHDA lesions of the nucleus, and DA antagonist injections into it. By contrast stereotypy induced by high doses of amphetamine is dependent on the striatum. The prefrontal cortex (PFC) and in particular the dorsal lateral part (DLPFC) appear to be particularly important in schizophrenia (Kerwin 1992). Lesions there are known to produce functional defects in humans reminiscent of many of the negative symptoms of schizophrenia, such as attention and cognitive defects and withdrawal. Despite this, no specific pathology is seen in the DLPFC in schizophrenics although there is some atrophy and neuronal loss which are normally old and could be congenital. That being so, it is necessary to explain why the symptoms become apparent only in adolescence. Weinberger (1987) points out that myelination is not complete in DLPFC until around the age of 20 and that lesions of that area in young monkeys do not seem to affect their behaviour immediately but do impede their ability to perform delayed response tasks in later life. Early adulthood is also apparently a time of maximal DA activity in the brain as evidenced by its concentration, turnover and receptor number. Thus it is possible (Weinberger 1987) that the full effect of DLPFC lesions will only manifest itself as behavioural defects when the DA system is fully functional. Lesions within the DLPFC would obviously make it difficult for DA to function properly in that region and this could initiate negative symptoms. How this would account for the positive mesolimbic symptoms is less clear but no area of the brain works in isolation and the prefrontal cortex (PFC) has intricate relationships with the basal ganglia projecting to, and receiving inputs from, them. In fact, 6-OHDA-induced lesions in the PFC in rats, which destroy DA cortical afferents (Pycock, Kerwin and Carter 1980), somehow result in increased subcortical DA function, as evidenced by increased HVA levels, receptor number and motor response to apomorphine and amphetamine. Whether this results from reduced DA inhibition in PFC is uncertain but stimulation of, or local injections of glutamate into, the ventromedial prefrontal and ventral anterior cingulate cortices have been found to increase A10 neuron firing and DA release in the nucleus accumbens. Although there is no evidence that the DA afferents to DLPFC are damaged in schizophrenics, if the cortical pathology does reduce the ability of DA to function there, this would be equivalent to deafferentation and, as in the experimental studies, lead to increased subcortical mesolimbic activity and positive symptoms (Fig. A DA antagonist could certainly counter the increased mesolimbic activity and the positive symptoms. On the other hand, they would not be expected to reduce negative symptoms if these arise through an already inadequate DA influence. This fits with clinical experience because most of the neuroleptics are ineffective in treating negative symptoms. In fact if the negative symptoms do result from loss of the actual cortical neurons, rather than input to them, they will be difficult to reverse and much will depend on the precise role of DA in the DLPFC (see later). Even if appropriate lesions could be produced it will always be difficult to tell if an animal is experiencing hallucinations.

Webster &2001 John Wiley & Sons Ltd 188 NEUROTRANSMITTERS buy 5 mg eldepryl otc medicine 2355, DRUGS AND BRAIN FUNCTION 5-HYDROXYTRYPTAMINE 189 Figure 9 generic eldepryl 5mg visa medications 122. The most prominent of these is the median forebrain bundle which contains both myelinated and unmyelinated 5-HT fibres. Although extensive branching of the neuronal processes results in a considerable overlap in the terminal axonal fields of the different nuclei, there is evidence for some topographical organisation of the areas to which different nuclei project (Fig. For instance, whereas fibres emanating from the dorsal Raphe nucleus (DRN) are the major source of 5-HT terminals in the basal ganglia and cerebellum, neurons in the median Raphe nucleus (MRN) provide the major input to the hippocampus and septum. There is also some evidence for morphological differences between DRN and MRN neurons which could impinge on their function. Thus, the terminals of neurons from the DRN are relatively fine, unmyelinated, branch extensively and seem to make no specialised synaptic contacts, suggesting en passant release of 5-HT (type I). The existence of co-transmitters, especially substance P, thyrotropin releasing hormone (TRH) and enkephalin, gives further options for functional specialisation of different neurons but, as yet, the distribution of these peptides within different nuclei has provided no specific clues as to how this might occur. In any case, species differences in the distribution of co-transmitters is a confounding factor. In short, although the 5-HT system seems to have a rather non-specific influence on overall brain function, in terms of the brain areas to which these neurons project, there is clearly much to be learned about possible functional and spatial specialisations of neurons projecting from different nuclei. SYNTHESIS The first step in the synthesis of 5-HT is hydroxylation of the essential amino acid, tryptophan, by the enzyme tryptophan hydroxylase (Fig. This enzyme has several features in common with tyrosine hydroxylase, which converts tyrosine to l-DOPA in 5-HYDROXYTRYPTAMINE 191 Figure 9. The primary substrate for the pathway is the essential amino acid, tryptophan and its hydroxylation to 5-hydroxytryptophan is the rate- limiting step in the synthesis of 5-HT. The cytoplasmic enzyme, monoamine oxidase (MAOA), is ultimately responsible for the catabolism of 5-HT to 5-hydroxyindoleacetic acid the noradrenaline synthetic pathway. First, it has an absolute requirement for O2 and the reduced pterin co-factor, tetrahydrobiopterin. Second, hydroxylation of trypto- phan, like that of tyrosine, is the rate-limiting step for the whole pathway (reviewed by Boadle-Biber 1993) (see Chapter 8). However, unlike the synthesis of noradrenaline, the availability of the substrate, tryptophan, is a limiting factor in the synthesis of 5-HT. Indeed, the activated form of tryptophan hydroxylase has an extremely high Km for tryptophan (50 mM), which is much greater than the concentration of tryptophan in the brain (10±30 mM). This means that not only is it unlikely that this enzyme ever becomes saturated with its substrate but also that 5-HT synthesis can be driven by giving extra tryptophan. First, it predicts that a dietary deficiency of tryptophan could lead to depletion of the neuronal supply of releasable 5-HT. Indeed, this has been confirmed in humans to the extent that a tryptophan-free diet can cause a resurgence of depression in patients who were otherwise in remission (see Chapter 20). In contrast, a tryptophan-high diet increases synthesis and release of 5-HT. In fact, when given in combination with other drugs that augment 5-HT transmission (e. Transport of tryptophan across the blood±brain barrier and neuronal membranes relies on a specific carrier for large neutral amino acids (LNAAs). Thus, although an increase in the relative concentration of plasma tryptophan, either through dietary intake or its reduced metabolism in a diseased liver, increases its transport into the brain, other LNAAs (such as leucine, isoleucine or valine) can compete for the carrier. It is known that consumption of carbohydrates increases secretion of insulin which, in addition to its well-known glucostatic role, promotes uptake of LNAAs by peripheral tissues. However, it seems that tryptophan is less affected by insulin than the other LNAAs in this respect and so its relative concentration in the plasma increases, thereby increasing its transport into the brain (see Rouch, Nicolaidis and Orosco 1999). The resulting increase in synthesis and release of 5-HT is claimed to enhance mood. Although this scheme is rather controversial, it has been suggested as an explanation for the clinical improvement in some patients, suffering from depression or premenstrual tension, when they eat carbohydrates.

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Abbreviations CorNu Corticonuclear fibers MVesSp Medial vestibulospinal tract CorVes Corticovestibular fibers MVNU Medial vestibular nucleus Flo Flocculus NL best eldepryl 5mg medications while breastfeeding, par Lateral cerebellar nucleus order 5mg eldepryl free shipping medicine for stomach pain, parvocellular IC Intermediate cortex region InfVesNu Inferior (spinal) vestibular nucleus NM, par Medial cerebellar nucleus, JRB Juxtarestiform body parvocellular region LC Lateral cortex NuCor Nucleocortical fibers LVesSp Lateral vestibulospinal tract SVNu Superior vestibular nucleus LVNu Lateral vestibular nucleus VC Vermal cortex MLF Medial longitudinal fasciculus Review of Blood Supply to Cerebellum and Vestibular Nuclei STRUCTURES ARTERIES Cerebellar Cortex branches of posterior and anterior inferior cerebellar and superior cerebellar Cerebellar Nuclei anterior inferior cerebellar and superior cerebellar Vestibular Nuclei posterior inferior cerebellar in medulla, long circumferential branches of basilar in pons Cerebellum and Basal Nuclei (Ganglia) 209 Cerebellar Corticonuclear, Nucleocortical, and Corticovestibular Fibers NuCor IC VC CorNu CorVes 4 NuCor 2 CorNu 3 LC 1 NM, par Nodulus NL, par JRB Flo SVNu LVNu MLF InfVNu MVNu LVesSp MVesSp Cerebellar Nuclei: 1= Medial (Fastigial) 2= Posterior Interposed (Globose) 3= Anterior Interposed (Emboliform) 4= Lateral (Dentate) 210 Synopsis of Functional Components, Tracts, Pathways, and Systems Cerebellar Efferent Fibers 7–20 The origin, course, topography, and general distribution of belloreticular-reticulospinal, 3) cerebellothalamic-thalamocortical- fibers arising in the cerebellar nuclei. In addition, some direct cerebellospinal several thalamic areas (VL and VA), to intralaminar relay nuclei in ad- fibers arise in the fastigial nucleus as well as in the interposed nuclei. Most of the latter nuclei project back to the cere- glutamate ( ), aspartate ( ), or gamma-aminobutyric acid ( ). For example, cerebello-olivary fibers from the den- mic fibers, whereas some GABA-containing cells give rise to cerebel- tate nucleus (DNu) project to the principal olivary nucleus (PO), and lopontine and cerebello-olivary fibers. Some cerebelloreticular neurons of the PO send their axons back to the lateral cerebellar cor- projections may also contain GABA. Clinical Correlations: Lesions of the cerebellar nuclei result in a The cerebellar nuclei can influence motor activity through, as ex- range of motor deficits depending on the location of the injury. Many amples, the following routes: 1) cerebellorubral-rubrospinal, 2) cere- of these are described in Figure 7–19 on page 208. Abbreviations ALS Anterolateral system OcNu Oculomotor nucleus AMV Anterior medullary velum PO Principal olivary nucleus BP Basilar pons PonNu Pontine nuclei CblOl Cerebello-olivary fibers RetForm Reticular formation CblTh Cerebellothalamic fibers RNu Red nucleus CblRu Cerebellorubral fibers RuSp Rubrospinal tract CC Crus cerebri SC Superior colliculus CeGy Central grey (periaqueductal grey) SCP Superior cerebellar peduncle CM Centromedian nucleus of thalamus SCP, Dec Superior cerebellar peduncle, decussation CSp Corticospinal fibers SN Substantia nigra DAO Dorsal accessory olivary nucleus SVNu Superior vestibular nucleus DNu Dentate nucleus (lateral cerebellar nucleus) ThCor Thalamocortical fibers ENu Emboliform nucleus (anterior interposed ThFas Thalamic fasciculus cerebellar nucleus) TriMoNu Trigeminal motor nucleus EWNu Edinger-Westphal nucleus VL Ventral lateral nucleus of thalamus FNu Fastigial nucleus (medial cerebellar nucleus) VPL Ventral posterolateral nucleus of thalamus GNu Globose nucleus (posterior interposed VSCT Ventral spinocerebellar tract cerebellar nucleus) ZI Zona incerta IC Inferior colliculus InfVNu Inferior (spinal) vestibular nucleus Number Key INu Interstitial nucleus 1 Ascending projections to superior LRNu Lateral reticular nucleus colliculus, and possibly ventral lateral and LVNu Lateral vestibular nucleus ventromedial thalamic nuclei MAO Medial accessory olivary nucleus 2 Descending crossed fibers from superior ML Medial lemniscus cerebellar peduncle MLF Medial longitudinal fasciculus 3 Uncinate fasciculus (of Russell) MVNu Medial vestibular nucleus 4 Juxtarestiform body to vestibular nuclei NuDark Nucleus of Darkschewitsch 5 Reticular formation Review of Blood Supply to Cerebellar Nuclei and Their Principal Efferent Pathways STRUCTURES ARTERIES Cerebellar Nuclei anterior inferior cerebellar and superior cerebellar SCP long circumferential branches of basilar and superior cerebellar (see Figure 5–21) Midbrain Tegmemtum paramedian branches of basilar bifurcation, short circumferential (RNu, CblTh, branches of posterior cerebral, branches of superior cerebellar CblRu, OcNu) (see Figure 5–27) VPL, CM, VL, VA thalamogeniculate branches of posterior cerebral, thalamo- perforating branches of the posteromedial group of posterior cerebral (see Figure 5–38) IC lateral striate branches of middle cerebral (see Figure 5–38) Cerebellum and Basal Nuclei (Ganglia) 211 Cerebellar Efferent Fibers CSp VL ThCor CM VPL ThFas Zl Position of SCP, NuDark, INu, OcNu, EWNu CblTh, and CblRu RNu SC CeGy 1 CeGy SCP ML 2 CblTh & RetForm RNu CblRu 4 3 CC SN PonNu DNu IC FNu SVNu MLF 5 ML ENu GNu CblOl SN LVNu 5 SCP, Dec InfVNu LRNu MVNu 5 VSCT DAO AMV 5 SCP PO TriMoNu MAO ALS & RuSp ML BP Cerebellospinal fibers 212 Synopsis of Functional Components, Tracts, Pathways, and Systems 7–21 Blank master drawing for pathways projecting to the cere- bellar cortex, and for efferent projections of cerebellar nuclei. This il- lustration is provided for self-evaluation of understanding of pathways to the cerebellar cortex and from the cerebellar nuclei, for the in- structor to expand on cerebellar afferent/efferent pathways not cov- ered in the atlas, or both. Cerebellum and Basal Nuclei (Ganglia) 213 214 Synopsis of Functional Components, Tracts, Pathways, and Systems Striatal Connections 7–22 The origin, course, and distribution of afferent fibers to, and enkephalinergic cells in the neostriatum (primarily the caudate) and efferent projections from, the neostriatum. Loss of neostriatal cell terminals in the tensive, complex, and in large part, topographically organized; only lateral and medial segments of the globus pallidus correlate, respec- their general patterns are summarized here. Afferents to the caudate tively, with the development of choreiform movements and later with and putamen originate from the cerebral cortex (corticostriate fibers), rigidity and dystonia. Loss of cortical neurons correlate, respectively, from several of the intralaminar thalamic nuclei (thalamostriate), from with personality changes and eventual dementia. Huntington chorea is the substantia nigra-pars compacta (nigrostriate), and from some of the rapid, unpredictable, and may affect muscles of the extremities, face, raphe nuclei. Neostriatal cells send axons into the globus pallidus (pa- and trunk; abnormal movements seem to flow through the body. Pa- leostriatum) as striopallidal fibers and into the substantia nigra pars tients commonly attempt to mask the abnormal movement by trying reticulata as a strionigral projection. Neurotransmitters: Glutamate ( ) is found in corticostriate Symptoms in Wilson disease (hepatolenticular degeneration) appear in fibers, and serotonin is found in raphestriatal fibers from the nucleus persons between 10 to 20 years of age. Four neuroactive substances are associated with striatal nuclei (ganglia) and the frontal cortex, with resultant spongy degener- efferent fibers, these being gamma-aminobutyric acid (GABA)( ), ation in the putamen and cortex. These patients may show athetoid dynorphin, enkephalin( ), and substance P( ). Enkephalinergic and movements, rigidity and spasticity, dysarthria, dysphagia, contractures, and GABA-ergic striopallidal projections are numerous to the lateral pal- tremor. A unique movement of the hand and/or upper extremity in lidum (origin of pallidosubthalamic fibers), while dynorphin-contain- these patients is called a flapping tremor (asterixis) sometimes described ing terminals are more concentrated in its medial segment (source of as a wing-beating tremor. Enkephalin and GABA are also present in stri- (Kayser-Fleischer ring) in these patients. Because substance P and In Parkinson disease (onset at 50 to 60 years of age), there is a pro- GABA are found in striopallidal and strionigral fibers, some of the for- gressive loss of dopaminergic cells in the substantia nigra-pars com- mer may be collaterals of the latter. Dopamine is present in nigrostri- pacta, of their terminals in the caudate and putamen, and of their den- atal projection neurons and in their terminals in the neostriatum. Patients Clinical Correlations: Degenerative changes and neuron loss in with Parkinson disease characteristically show a resting tremor (pill- the caudate nucleus and putamen result in movement disorders. Ex- rolling), rigidity (cog wheel or lead pipe), and bradykinesia or hypokinesia. In persons with Parkinson have a distinct stooped flexed posture and a festinating gait. Behavioral disease, a loss of the dopamine-containing cells in the pars compacta of changes are also seen. Parkinson disease and Huntington disease are the substantia nigra and of their nigrostriatal terminals in the caudate progressive neurodegenerative disorders.

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B GABAC RECEPTORS Early studies of the action of GABA and its analogues on spinal neurons revealed that the depressant action of one of these proven 5 mg eldepryl medicine glossary, cis-4-aminocrotonic acid (CACA) discount eldepryl 5 mg visa symptoms 9f anxiety,was not blocked by bicuculline. Several analogues of GABA shared the same properties and did not interact with the then newly described GABAB receptors. In 1984,the term GABAC was introduced to distinguish this third class of GABA receptor (Johnston 1996). Like GABA receptors,GABA receptors activate anion channels permeable to ClÀ (and A C HCO À) and the responses are similarly governed by the distribution of ClÀ across the 3 neuronal membrane. GABAC RECEPTOR PHARMACOLOGY GABAC receptors are defined by their insensitivity to bicuculline and their activation by conformationally restricted analogues of GABA such as CACA and (‡)-CAMP (1S,2R-2-(aminomethyl)cyclopropanecarboxylic acid). They are blocked by picrotoxin but can be selectively antagonised by TPMPA (1,2,5,6-tetrahydropyridin4-ylphosphinic acid). Unlike GABAA receptors,they are not affected by benzodiazepines,barbiturates or anaesthetics (Barnard et al. STRUCTURE OF GABAC RECEPTORS The best evidence for the existence of functional GABAC receptors and the clearest indication as to their molecular identity comes from work on the retina. Expression of retinal mRNA in Xenopus oocytes produces GABA-gated chloride channels with conventional GABAA receptor pharmacology as well as channels with characteristics of GABAC receptors (i. The basis of this distinction was made clear with the cloning from a retinal cDNA library of a new GABA receptor subunit termed r (Cutting et al. Originally classed as GABAA subunits,with which they have $35% sequence identity,they are now accepted as a distinct group of subunits,forming the basis of the relatively simple,and evolutionarily older,GABAC receptors. Unlike subunits of the GABAA receptor, r subunits form fully functional homomeric receptors and do not co-assemble with a or b subunits. These homomeric receptors are similar to native GABAC receptors,in that they are activated by GABA and CACA,blocked by picrotoxin and TPMPA but not bicuculline,and unaffected by barbiturates,benzodiazepines or anaesthetics (Fig. Receptors formed from r subunits have a higher affinity for GABA than many GABAA receptors formed from abg combinations,have a lower single-channel conductance and produce currents that decay more slowly after removal of GABA. Picrotoxinin is the active component of picrotoxin and also acts at GABAA receptors. The receptors can form as homomeric assemblies of r subunits but native receptors may be heteromeric assemblies of r subunits (e. Activation of these presynaptic receptors inhibits glutamate release from the bipolar cells. However,the true molecular composition of native GABAC receptors is still under investigation. While homomeric receptors formed from r subunits share many features of retinal GABAC receptors,a number of discrepancies have been noted in the details of ion permeability, single-channel conductance and channel open time (Wotring,Chang and Weiss 1999). Thus,it has been suggested that native GABAC receptors may be composed of heteromeric assemblies of r subunits or,in certain cases,that such assemblies may also contain a g2 subunit (Qian and Ripps 1999). All three r subunits have been identified in brain,but their precise location and the functional significance of this expression is unclear. In particular,the basis of GABAC receptor-like responses seen,for example,in the spinal cord,cerebellum,optic tectum and hippocampus is yet to be determined. It is involved in many metabolic pathways,is an essential component of proteins,and is found throughout the brain. A neurotransmitter role for glycine was first identified in the spinal cord,where it was found to be differentially distributed between dorsal and ventral regions and shown to cause hyperpolarisation of motoneurons (Werman et al. This inhibitory action of glycine is distinct from its 246 NEUROTRANSMITTERS,DRUGS AND BRAIN FUNCTION subsequently identified role as a co-agonist at NMDA-type glutamate receptors (Chapter 10),and is mediated by receptors that share many features with GABAA receptors (see below). Glycine-mediated neurotransmission plays a key role in spinal cord reflexes, mediating reciprocal and recurrent inhibition of motoneurons by Renshaw cells,and is important in motor control and sensory pathways. Glycine receptors are also found in higher brain centres including the hippocampus,cortex and cerebellum. NEUROCHEMISTRY OF GLYCINE SYNTHESIS AND CATABOLISM OF GLYCINE The details of glycine metabolism within neural tissue are poorly understood,and it is unclear to what extent neurons depend on de novo synthesis or uptake of glycine. Two enzymes are important in glycine metabolism; serine hydroxymethyltransferase (SHMT),which is thought to be present in the mitochondria of both neurons and glia,and the four-enzyme complex known as the glycine cleavage system (GCS),present in glia. SHMT catalyses the interconversion of L-serine and glycine while GCS catalyses the breakdown of glycine. Within neurons the action of SHMT leads to the conversion of L-serine to glycine,while in glia the coupling of SHMT and GCS results in the conversion of glycine to L-serine (Verleysdonk et al.

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