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By X. Snorre. University of Science and Arts of Oklahoma.

The effects of nicotine significantly less susceptible to this stimulation of motor on the body and egg-laying muscles are mediated through activity by ethanol best 10 mg ezetimibe. However order ezetimibe 10 mg with amex, these dopamine-depleted flies a nicotinic receptor known as the levamisole receptor (57 10 mg ezetimibe with visa, exhibited no abnormalities in their sensitivities to ethanol- 58) order ezetimibe 10 mg online. The antihelminthic drug [and ganglionic nAChR ago- induced uncoordination or immobilization. Thus, the stim- nist (59)] levamisole is a potent agonist of this receptor; like ulation of motor activity by ethanol may involve ethanol- nicotine, levamisole causes body muscle hypercontraction induced enhancement of dopaminergic transmission in and (at high doses) spastic paralysis. Although the levamisole brain areas controlling locomotion, whereas the other be- receptor is found on nematode muscle, its pharmacologic havioral effects of ethanol are likely to involve other neuro- profile generally resembles that of ganglionic nicotinic re- transmitter systems. By screening for levamisole-resistant The genetic analysis of ethanol response mechanisms in mutants, it has been possible to identify genes affecting the Drosophila is still in its early stages. However, it is already function of the levamisole receptor (60). Mutations confer- clear that mutants with altered responses to ethanol can be ring strong resistance to levamisole have been identified in identified in straightforward genetic screens, and at least in six genes. Three of these genes, unc-38, unc-29, and lev-1, some cases analyzed in the context of well-defined neuronal encode nicotinic receptor subunits (61,62). Perhaps the greatest promise for future protein is most similar to the insect -like subunits ALS and studies is the possibility that novel ethanol response genes, SAD (49% amino acid identity); among vertebrate receptor possibly including the direct molecular targets of ethanol, subunits, the closest similarity is to neuronal subunits can be identified in ethanol-resistant or ethanol-hypersensi- (61). UNC-29 and LEV-1 are closely related proteins whose tive screens. Three addi- tional genes conferring strong levamisole resistance, unc-50, Nicotine unc-74, and unc-63, have not been cloned, but have been Tobacco has been implicated in more deaths than any other shown to be required for assembly of a functional levamisole addictive substance (51), yet the biochemical basis for com- receptor as assayed in vitro (63). In addition to conferring pulsive tobacco use remains poorly understood. The sub- resistance to levamisole (and other nicotinic agonists), mu- stance most responsible for the addictive properties of to- tations in these genes cause defects in the coordination of bacco is nicotine, a potent stimulant and cholinergic body movement (60). Long-term exposure to nicotine is known to cause (lev-8, lev-9, and lev-10) confer weaker resistance to levami- adaptive changes in the activity and number of nicotinic sole, do not cause defects in locomotion, and have no detect- receptors in the brain, which are thought to be important able effect on the biochemical properties of the receptor as for nicotine addiction (52). For example, nicotinic receptors assayed in vitro (60,63). Thus, the proteins encoded by these exist in multiple functional states, some of which are rela- genes have been hypothesized to regulate the activity of the tively refractory to channel opening though they retain af- receptor indirectly. Chronic exposure to nicotine or other Long treatments with nicotine and other nicotinic recep- agonists results in an increased fraction of receptors adopt- tor agonists lead to adaptation (57). Animals treated with ing the lower activity states, leading to an attenuation of exogenous nicotine initially hypercontract to the point of the overall nicotine response (53). Long-term nicotine treat- spastic paralysis; however, after several hours in the presence ment also causes a long-lasting functional inactivation of of nicotine, they recover their ability to move and regain some nicotinic receptors (54), which has a slower time much of their body length. Moreover, when nico- treatment can also either increase or decrease the number tine-adapted animals are removed from nicotine, their loco- of nicotinic receptors on the cell surface, effects that appear motive behavior becomes uncoordinated and resembles that to be mediated at the level of protein turnover (55,56). The of mutants with strong defects in the levamisole receptor cellular pathways that promote these changes are not well (i. Thus, long treat- understood; for example, little is known about the cellular ments with nicotine cause nicotine dependence in addition 270 Neuropsychopharmacology: The Fifth Generation of Progress to nicotine tolerance in the C. However, dopamine is probably not the only neuro- term nicotine treatment also down-regulates levamisole re- transmitter involved in cocaine addiction, since mice lack- ceptors in the egg-laying muscles. Overnight treatment with ing the vesicular dopamine transporter will still self-admin- nicotine leads to an almost complete attenuation of levami- ister cocaine after repeated administration of the drug (66, sole sensitivity with respect to egg laying, and this attenua- 67). Although dopaminergic transmission in the limbic re- tion of levamisole response persists for up to 24 hours after ward pathways has been implicated in the reinforcing prop- removal from nicotine. This loss of levamisole responsive- erties of a wide range of addictive substances in addition to ness is accompanied by a corresponding decrease in the cocaine, the molecular and cellular mechanisms that lead abundance of UNC-29–containing receptors in the vulval to addiction in these neurons are not well understood. Interestingly, the nicotine-dependent de- of cocaine action may be accessible to genetic analysis. For example, at low doses treated flies possibility that direct phosphorylation of nicotinic receptors become hyperactive and exhibit compulsive, continuous might represent a signal for increased turnover. At intermediate doses animals move ture, it should be possible to test this hypothesis, as well more slowly and display stereotyped locomotive behaviors as identify other genes required for long-term responses to such as circling. Finally, at high doses animals undergo nicotine in C. Repeated treat- Another set of genes, the weak levamisole-resistance ment of flies with low doses of cocaine results in an increased genes lev-8 and lev-9, appear to represent positive regulators behavioral response, a phenomenon known as sensitization; of nicotinic receptor activity. Mutations in these genes con- cocaine sensitization also occurs in mammals and is thought fer partial resistance to levamisole and nicotine with respect to underlie some aspects of addiction in humans. Interest- to body muscle contraction and strong resistance with re- ingly, male flies are more sensitive to cocaine than females, spect to egg laying (65). However, lev-8 and lev-9 mutations a sexual dimorphism that also holds true in mammals (69).

Brief because the HIV virus is spread more readily from men to periods of depression are especially common during chronic women than from women to men ezetimibe 10mg low price. Females patients who intoxication or withdrawal or in association with psychoso- are intravenous drug users and who also engage in prostitu- cial stressors that are related to the dependence purchase ezetimibe 10 mg online. Insomnia is tion or other forms of high-risk sexual behavior are at ex- common buy 10mg ezetimibe amex, especially during withdrawal; sexual dysfunction buy discount ezetimibe 10 mg online, tremely high risk of HIV infection (60). Cocaine use has especially impotence, is common during intoxication. De- been found to be a significant risk factor as a single drug lirium or brief, psychotic-like symptoms are occasionally of abuse or when used in combination with heroin or other seen during opioid intoxication (54). The data on psychiatric comorbidity among opioid ad- As mentioned earlier, mortality is high, and studies have dicts and its negative effect on outcome (55) have stimulated found annual death rates of approximately 10 per 1,000 or research on the effect of combining psychiatric and sub- greater, which is substantially higher than demographically stance abuse treatment. Several studies have now shown matched samples in the general population (62). Common that tricyclic antidepressants can be useful for chronically causes of death are overdose, accidents, injuries, and medical depressed opioid addicts who are treated with methadone complications such as cellulitis, hepatitis, AIDS, tuberculo- maintenance (56). Two studies have shown that profes- sis, and endocarditis. The cocaine and alcohol dependence sional psychotherapy can be useful for psychiatrically im- that is often seen among opioid-dependent persons contrib- paired, methadone-maintained opioid addicts, although an- utes to medical morbidity by cirrhosis, cardiomyopathy, other study found no psychotherapy effect (57–59). The myocardial infarction, or serious cardiac arrhythmias. In been a reduction in psychiatric symptoms such as depres- most cases, infection is asymptomatic and is evident only sion, although some studies have shown reductions in sub- by the presence of a positive tuberculin skin test. As After rising rapidly in the late 1970s and early 1980s, a result, these patients are sometimes excluded from metha- the incidence of new HIV infections among intravenous done treatment because of the severity of their psychotic drug users, of whom opioid-dependent persons constitute 1514 Neuropsychopharmacology: The Fifth Generation of Progress a large proportion, decreased (63). However, as a result of mediately after delivery also appears to reduce the incidence high levels of needle sharing and other risky behavior in the of HIV infection. Because of the long incuba- psychiatric and medical care within agonist and other sub- tion period before the development of AIDS, it is expected stance abuse treatment programs (70). Clinical experience that future years will continue to see high levels of morbidity and National Institute on Drug Abuse demonstration and mortality associated with HIV infection, although the projects have shown that integration of these services with advent of new pharmacotherapies for HIV has extended agonist maintenance can be done, and with very positive many lives. Related to this line of research are several important interactions between methadone and studies that have shown improved compliance with directly drugs used to treat HIV infection. Information is not com- observed antituberculosis pharmacotherapy (71). These plete, however, and more studies are needed to map out findings have important implications for tuberculosis con- the extent of these interactions completely. One important trol policies in methadone programs because intravenous interaction is that methadone increases plasma levels of zi- drug users are at very high risk of tuberculosis infection and dovudine; the associated symptoms resemble methadone because maintenance programs provide settings in which withdrawal. There have been instances in which methadone directly observed therapy can be easily applied. Similar prin- doses have been increased in response to complaints of with- ciples apply to administration of psychotropic medication drawal, with increasing doses compounding the problem. Harm Reduction This interaction can be important if the patient discontinues either of these two drugs while taking methadone, because Harm reduction is concerned with minimizing various nega- the result may be a sudden rise in methadone blood levels tive consequences of addiction. As such, the focus is shifted with signs and symptoms of overmedication (65,66). Examples of harm reduction include seen in children born to opioid-dependent women. Perhaps needle exchange programs, efforts directed at reducing drug- the most serious is premature delivery and low birth weight, use-associated behaviors that may result in the transmission a problem that can be reduced if the mother is receiving of HIV, and making changes in policies (including increas- methadone maintenance and prenatal care (67). Another is ing treatment availability) that reduce heroin use and the physiologic dependence on opioids, seen in about half the criminal behavior associated with drug procurement. Harm infants born to women maintained on methadone or depen- reduction refers to reducing harm not only to the individual dent on heroin or other opioids. Effective treatments for addict, but also to family, friends, and society generally. For example, Reuter and The possibility that breast-feeding may cause adverse ef- Caulkins pointed out the benefit of integrating drug use fects in infants of methadone-maintained mothers was stud- reduction and harm reduction components into a single ied. It was found that methadone was present in the breast framework (74), because total harm may be lowered by re- milk of women maintained on doses as high as 180 mg, ducing either component. Roche and colleagues proposed but the concentration was very low, and no adverse effects a model for an integrated addiction treatment strategy that were observed in the infants (68). HIV infection is seen in incorporates harm reduction and use reduction with absti- about one-third of infants born to HIV-positive mothers, nence and nonuse (75), in addition to other critical elements but this incidence can be reduced to about 10% if HIV- such as factors related to culture and gender. Additionally, positive pregnant women are given zidovudine before deliv- MacCoun provided a template for integrating harm reduc- ery (69). HIV can also be transmitted by breast-feeding, tion with prevalence reduction (discouraging the engage- and thus infant formula feeding is recommended for babies ment in drug use) and quantity reduction (encouraging the of HIV-positive mothers, except in some developing coun- reduction in frequency or extent of drug use) (76). Thor- With regard to opioids, much of the health-related harm ough washing of infants born to HIV-infected mothers im- from their improper or illicit use is secondary to elements Chapter 105: Treatment of Opioid Addiction 1515 other than the substances themselves (77). Funds saved from these hygienic methods of administration and poor injection cost reductions have often not been invested in outpatient technique are typically more serious than the constipation treatment.

There is a need for physical activity and the memory is comparatively preserved buy ezetimibe 10 mg with visa, so that supervised outings may be possible ezetimibe 10 mg without prescription. He continued to wear expensive suits and was often seen order ezetimibe 10mg on-line, up to his shoulder purchase 10 mg ezetimibe, feeling around in rubbish bins on street corners. When one asked if he had lost something and whether one could be of any assistance, he would look back blankly, but utter no words. It had elements of “a strong urge to explore the environment” and perhaps, hoarding. The man himself, however, did not appear to be self-conscious or distressed. He was later met by the author in a specialized dementia unit. INITIAL COGNITIVE TESTING Neuropsychological testing has a place in the comprehensive assessment of many people with dementia. In the initial assessment, a simple tool allows a degree of quantification. Abbreviated mental test score (AMTS) The AMTS (Hodkinson, 1972) is probably the briefest. If the patient scores 6 or less correctly, there is a need for further assessment. Make sure the patient is not delirious and is able to attend to the task. Give the patient an address, and ask him or her to repeat it at the end of the test What is the year? What is the name of the hospital or number of the residence where the patient is situated? Can the patient recognize two persons (the doctor, nurse, home help, etc. In which year did the First World War begin (adjust this for a world event the patient would have known during childhood)? What is the name of the present monarch (head of state, etc. Mini mental state examination (MMSE) The mini mental state examination (MMSE; Folstein et al, 1975) is the most commonly used cognitive screening test. It is a 30-point questionnaire which samples memory and orientation, language and constructional skills. Make sure the patient is not delirious (can attend to the task at hand) and has no visual, hearing or physical difficulties. The MMSE • Orientation in time: what is the year, month, date, season, day of the week? Also, there may be delusions Frontotemporal dementia Either of the following: (FTD) 1. Decline in regulation of personal or interpersonal conduct (loss of empathy for others; socially inappropriate behavior that are rude, sexually explicit; mental rigidity; decline in personal hygiene; obsessional behaviors), or 2. Impaired reasoning or handling of complex tasks, out of proportion to impairments of recent memory or spatial ability. Also, there is often rapid decline in language skills Pridmore S. American Journal of Psychiatry 1998; 154 (Supplement 5), 1-39. Early and presenting symptoms of dementia with Lewy Bodies. Promoter DNA methylation regulates progranulin expression and is altered in FTLD. Is there a role for physical activity in preventing cognitive decline in people with mild cognitive impairment? Racial differences in the progression of cognitive decline in Alzheimer disease. Endogenous and exogenous estrogen, cognitive function, and dementia in postmenopausal women. Brain morphology in older African Americans, Caribbean Hispanics, and whites from northern Manhattan. Neuro pathological staging of Alzheimer-related changes. Time until institutionalization and death in patients with dementia. Another nail in the coffin of the cognitive paradigm of dementia. Neuroscience and Biobehavioural Reviews 2016, in press.

Al- though several different kinases have been demonstrated to Immunoblot analyses of brains from patients with tauopa- be capable of phosphorylating tau in vitro generic 10mg ezetimibe with amex, the specific ki- thies other than AD have demonstrated that insoluble tau nases that are responsible for the phosphorylation of tau in fractions are detectable using many different phosphoryla- the living human CNS remain to be identified generic ezetimibe 10 mg on-line. Only two tion-dependent antibodies to epitopes spanning the tau kinases order ezetimibe 10mg with amex, glycogen synthase kinase-3 (GSK-3 ) and cyclin- molecule buy 10mg ezetimibe otc, suggesting that the filamentous inclusions in these dependent kinase 5 (Cdk5), have been copurified with MTs diseases are composed of hyperphosphorylated tau similar 1344 Neuropsychopharmacology: The Fifth Generation of Progress FIGURE 94. Schematic representation of sar- kosyl-insoluble tau bands from different tauopa- thies before ( ) and after ( ) dephosphoryla- tion. The insoluble tau composed of all six isoforms shows three major bands (60, 64, and 68 kDa) and one minor band (72 kDa) before de- phosphorylation. Insometauopathies,3Rtauiso- forms are major components of the insoluble fraction, running as two major bands (60 and 64 kDa) and one minor band (68 kDa). Tauopathies with insoluble tau consisting of 4R tau isoforms shows two major bands (64 and 68 kDa) and one minor band (72 kDa). Three types of abnormal tau isoform 17, three major clinical syndromes have been delineated, profiles have been found in tauopathies other than AD (Fig. For example, similar to AD, three predominant PHF- tia-parkinsonism-amyotrophy complex (DDPAC) (55, tau–like bands of 60, 64, and 68 kDa and one minor band 147), pallido-ponto-nigral degeneration (PPND) (148), of 72 kDa are observed in Down syndrome, GSS disease, and MSTD (64). However, it is important to note that ALS/PDC of Guam, Niemann-Pick disease type C, and more than 20 kindreds caused by diverse tau gene muations some FTDP-17 kindreds caused by certain tau mutations and variably characterized phenotypes have been reported (17,23,29,43,72). Clinical characteristics of these FTDP-17 tau- all six tau isoforms in several studies. On the other hand, opathies variably include memory and language impair- biochemical analyses of Pick disease have shown a character- ments, behavioral and psychiatric abnormalities, extrapy- istic pattern of tau isoform composition consisting of two ramidal signs, and motor deficits (50), each of which pre- major tau bands of 60 and 64 kDa and one minor tau band sumably reflects differential degeneration of specific brain of 68 kDa (34,141). However, all FTDP-17 brains from affected pa- positive for anti-phospho-tau antibody 12E8, which recog- tients share a common neuropathology characterized by nizes an epitope in E10, but our study demonstrated weak abundant neuronal and to a lesser extent glial fibrillary le- but specific recognition (34). Further, several studies have sions composed of hyperphosphorylated tau proteins associ- indicated that these bands include only 3R tau isoforms ated with a remarkable loss of neurons in affected regions (142,143). The third type of abnormal tau isoform profile (144,149–151). Because predominantly consist of 4R tau isoforms (64,110,144, the pathologic hallmarks of these disorders are tau lesions 145). Thus, as expected, several research groups discovered multiple tau gene muta- FRONTOTEMPORAL DEMENTIA WITH tions in 1998, and these mutations were found to segregate PARKINSONISM LINKED TO CHROMOSOME with FTDP-17 patients, but they were not seen in normal 17: CAUSED BY MULTIPLE EXONIC AND individuals (151,154,155). Further studies have identified INTRONIC TAU GENE MUTATIONS at least 20 distinct pathogenic mutations in exons and in- trons of the tau gene in many FTDP-17 kindreds, many FTDP-17 is a group of familial neurodegenerative tauopa- of which were identified for the first time with the identifi- thies characterized by diverse but overlapping clinical and cation of a tau gene mutation. Approximately 10 missense neuropathologic features (50,60,146). According to several mutations were found in exons of the tau gene, and they reports on clinical and neuropathologic features of FTDP- include K257T, I260V (Hutton M, personal communica- Chapter 94: Tau Protein and Tauopathy 1345 tion), and G272V (154) in exon 9; N279K (142), P301L E10 caused by these mutations results in increased levels of (142,152,155), P301S (156,157), and S305N (158,159) in E10 tau mRNA in FTDP-17 brains presumably owing E10; V337M (155) in exon 12; and G389R (160) and to greater E10 usage of the E10 5′ splice site as demonstrated R406W (154) in exon 13 (numbered according to the long- by exon-trapping experiments (154,159). Biochemical anal- est CNS tau isoform consisting of 441amino acids). More- yses of tau extracted from autopsied brain samples of pa- over, two silent mutations have been reported, including tients with PPND (N279K), DDPAC (E10 14) and L284L (159) and S305S (161) in E10 and a mutation result- MSTD (E10 3) have shown a predominance of 4R tau ing in the deletion of single amino acid K280 (159,167) isoforms (111,145,151). On the other hand, intronic tau gene mutations in mutations affect multiple cis-acting elements that enhance FTDP-17 kindreds are clustered around the 5′ splice site or suppress the usage of 5′ splice site of E10 (151,154,159). They contain E10 3 (151), A stem-loop structure consisting of sequences around the E10 12 (163), E10 13 (164), E10 14 (145,164), 5′ splice site in the intron following E10 is thought to in- E10 16 (164,165), and E10 33 (162). The currently hibit the splicing of E10 presumably by blocking the associa- known tau gene mutations in FTDP-17 kindreds are listed tion of snRNA with the splice site (151,154). The S305N mutation has also frequent than previously recognized. However, the S305S mutation, which increases the be pathogenic by one or more abnormalities in tau proteins, 4R/3R ratio like the S305N mutation, has been demon- and at present, two mechanisms have been proposed to me- strated to weaken the 5′ splice site (161). Another potential diate the effects of these mutations based on recent molecu- regulatory element might be an exon-splicing enhancer lar and biochemical analyses (111,154,159,166). The first (ESE) or exon-splicing silencer (ESS) element within E10 mechanism involves perturbations of the alternative splicing adjucent to the following intron (159). The N279K muta- of E10 by mutations in E10 or around the 5′ splice site in tion is thought to augment the ESE and consequently cause the intron following E10, thereby resulting in an altered an increase in the 4R/3R ratio of tau isoforms because of ratio of 4R tau to 3R tau proteins. The second pathogenic the fact that it raises the purine content of this purine-rich mechanism directly impairs the ability of tau to bind to domain (i. The silent mutation 4R/3R ratio of brain tau isoforms has been demonstrated L284L is likely to disturb the ESS (159), but it also is possi- in brains of FTDP-17 patients with mutations clustered ble that this mutation augments the effects of the ESE. The altered splicing of the 4R/3R tau isoform ratio is likely to produce an excess FIGURE 94. The muta- tion sites are depicted on the long- est tau isoform.

The effects of nicotine on tests Moreover order ezetimibe 10 mg, a correlation between cortical ACh release and of reinforcement and behavioral sensitization are primarily the state of behavioral activation or sleep has been observed mediated through the mesolimbic dopamine system (39) discount ezetimibe 10 mg otc. Thus purchase 10mg ezetimibe visa, it was hypothesized that cholinergic input Indeed 10 mg ezetimibe amex, the ventral tegmental area (VTA) may be sufficient to the neocortex from the basal forebrain is critical for regu- to mediate the reinforcing properties of nicotine, as local lating arousal (see ref. These neurons largely do not inner- preference (41). Chapter 1: Acetylcholine 7 Basal forebrain cholinergic neurons may also be involved lesions increased sucrose consumption, similar lesions did in modulating cortical processing of stimuli with condi- not affect discrimination or contrast effects (57). Neverthe- tioned or unconditioned rewarding properties because these less, the hypothesis of Winn (58) is that lesions of the PPT neurons are more responsive to stimuli with a high incentive affect responding for rewarding stimuli similarly to lesions value. Novel stimuli that typically elicit orienting responses of the frontal cortex, so that the role of the PPT, like that of and attention in animals increase cortical ACh release, but the basal forebrain, is expanded into higher-order cognitive this effect is diminished with repeated exposure if the stimu- processes. In contrast, if the stimulus is repeatedly paired with an incentive stimulus (e. Pontomesencephalic cholinergic neurons are also The hypothesis of cholinergic involvement in learning and involved in motivation and reward, although these effects memory processes arose from several findings. Both destruc- are likely mediated, in part, by projections to the dopamine tion of the basal forebrain complex and the administration neurons within the VTA (44,45). While a significant proportion of the The original finding that lesions of the basal forebrain PPT neurons that project to the tegmental dopamine neu- could produce deficits in a variety of cognitive tasks sug- rons are noncholinergic (44), the cholinergic input per se gested a role for ACh in cognitive function. Electrolytic, appears to stimulate dopamine neurons (47). Thus, ascend- radiofrequency, or nonspecific excitotoxic lesions of cholin- ing projections from the PPT to the dopamine cells may ergic subnuclei within the basal forebrain (particularly the regulate the ability of mesostriatal dopamine neurons to medial septum/diagonal band) profoundly impair perfor- affect incentive/motivational processes. These deficits appeared modulate the rewarding qualities of addictive drugs. Lesions to be reversed following regeneration of cholinergic projec- of the PPT reduce the self-administration of nicotine (48) tions across a bridging graft (61) or after grafting of ACh- and opiates (49). Moreover, conditioned place preference producing cells in the hippocampus (62). These findings for food, opiates (50), morphine (51), and amphetamine have been interpreted as support for the hypothesis of cho- (52) is blocked or reduced by PPT lesions, whereas cocaine- linergic involvement in cognitive functions; however (as induced reward is unaffected (53). Although the mesolimbic with arousal and sleep), noncholinergic neurons within the dopamine pathway is known to be involved in drug reward basal forebrain may likewise be involved in these effects, (see ref. It is also not known whether the effect Novel approaches for selectively destroying cholinergic of PPT lesions on these processes is mediated through pro- neurons depend on the differential sensitivity of basal fore- jections to areas other than the dopamine cell groups within brain neurons to excitotoxins and new types of immunotox- the VTA. Systematic studies have demonstrated that cholinergic The PPT may have another, more critical, role in motiva- and noncholinergic neurons within the basal forebrain are tion and reward via afferent inputs from the striatum (55). Based on the results of these stud- ulant-induced orofacial stereotypy, yet no difference is ob- ies, new methods for preferentially destroying cholinergic served in stimulant-induced locomotion or other measures neurons have been described (63). These data may implicate the porin toxin has been developed that takes advantage of the PPT (and its innervation from the striatum) in response fact that basal forebrain cholinergic neurons are particularly selection when discrimination is involved because the dis- enriched with low-affinity receptors for nerve growth factor ruption of responding for conditioned reinforcement re- (64). The toxin selectively binds to the receptor for nerve sulted from decreased discrimination of response between growth factor and then kills the neuron expressing the recep- a lever associated with reinforcement and an inactive lever tor. More excitingly, recent studies suggest that IgG–sa- (56). However, a recent study found that although PPT porin can be used to destroy the cholinergic innervation of 8 Neuropsychopharmacology: The Fifth Generation of Progress conditioning but impairments in discrete cue (trace) condi- tioning (69). Both sets of data may suggest that the atten- tional processing of discrete stimuli is disrupted following cholinergic depletion from posterior cortical regions. It is possible, however, that the depletion of ACh from caudal or rostral cortical regions alone may be insufficient to impair performance of some tasks, whereas combined depletions may have more than additive effects (70). Other investigators have further argued that the choliner- gic innervation of rostral (e. Direct pharmacologic manipulation of basal forebrain neurons has been used to alter activated cholinergic efflux in the frontal cortex and performance of tasks related to stimulus process- ing or detection (72). Selective excitotoxic lesions or phar- macologic manipulation of the nucleus basalis has also been reported to impair performance in a five-choice serial reac- tion task that requires animals to detect and respond to brief visual stimuli (73). Interestingly, the observation that appetitive pavlovian learning for a discrete cue is enhanced after nucleus basalis lesions (74) suggests that attentional processing of discrete cues may not be affected by depletion of ACh from the rostral neocortex except when divided attention is required. The findings of these latter studies are also bolstered by advances in the measurement of ACh FIGURE 1. Acetylcholinesterase staining of the nucleus basalis magnocellularis after infusion of saline solution or AMPA to de- transmission in vivo, which allows investigators to quantify stroy cholinergic neurons preferentially. Low concentrations of directly the extent of the lesions produced by the toxins for the glutamatergic agonist AMPA selectively destroy cholinergic the first time (75). Taken together, the available data seem neurons (measured by acetylcholinesterase staining) and spare -aminobutyric acid (GABA) neurons (left). In contrast, control to suggest that basal forebrain cholinergic neurons are capa- sections show robust acetylcholinesterase staining after infusion ble of regulating the cortical processing of sensory stimuli of saline solution (right). This process allows more specific cholin- within a variety of domains, which may be explained by a ergic lesions to be generated, so that the function of the neurons role for basal forebrain ACh in the regulation of cortical in behavioral processes can be clarified.

For example ezetimibe 10 mg free shipping, Astrocytes expedite the removal of evoked increases in small increases in [K ] cause breakdown of glycogen (18) generic ezetimibe 10mg on-line, [K ] and limit its accumulation to a maximum level of o o perhaps providing fuel for nearby active neurons (see the 10 to 12mM discount ezetimibe 10 mg visa, the ceiling level seen with intense activity following) order ezetimibe 10 mg without prescription. Neurons, and perhaps Neurons and glial cells do not make functional synaptic blood vessels, also participate in [K ] regulation, but glial o or gap junction contacts with one another; therefore, inter- mechanisms are probably most important. Two general actions between these cell types must occur via the narrow mechanisms of astrocyte K removal have been proposed extracellular space (ECS) between them (16). There may (39): 1) net K uptake into astrocytes (by transport mecha- be rare exceptions to this rule (19,20). In the mammalian nisms and/or Donnan forces) and 2) K redistribution central nervous system (CNS), the ECS is a uniform and through astrocytes, which is known as K spatial buffering. Brain ECS is a dynamic compartment in terms of its the nature of the [K ] increase as well as brain region (38). Because of If glial cells take up K during neural activity and release the extreme narrowness of the ECS, molecules released from it thereafter, a transient increase in glial [K ] should result. Glial cells Astrocyte [K ] does transiently increase during neural ac- i interact with neurons by influencing the contents (e. It active neurons and the increase in [K ] , indicating that o should be emphasized that nearly every neuron in the brain the K released from neurons is passing by way of the shares common ECS with adjacent astrocytes, and astrocytic ECS into glial cells (40–42). Uptake of K into glial cells processes entirely surround synapses. It has been surprising depends on the glial Na pump (38,42–44), an anion to discover that glial cells release and express receptors for transporter that cotransports K and Na with Cl (43) a wide range of informational molecules, including neuro- and Donnan forces that propel KCl into glial cells in the transmitters (22); this greatly expands the possibilities for face of elevated [K ] (42) (Fig 10. It has not been deter- o glial–neuronal interactions. Indeed, astrocytes are in a posi- mined with certainty which of these mechanisms is quanti- tion to sense and modulate synaptic transmission through tatively most important for K uptake. The astrocyte Na the pervasive lamellar processes that surround synaptic con- pump, however, is exquisitely sensitive to elevations of tacts (7). Even a 1 mM increase in [K ] activates the Na o o pump in these cells indicating, perhaps, that this is the major mechanism of K sequestration (44). Neurons, of course, FUNCTIONS must eventually reaccumulate K lost during activity using their Na pump, but only glial cells show net accumulation Ion Homeostasis of K (Fig. It is interesting to note that the neuronal One of the best-established functions of astrocytes is regula- Na pump is not sensitive to small increases in [K ] and o tion of brain [K ]. Astrocytes are also likely to participate is probably activated mainly by increases in intracellular o in the regulation of extracellular pH, but this aspect of astro- [Na ] (45). In fact, under conditions of diminished energy supply, glial cells actually contribute K to the ECS, rather than take it up (49). Transmitter Synthesis Glutamate is one of the most common amino acids in the brain, present at millimolar concentrations in brain tissue homogenate. It is also the predominant excitatory neuro- transmitter (50). Only a small fraction of total brain gluta- mate is packaged for synaptic release and astrocytes are inti- mately involved in the synthesis of this crucial vesicular pool of glutamate. Although glutamate can be derived from neuron glucose metabolism, carbon-labeling experiments reveal that astro- FIGURE 10. Schematic representation of mechanisms of K cyte-derived glutamine is the principal precursor of synapti- uptake in astrocytes. K released by firing neurons is actively cally released glutamate (51,52). The synthesis and release accumulated by astrocytes in three ways. The sodium pump and an anion transporter both take up K ; the sodium pump relies of glutamine by astrocytes is part of a biochemical shuttle directly on the availability of ATP, whereas the anion transporter mechanism called the glutamate-glutamine cycle (53) (Fig is indirectly powered by the energy stored in the transmembrane 10. After release from the presynaptic terminal, glutamate Na gradient. The presence of channels for Cl and K , allow Donnan forces to produce KCl influx. These mechanisms along is taken up primarily by astrocytes (54,55). In the glial cell, with K spatial buffering (seetext), prevent [K ] from exceeding glutamate is converted to glutamine through the ATP-de- o 12 mM. Increases in [K ] are seen during neural activity as [K ] i o pendent enzyme glutamine synthetase, located exclusively increases. In fact, glutamine synthetase is localized to astrocytic processes surrounding glutamatergic synapses The idea that focal increases in [K ] could be redistrib- o uted by glial cells was introduced by Kuffler and colleagues (46). They realized that the selective K permeability of glia coupled with their low-resistance intercellular connections (mediated by gap junctions), would permit them to trans- port K from focal areas of high [K ] , where a portion o of the glial network would be depolarized, to areas of normal [K ] , where the glial network would have a near normal o membrane potential (46).