S. Ortega. Governors State University.

Receptors formed from r subunits have a higher affinity for GABA than many GABAA receptors formed from abg combinations cheap 100mg avanafil with amex,have a lower single-channel conductance and produce currents that decay more slowly after removal of GABA order 200 mg avanafil mastercard. Picrotoxinin is the active component of picrotoxin and also acts at GABAA receptors generic avanafil 200 mg line. The receptors can form as homomeric assemblies of r subunits but native receptors may be heteromeric assemblies of r subunits (e safe 100 mg avanafil. Activation of these presynaptic receptors inhibits glutamate release from the bipolar cells discount avanafil 50mg with mastercard. 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. The L-serine derived from glycine may be further metabolised,or released from glial cells to be taken up into neurons,forming a cycle analogous to the glutamine±glutamate cycle shown in Fig. Glycine can also be formed by the action of aminotransferases (such as alanine- glyoxylate transaminase or glycine transaminase),in which the amino group from a donor amino acid is transferred onto glyoxlate,producing glycine and a keto acid. As described above,it seems likely that a common transport mechanism (VIAAT) is responsible for the accumulation of both amino acids. This will be determined by the expression of the respective biosynthetic enzymes and plasma membrane transporters. The extent and significance of such co-release is unclear,but its effects will obviously depend on the types of pre- and postsynaptic receptors present at the synapse. Possible benefits of co-release may stem from the different kinetic properties of GABAA and glycine receptors,the ability to activate GABAB receptors or the modulatory action of glycine at NMDA receptors. UPTAKE OF GLYCINE Glycine is removed from the extracelluar space by high-affinity uptake into neurons and glia. All are members of the Na‡- and ClÀ-dependent family transporters and are encoded by two independently regulated genes, GLYT1 and GLYT2. Three GLYT1 isoforms (1a,b and c) and two GLYT2 isoforms (2a and b) are generated by alternative splicing (reviewed by AMINO ACIDS: INHIBITORY 247 Figure 11. The receptors are shown with a pentameric assembly but the a and b subunits are distinct from those that form GABAA receptors. Picrotoxin is also an effective glycine antagonist and in recombinant systems is selective for homomeric receptors Palacin et al. The distribution of the transporters with respect to glycine receptors has led to the suggestion that both transporters are associated with glycinergic synapses,while GLYT1 may also regulate extracellular glycine levels at glutamatergic synapses and hence affect the activity of NMDA receptors. Relatively few selective blockers of glycine uptake have been described.

Even under these conditions discount 100 mg avanafil with amex, optimal sarcom- is on the ordinate discount avanafil 200 mg overnight delivery, any increase in the force of contraction ere length is not exceeded cheap 200mg avanafil. Instead generic avanafil 100mg line, the sarcomeres appear that results in either increased arterial pressure or stroke vol- to realign so that there are more of them in series buy avanafil 100mg without a prescription, allowing ume shifts the stroke work curve upward and to the left. If the ventricle to dilate without stretching sarcomeres be- stroke volume alone were the dependent variable, a change yond their optimal length. Factors other than end- Starling’s law explains the remarkable balancing of the diastolic fiber length can influence the force of ventricular output between the two ventricles. Different conditions produce different relation- to pump 1% more blood than the left heart each minute ships between stroke volume (or work) to end-diastolic fiber without a compensatory mechanism, the entire blood vol- length. For example, increased sympathetic nerve activity ume of the body would be displaced into the pulmonary causes release of norepinephrine (see Chapter 3). A similar error in the oppo- nephrine increases the force of contraction for a given end- site direction would likewise displace all the blood volume diastolic fiber length (Fig. Fortunately, Starling’s law pre- contraction causes more blood to be ejected against a given vents such an occurrence. If the right ventricle pumps aortic pressure and, thus, raises stroke volume. A change in slightly more blood than the left ventricle, left atrial filling (and pressure) will increase. As left atrial pressure increases, Norepinephrine Normal Digitalis Failure End-diastolic fiber length End-diastolic volume End-diastolic pressure Atrial pressure End-diastolic fiber length End-diastolic ventricular pressure FIGURE 14. Several other combinations of variables can be used to plot a on the ventricular function curve. In constant, and stroke volume can be substituted for stroke work if ar- heart failure, contractility is decreased, so that stroke volume terial pressure is constant. End-diastolic fiber length and volume are and/or stroke work are decreased at a given end-diastolic fiber related by laws of geometry, and end-diastolic volume is related to length. Digitalis raises the intracellular calcium ion concentration end-diastolic pressure by ventricular compliance. CHAPTER 14 The Cardiac Pump 241 the force of contraction at a constant end-diastolic fiber length reflects a change in the contractility of the heart. B (The cellular mechanisms governing contractility are dis- cussed in Chapter 10. When an increase in contractility is accompanied by an increase in arterial pressure, the stroke volume may remain constant, and the increased contractility will not be evident by plotting the stroke volume against the end-diastolic fiber length. However, if stroke work is plotted, a leftward shift of the ventricular function curve is observed (see Fig. A ventricular function curve with stroke volume on the ordi- Time nate can be used to indicate changes in contractility only when arterial pressure does not change. During heart failure, the ventricular function curve is shifted to the right, causing a particular end-diastolic fiber length to be associated with less force of contraction and/or shortening and a smaller stroke volume. As described in Chapter 10, cardiac glycosides, such as digitalis, tend to B normalize contractility; that is, they shift the ventricular curve of the failing heart back to the left (see Fig. A Time The collection of ventricular function curves reflecting changes in contractility in a particular heart is known as a family of ventricular function curves. In the normal heart, the force of contraction is also increased by myocardial hypertrophy. A Regular, intense exercise results in increased synthesis of contractile proteins and enlargement of cardiac myocytes. B The latter is the result of increased numbers of parallel my- ofilaments, increasing the number of actomyosin cross- bridges that can be formed. As each cell enlarges, the ven- Force (load) tricular wall thickens and is capable of greater force development. The ventricular lumen may also increase in size, and this is accompanied by an increase in stroke vol- FIGURE 14. The hearts of appropriately trained athletes are capa- volume, and the force-velocity relationship are shown for (A) ble of producing much greater stroke volumes and cardiac normal and (B) elevated aortic pressure. These changes slows the velocity of shortening, decreasing ventricular empty- are reversed if the athlete stops training. In heart disease, al- though myocardial hypertrophy initially has positive ef- fects, it ultimately has negative effects on myocardial force development.

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This has confirmed that the extracellular concen- tration of 5-HT in all brain regions studied to date is lower during both SWS and REM sleep than in the awake state (see Portas purchase avanafil 50mg online, Bjorvatn and Ursin 2000) buy avanafil 100mg without a prescription. Interestingly discount avanafil 100mg with amex, if behaviour is maintained at a constant level buy generic avanafil 200mg on-line, the activity of 5-HT neurons does not show circadian variation although 5-HT turnover in the brain areas to which they project 492 NEUROTRANSMITTERS buy 50 mg avanafil amex, DRUGS AND BRAIN FUNCTION Figure 22. Neurons that release 5-HT are clustered in two groups of nuclei in the pons and upper brainstem. The reasons for this apparent dissociation between firing rate and transmitter release are not clear but it does suggest that neuronal firing rate is not necessarily a reliable indicator of transmitter release in the terminal field. In so doing, they are responsible for gating motor output and coordinating this with homeostatic and sensory function (Jacobs and Azmitia 1992; Jacobs and Fornal 1999). This would be consistent with evidence that, like the noradrenergic system, increases in the firing rate of neurons in the DRN precede an increase in arousal. The frequency of discharge would code the state of arousal and prime target cells for forthcoming changes in the response to sensory inputs. Apart from the problem of trying to associate the effects of 5-HT with specific nuclei, there is also no clear picture of which 5-HT receptors mediate any of these changes in sleep and waking. This is not least because of the large number of receptor subtypes, the limited receptor selectivity of most test drugs, species differences in the response, as well as time- and dose-related differences in the response to any given agent. Nevertheless, it is evident that activation of many different receptor subtypes affect the sleep±waking cycle. For instance, recent evidence suggests that activation of 5-HT1A, 5-HT1B, 5-HT2A/C and 5-HT7 receptors in the SCN all affect circadian rhythms. Activation of 5-HT1B (presynaptic) receptors in the retinohypothalamic tract is thought to attenuate 5-HT release and so blunt light inputs to the SCN and reduce its phototic regulation. In contrast, postsynaptic 5-HT7 receptors, 5-HT2C, and possibly postsynaptic 5-HT1A receptors, are thought to have an important role in phototic entrainment and to mediate phase-shifts in circadian rhythms (reviewed by Barnes and Sharp 1999). In addition to these effects on circadian rhythms, it is clear that 5-HT receptors affect sleep more directly. A detailed review of this subject is to be found in Portas, Bjorvatn and Ursin (2000) but key findings are summarised here. Postsynaptic : 5-HT3 : Postsynaptic : The actions of 5-HT1A receptor agonists in rats depend on their route of administration (Bjorvatn and Ursin 1998). When they are given systemically they cause a transient increase in waking time and a reduction in SWS and REM sleep which is followed by a delayed increase in SWS. This latter response is possibly mediated by activation of inhibitory postsynaptic 5-HT1A receptors in the nucleus basalis (Table 22. Certainly, local infusion of 5-HT1A agonists into this area increases SWS. Another contributory factor is suggested by the reduction in waking and increase in SWS following intrathecal infusion of 8-OH-DPAT. This is thought to reflect inhibition of primary sensory afferents, by activation of presynaptic 5-HT1A receptors, an action which would be conducive with induction of sleep. However, infusion of low concentrations of the 5-HT1A agonist, 8-OH- DPAT, into the DRN to activate autoreceptors induces a type of REM sleep which is explained by a reduction in the firing rate of 5-HT neurons. In turn, this is presumed to result in disinhibition of mesopontine cholinergic neurons in the PPT and LTD nuclei which are responsible for REM sleep. Such a scheme is supported by evidence that local infusion of a 5-HT1A agonist into these areas reduces REM sleep, presumably by inhibition of mesopontine cholinergic neurons by postsynaptic 5-HT1A receptors. Administration of 5-HT1B receptor agonists increases waking time and reduces REM sleep. This is consistent with recent evidence gathered from 5-HT1B-receptor knock- out mice which exhibit more REM sleep and less SWS than the wild-type. Moreover, 5-HT1B agonists reduce, while antagonists increase, REM sleep in the wild-type mouse, but neither type of compound has any effect in the knock-outs (Boutrel et al. Unfortunately, it is not known whether these actions are mediated by presynaptic, postsynaptic or heteroceptors and therefore whether 5-HT activity is increased or decreased. However, these findings are confounded by evidence that activation of 5-HT2C receptors increases SWS.

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Postganglionic of the calcarine sulcus or follow an arching route (the Meyer cheap avanafil 200mg with amex, or Meyer- sympathetic fibers to the head originate from the superior cervical gan- Archambault loop) through the temporal lobe to the lower bank (lingual glion buy generic avanafil 200mg on-line. Although not shown quality avanafil 200 mg, descending projections to the intermedio- gyrus) of the calcarine sulcus 200 mg avanafil with amex. Temporal lobe lesions involving the lateral cell column also originate from various hypothalamic areas and Meyer-Archambault loop purchase 50 mg avanafil with visa, or involving fibers entering the lingual nuclei (hypothalamospinal fibers), some of which receive retinal input. A homonymous Neurotransmitters: Acetylcholine is the transmitter found in inferior quandrantanopia is seen in patients with damage to upper (pari- the preganglionic and postganglionic autonomic fibers shown in this il- etal) parts of the geniculocalcarine radiations or to these fibers as they lustration. In addition, N-acetylaspartylglutamate is present in some enter the cuneus. Damage to the visual cortex adjacent to the calcarine sulcus (distal Clinical Correlations: Total or partial blindness in one or both posterior cerebral artery occlusion) results in a right (or left) homony- eyes may result from a variety of causes (such as gliomas, meningiomas, mous hemianopsia. With the exception of macular sparing, this deficit is strokes, aneurysms, infections, and demyelinating diseases); lesions may the same as that seen in optic tract lesions. A complete lesion (for ex- Vascular lesions (as in the lateral medullary syndrome), tumors (such ample, a transection) of the optic nerve will result in blindness and loss as brainstem gliomas), or syringobulbia may interrupt the descending pro- of the pupillary light reflex (direct response) in the eye on the injured jections from hypothalamus (hypothalamospinal fibers) and midbrain side and a loss of the pupillary light reflex (consensual response) in the to the intermediolateral cell column at upper thoracic levels. On the other hand, shin- result in a Horner syndrome (ptosis, miosis, and anhidrosis) on the ipsilat- ing a light in the normal eye will result in a pupillary light reflex (direct eral side. The enophthalmos (a slight sinking of the eyeball into the or- response) in that eye and a consensual response in the blind eye. A pi- bit) frequently mentioned in relation to Horner syndrome is not really tuitary adenoma may damage the crossing fibers in the optic chiasm (pro- very apparent in afflicted patients. Abbreviations CC Crus cerebri PoCom Posterior commissure CilGang Ciliary ganglion PrTecNu Pretectal nucleus EWNu Edinger-Westphal nucleus PulNu Pulvinar nuclear complex ILCC Intermediolateral cell column RetF Reticular formation LGNu Lateral geniculate nucleus RNu Red nucleus MGNu Medial geniculate nucleus SC Superior colliculus ML Medial lemniscus SC,Br Superior colliculus, brachium OcNr Oculomotor nerve SCerGang Superior cervical ganglion OpCh Optic chiasm SN Substantia nigra OpNr Optic nerve WRCom White ramus communicans OpTr Optic tract Review of Blood Supply to OpTr, MGB, LGB, SC, and Midbrain Tegementum, Including PrTecNu STRUCTURES ARTERIES OpTr anterior choroidal (see Figure 5–38) MGNu, LGNu thalamogeniculate branches of posterior cerebral (see Figure 5–38) SC and PrTecNu long circumferential branches (quadrigeminal) of posterior cerebral, posterior choroidal, and some from superior cerebellar (to SC) (see Figures 5–27 and 5–38) Midbrain paramedian branches of basilar bifurcation, medial branches Tegmentum of posterior cerebral and posterior communicating, short circumferential branches of posterior cerebral (see Figure 5–27) Optic, Auditory, and Vestibular Systems 221 Pupillary Pathways Dilator muscles of iris Sphincter mus. Optic radiations (in retrolenticular Cuneus limb of internal capsule) Lingual gyrus CalSul 7–26 The origin, course, and distribution of the visual pathway are Neurotransmitters: Cholecystokinin ( ) is present in some shown. Uncrossed retinogeniculate fibers terminate in laminae 2, 3, geniculocalcarine fibers. N-acetylaspartylglutamate is found in some and 5, while crossed fibers end in laminae 1, 4, and 6. Geniculocal- retinogeniculate fibers, and in some lateral geniculate and visual cor- carine fibers arise from laminae 3 through 6. Upper-case let- ters identify the binocular visual fields (A, B, C, D), the macula (M), and the monocular visual fields (A , B , C , D ). This illustration is provided for self-evaluation of visual pathway understanding, for the instructor to expand on aspects of the visual pathways not covered in the atlas, or both. Optic, Auditory, and Vestibular Systems 225 226 Synopsis of Functional Components, Tracts, Pathways, and Systems Auditory Pathways 7–29 The origin, course, and distribution of the fibers collectively hearing loss and conduction hearing loss, and to lateralize the deficit. Central to the cochlear nerve and the Weber test, a tuning fork (512 Hz) is applied to the midline of the fore- dorsal and ventral cochlear nuclei this system is, in a general sense, bi- head or apex of the skull. In the normal patient, the sound (conducted lateral and multisynaptic, as input is relayed through brainstem nuclei through the bones of the skull) is heard the same in each year. Synapse and crossing (or re-crossing) of nerve deafness (lesions of the cochlea or cochlear nerve), the sound is best of information can occur at several levels in the neuraxis. Conse- heard in the normal ear, while in conductive deafness, the sound is best heard quently, central lesions rarely result in a total unilateral hearing loss. In the Rinne test, a tuning fork (512 Hz) is placed The medial geniculate body is the thalamic station for the relay of au- against the mastoid process. When the sound is no longer perceived, the ditory information to the temporal cortex. In middle ear disease, the sound is not heard at the external meatus nuclei. Dynorphin-containing and histamine-containing fibers are also after it has disappeared from touching the mastoid bone (abnormal or neg- present in the cochlear nuclei; the latter arises from the hypothalamus. Therefore, a negative Rinne test signifies conductive noradrenergic projection to the cochlear nuclei and to the inferior col- hearing loss in the ear tested. In mild nerve deafness (cochlea or cochlear liculus originates from the nucleus locus ceruleus. Cells in the superior nerve lesions), the sound is heard by application of the tuning fork to the olive that contain cholecystokinin and cells in the nuclei of the lateral lem- mastoid and movement to the ear (the Rinne test is positive). In severe niscus that contain dynorphin project to the inferior colliculus.

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