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Patients who are Te frst time a person is infested with S purchase discount voltaren online arthritis in knee and back. However buy cheap voltaren 50mg on-line arthritis medication nz, pruritus might transplant recipients buy voltaren 100 mg on-line arthritis in back l4 l5, mentally retarded or physically inca- occur within 24 hours after a subsequent reinfestation. Scabies pacitated persons, HIV-infected or human T-lymphotrophic in adults frequently is sexually acquired, although scabies in virus-1-infected persons, and persons with various hemato- children usually is not. Crusted scabies is associated with greater transmissibility than scabies. No controlled therapeutic studies for crusted scabies have been conducted, and the appropriate treatment remains 90 MMWR December 17, 2010 unclear. Substantial risk for treatment failure might exist with especially if treatment with topical scabicides fails. Epidemics a single topical scabicide or with oral ivermectin treatment. Additional treatment on days 22 and 29 might be required for severe cases. Ivermectin should be Infants, Young Children, and Pregnant or combined with the application of either 5% topical benzyl Lactating Women benzoate or 5% topical permethrin (full body application to Infants, young children, and pregnant or lactating women be repeated daily for 7 days then 2 times weekly until release should not be treated with lindane; however, they can be treated from care or cure). Lindane should be avoided because of the with permethrin. Ivermectin is not recommended for pregnant risks for neurotoxicity associated with both heavy applications or lactating patients, and the safety of ivermectin in children and denuded skin. Fingernails should be closely trimmed to who weigh <15 kg has not been determined. HIV Infection Follow-Up Patients who have uncomplicated scabies and also are Patients should be informed that the rash and pruritus infected with HIV should receive the same treatment regimens of scabies might persist for up to 2 weeks after treatment. HIV-infected patients and Symptoms or signs that persist for >2 weeks can be attributed others who are immunosuppressed are at increased risk for to several factors. Treatment failure can be caused by resistance crusted scabies, for which ivermectin has been reported to to medication, although faulty application of topical scabicides be efective in noncontrolled studies involving only a limited also can contribute to persistence — patients with crusted number of participants. HIV-infected patients with crusted scabies might have poor penetration into thick scaly skin and scabies should be managed in consultation with an infectious harbor mites in these difcult-to-penetrate layers. Reinfection from family members or fomites can occur in the absence of appropriate contact treatment and washing of Sexual Assault and STDs bedding and clothing. Even when treatment is successful and reinfection is avoided, symptoms can persist or worsen as a Adults and Adolescents result of allergic dermatitis. Finally, the presence of household Te recommendations in this report are limited to the iden- mites can cause symptoms to persist as a result of cross reactiv- tifcation, prophylaxis, and treatment of STDs and conditions ity between antigens. Retreatment can be considered after 1–2 commonly identifed in the management of such infections. Treatment with an alternative regimen is recom- specimens for forensic purposes, and management of potential mended for persons who do not respond to the recommended pregnancy or physical and psychological trauma are beyond treatment. Management of Sex Partners and Examinations of survivors of sexual assault should be Household Contacts conducted by an experienced clinician in a way that minimizes further trauma to the survivor. Te decision to obtain genital Sexual contacts and those that have had close personal or or other specimens for STD diagnosis should be made on an household contact with the patient within the preceding month individual basis. Care systems for survivors should be designed should be examined and treated. Evidentiary privilege an epidemic can only be achieved by treatment of the entire against revealing any aspect of the examination or treatment population at risk. Ivermectin can be considered in this setting, also is enforced in most states. Although it rarely occurs, STD diagnoses might later be accessed, and the survivor and clinician Vol. While collection of to result in positive test results at the initial examination, testing specimens at initial examination for laboratory STD diagnosis can be repeated during the follow-up visit, unless prophylactic gives the survivor and clinician the option to defer empiric treatment was provided. If treatment was provided, testing should prophylactic antimicrobial treatment, compliance with follow be conducted only if the survivor reports having symptoms. Among sexually treatment was not provided, follow-up examination should be active adults, the identifcation of an STD might represent an conducted within 1 week to ensure that results of positive tests infection acquired prior to the assault, and therefore might be can be discussed promptly with the survivor and that treatment more important for the psychological and medical management is provided. Serologic tests for syphilis and HIV infection can of the patient than for legal purposes. Such conditions are relatively Acquiring HIV Infection). However, a postassault examination presents an important opportunity to identify Compliance with follow-up visits is poor among survivors or prevent STDs. Chlamydial and gonococcal infections in of sexual assault (477,478). As a result, routine preventive women are of particular concern because of the possibility of therapy after a sexual assault should be encouraged. In addition, HBV infection can be pre- ing prophylactic regimen is suggested as preventive therapy: vented by postexposure administration of hepatitis B vaccine. Reproductive-aged female survivors should be evaluated for Tis vaccine should be administered to sexual assault pregnancy, if appropriate. Follow-up doses Evaluating Adults and Adolescents for of vaccine should be administered 1–2 and 4–6 months Sexually Transmitted Diseases after the frst dose. Initial Examination • An empiric antimicrobial regimen for chlamydia, gonor- rhea, and trichomonas. An initial examination might include the following • Emergency contraception. Ceftriaxone 250 mg IM in a single dose • Wet mount and culture or point-of-care testing of a OR vaginal-swab specimen for T. Te wet Cefxime 400 mg orally in a single dose mount also should be examined for evidence of BV and PLUS candidiasis, especially if vaginal discharge, malodor, or Metronidazole 2 g orally in a single dose itching is evident. PLUS • A serum sample for immediate evaluation for HIV infec- Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally tion, hepatitis B, and syphilis. Decisions to perform these twice a day for 7 days tests should be made on an individual basis. Follow-Up Examinations For those requiring alternative treatments, refer to the specifc sections in this report relevant to the specifc agent. After the initial postassault examination, follow-up exami- Te efcacy of these regimens in preventing infections after nations provide an opportunity to 1) detect new infections sexual assault has not been evaluated. Clinicians should counsel acquired during or after the assault; 2) complete hepatitis B patients regarding the possible benefts and toxicities associated vaccination, if indicated; 3) complete counseling and treatment with these treatment regimens; gastrointestinal side efects can for other STDs; and 4) monitor side efects and adherence to occur with this combination. Examination for STDs can be repeated within 1–2 weeks of the assault. Because infectious agents acquired through assault might not have produced sufcient concentrations of organisms 92 MMWR December 17, 2010 other Management Considerations the assailant(s) (e. In consensual the assault, survivor, or assailant that might increase risk for sex, the risk for HIV transmission from vaginal intercourse HIV transmission. Te risk for HIV transmission from oral sex is substan- discussed with the patient: 1) the unproven benefit and tially lower. Site of exposure to ejaculate, viral load in ejaculate, and potential benefts (i.

Second buy 100 mg voltaren visa arthritis pain relief medication, and perhaps of more concern purchase 50 mg voltaren visa arthritis in neck numb fingers, is the fact that a The first open trial of VNS by Rush and colleagues in­ majority of patients (up to 100% in some studies) relapse in cluded 30 nonpsychotic patients with treatment-resistant the month after treatment best purchase voltaren rheumatoid arthritis remedies. Both the antidepressant response unipolar or bipolar depression (136). Szuba, personal communication) and relapse rate (109) of epilepsy, the stimulator was attached to the left vagal are improved by increasing the number of weeks of treat­ nerve, which can be accessed peripherally in a procedure ments but, as with ECT, the most severely ill patients may similar to implanting a cardiac pacemaker, and compared respond partially and relapse quickly. Combination treat­ to the right VN has fewer afferent fibers to the autonomic ment strategies (slow right and fast left) and maintenance system controlling cardiac and gastric physiologic functions rTMS strategies are being employed to improve response (137). Twelve of 30 patients (40%) met criteria for treat­ and keep patients in remission. None of the patients discontinued techniques are being developed to assist in focusing the mag­ treatment because of adverse events. The most common netic impulse on specific cortical structures. VNS may be an effective treatment in resistant depres­ Using these techniques, rTMS can help in elucidating sion. The two variables that predicted clinical response to the neuronal pathways involved in depression. Initial studies VNS included previous response to ECT (only one of 19 using functional neuroimaging and rTMS have shown that patients who had received ECT had a sustained response many of the effects of rTMS occur at brain regions distant to VNS) and decreased stimulator output. Encouragingly, from the site of stimulation including the caudate, orbito­ of the ten responders with available follow-up data over 4 frontal cortex bilaterally, and cerebellum (124). These stud­ to 9 months, all have demonstrated continued response. The Chapter 76: Electroconvulsive Therapy 1105 adverse side effect profile and costs could be dramatically 7. Multiple monitored electroconvulsive reduced if a method of stimulating the VN could be treatment. Textbook trodes is $9,200, and the additional cost of the surgical of psychopharmacology. Washington, DC: American Psychiatric procedure raises the total costs to approximately $12,000 Press, 1995:523–543. Convuls Ther 1997; be expected for acute and 1-year maintenance treatment 13(3):125–127. ECT, research, and professional ambivalence [edito­ for ECT; however, insurance coverage may depend on the rial] [see comments]. VNS is approved The clinical science of electroconvulsive therapy, vol. Some researchers have questioned the benefit of electrical 12. Experimental studies of the mode of action of electroconvulsive therapy. Acta Psychiatr Neurol Scand 1960;35: stimulation, which does not produce a seizure (138), argu­ 1–141. Monitoring the duration of electroconvul­ to provide any clinical benefit (139). Arch vulsant hypothesis assumes that the beneficial effects from Gen Psychiatry 1982;39(10):1189–1191. ECT derive not from the convulsion, but the anticonvulsant 14. Seizure duration and clinical effect in electrocon­ vulsive therapy. Slow rTMS dampens neuronal excitability (100) and of ECT in endogenous depression. Br J Psychiatry 1976;129: theoretically may be useful in treating epilepsy (140). A theory of convulsive therapy in endoge­ nous depression: significance of hypothalamic functions. Psy­ rTMS to precipitate a convulsion in animal models to deter- chiatry Res 1980;2(1):49–61. J investigations using animal models could potentially cause Ect 1999;15(1):60–75. Effects of electrode tures) and spare brain sensitive structures that cause side placement on the efficacy of titrated, low-dose ECT. Together rTMS and VNS have the potential sive therapy on plasma vasopressin and oxytocin. Biol Psychiatry of providing valuable insight into the pathophysiology of 1998;44(7):610–616. The effects of ECT ACKNOWLEDGMENT stimulus dose and electrode placement on the ictal electroen­ cephalogram: an intraindividual crossover study. EEG manifesta­ grant MH56617-03 from the National Institute of Mental tions during ECT: effects of electrode placement and stimulus Health, the National Alliance for Research in Schizophrenia intensity. The clinical science of electroconvulsive therapy, vol. Washington, DC: American Psychiatric Press, 1993: 93–109. The clinical utility of ictal EEG seizure adequacy REFERENCES models. Psychosurgery in the treatment of mental of ECT seizure adequacy. Electroencephalogr Clin Neurophysiol disorders and intractable pain Springfield, IL: Charles C Thomas, 1997;103(6):599–606. Pharmacologic treatment of schizophrenia New York: threshold over the course of electroconvulsive therapy affect Nervous and Mental Disease Publishing, 1938. Curare: a preventive of traumatic complications in of adequate stimulus intensity with unilateral ECT. Can we teach psychiatric relaxant in electroshock therapy. Am J Psychiatry 1952;108: residents to rate seizure regularity? ECT technique: electrode placement, stimulus type, Convuls Ther 1994;10(2):153–164. Cerebral blood flow and metabolic rate during sei­ of electroconvulsive therapy, vol. Effects of electroconvulsive sant medications and short-term clinical response to ECT [see therapy on EEG and cerebral blood flow in depression. The cerebral hemody­ intensity and electrode placement on the efficacy and cognitive namic response to electrically induced seizures in man.

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FIGURE 3-23 FIGURE 3-24 Gross specim en of a liver in prim ary system ic am yloidosis discount voltaren 100 mg fast delivery rheumatoid arthritis medication not working. The Photom icrograph showing extensive am yloid deposition in the liver liver is grossly enlarged buy generic voltaren canada arthritis diet ginger. The prothrom bin tim e was increased in one sixth of patients at the tim e of diagnosis purchase voltaren 50mg on-line rheumatoid arthritis young living essential oils. FIGURE 3-25 It has been shown that prolongation of throm bin tim e occurs in Alkaline phosphatase, aspartate am inotransferase, and bilirubin 40% of patients. A deficiency in factor X occurs in 15% but values within 30 days of diagnosis of prim ary system ic am yloido- is not associated with bleeding. The serum alkaline phosphatase level was increased in one low carotene or serum B12 level occurs infrequently. H yperbilirubinem ia was an infrequent finding but when present was associated with short survival. Alm ost half of patients had 5% or fewer plasm a cells in the bone m arrow at the tim e of diag- nosis. About one fifth of patients had bone m arrow plasm acytosis of 20% or m ore. M ultiple m yelom a m ust be considered in this set- ting. Overt congestive heart failure is present in about one sixth of patients at the tim e of diagnosis. FIGURE 3-30 Electrocardiogram in a patient with primary systemic amyloidosis, showing low voltage in the limb leads or loss of anterior septal forces that mimics the findings in myocardial infarction. Arrhythmias may include atrial fibrillation, junctional tachycardia, premature ventricular complexes, or heart block. O nly 24% had no septal thickness is associated with shorter increased septal thickness. Patients with a septal thickness of FIGURE 3-31 15 m m or m ore had a m edian survival of Echocardiogram of a patient with prim ary 7 m onths, whereas in those with a septal system ic am yloidosis showing m arked thickness less than 15 m m the m edian sur- thickness of the ventricular wall. The ventricular cavity is greatly reduced in volum e. N ephrotic syndrom e or renal failure was 30 present in 28% of patients, congestive heart failure (CH F) in 17% , 5 and carpal tunnel syndrom e in 21%. The diagno- 56 sis will be confirmed in 80% of patients. Experience in the staining technique and 40 interpretation of the fat aspirate is important before routine use. A bone marrow aspirate 20 and bone marrow biopsy specimen should be obtained to determine the degree of plas- 0 Abdominal Bone Rectum Kidney Carpal Liver Small Skin Sural Heart macytosis, and results of amyloid stains are fat marrow ligament intestine nerve positive in more than half of patients. Either (212) (394) (194) (81) (20) (32) (23) (19) (21) (16) the abdominal fat aspirate or bone marrow Presence of amyloid in tissue (number of patients) biopsy specimen is positive in 90% of patients. W hen amyloid is still suspected and the test results of these tissues are negative, one should proceed to performing a rectal biopsy, which is positive in approximately 80% of patients. W hen the test results for these sites are negative, tissue should be obtained from an organ with suspected involvement. The specim en shows the characteristic apple-green birefringence when stained with Congo red dye and Analysis of m edian survival in patients with prim ary system ic am y- viewed with a polarizing light source. The m edian sur- vival of 474 patients seen within 1 m onth of diagnosis was 13. The m edian duration of survival was 4 m onths for the 80 patients who exhibited congestive heart failure on presentation. O f the 285 patients who died, death was attributed to cardiac involvem ent 6% from congestive heart failure or arrhythm ias in 48%. The actual percentage of cardiac- related deaths was probably higher because som e patients whose death was attributed to Other prim ary am yloidosis alm ost certainly had term inal cardiac arrhythm ia. Because M P 18 amyloid fibrils consist of monoclonal immunoglobulin light chains, 80 M PC 17 treatment with alkylating agents that are effective against plasma cell C 8. W e treated 220 patients who had positive 60 results on biopsy. The patients were randomized to receive colchicine P<0. Patients were stratified accord- 40 ing to their chief clinical manifestations: renal disease (105 patients), cardiac involvement (46), peripheral neuropathy (19), or other (50). In patients who had a reduc- Survival, y tion in serum or urine monoclonal protein at 12 months, the overall duration of survival was 50 months; whereas among those without a reduction in monoclonal protein at 12 months, the duration of sur- vival was 36 months (P < 0. Thirty-four patients (15% ) survived for 5 years or longer. H igh-dose dexam ethasone has been reported to be beneficial in treating patients with prim ary system ic am yloidosis. M ore intensive therapy consisting of High-dose dexamethasone high-dose chem otherapy followed by rescue with peripheral stem Stem cell transplantation cells shows prom ise. Secondary Amyloidosis CAUSES OF SECONDARY AM YLOIDOSIS PRESENTING CLINICAL FEATURES OF SECONDARY AM YLOIDOSIS Cause Patients, n Rheumatic disease Feature Patients, % Rheumatoid arthritis 31 Proteinuria or renal insufficiency 91 Ankylosing spondylitis 5 Diarrhea, obstipation, or malabsorption 22 Other 6 Goiter 9 Total 42 Hepatomegaly 5 Infection Neuropathy or carpal tunnel syndrome 3 Inflammatory bowel disease 6 Lymphadenopathy 2 Bronchiectasis 5 Hematuria 2 Osteomyelitis 5 Cardiac amyloidosis 0 Other 3 Total 19 Malignancy 2 None 1 FIGURE 3-43 Presenting features of secondary am yloidosis. Proteinuria is the m ost frequent laboratory finding in patients with secondary am y- loidosis. Involvem ent of the gastrointestinal tract as m anifested by FIGURE 3-42 diarrhea, obstipation, or m alabsorption occurred in one fifth of Causes of secondary am yloidosis. Treatm ent of secondary am yloidosis depends on the frequent cause of secondary am yloidosis. Fam ilial M editerranean fever frequently is asso- patients, rheum atoid arthritis was present for a m edian of 18 years ciated with secondary am yloidosis unless the patient is treated with before the diagnosis was m ade. The clinical target organ was the kidney in 91% of 17 17 17 patients. Fam ilial or 2 1 hereditary am yloidosis has an autosom al dom inant pattern of inheritance. In 2 1 1 our practice, the geographic distribution is wide and not associated 2 1 1 1 6 1 5 with clustering. Frequently, a fam ily history of am yloidosis was not 1 1 1 2 1 1 3 4 obtained until after am yloidosis was diagnosed. M ore than 50 3 2 transthyretin m utations have been recognized. Late onset may CLASSIFICATION OF FAM ILIAL AM YLOIDOSIS occur with the development of symptoms in the seventh or eighth decade of life. The nephropathic form is most often caused by familial M editerranean fever. This form affects persons of M editerranean descent and is characterized by recurrent episodes of fever and abdomi- Classification Major protein component nal pain that begin in childhood.

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Mice plays a primary role in nicotinic transmission in sympathetic ganglia and that the 7 subunit also contributes to the ob- served currents (18 generic voltaren 50mg overnight delivery arthritis treatment diet exercise,19) purchase generic voltaren line arthritis in knee operation. Picciotto and Meenakshi Alreja: Department of Psychiatry cheap voltaren 100mg arthritis pain relief in hands, electrophysiologic and immunoprecipitation studies of Yale University School of Medicine, New Haven, Connecticut. David Jentsch: Department of Neuroscience, University of Pittsburgh, nAChR subunits from ganglionic neurons (20). In studies of knockout mice, disruptions of two nico- tinic-receptor subunits expressed in sympathetic ganglia, 7 (9) and 2 (11), do not grossly alter ganglionic function. In contrast, if the 2 and the 4 nAChR-subunit mutations are combined (13), or if the 3 nAChR subunit is knocked out (6), mutant mice die perinatally of severe autonomic FIGURE 1. The principal source of cholinergic input to the cortex and failure. These experiments suggest that a nicotinic choliner- hippocampus is the basal forebrain complex, whereas the pedun- gic receptor composed of the 3/ 4or 2 subunit, or both, culopontine and laterodorsal tegmental areas innervate brain is responsible for mediating direct neurotransmission by stem and midbrain targets preferentially. Cholinergic interneu- rons are found in the olfactory tubercle, striatum, nucleus accum- ACh between ganglionic neurons. BFC, basal forebrain complex;VTA, Muscarinic function has also been studied in the auto- ventral tegmental area;IPN, interpeduncular nucleus;PPT, pe- nomic ganglia with knockout technology. Mutation of the dunculopontine tegmental nucleus;LDT, laterodorsal tegmental nucleus. M1 muscarinic receptor is sufficient to abolish the M cur- rent, a muscarine-mediated potassium current, in the sym- pathetic ganglia, but M1 mutation does not significantly perturb ganglionic function (14). KNOCKOUTS OF MUSCARINIC AND NICOTINIC SUBUNITS Subunit Knockout Knockout Phenotype References Muscarinic receptors M1 Viable Disruption of M current and (14,21) muscarinic seizures M2 Viable Disruption of muscarinic (15,21) receptor-dependent movement and temperature control and antinociception M4 Viable Enhancement of D1 (16,21) receptor-mediated locomotor stimulation Nicotinic subunits α3 High mortality Impaired growth, megalocystis (6) rate before (inflamed urinary bladder) and and after mydriasis (widely dilated ocular weaning pupils) α4 Viable Reduced antinociception (7) α5 Viable Not yet reported (8) α7 Viable Largely normal; lack MLA-sensitive (9,22) nicotine response in hippocampal interneurons; may have slightly decreased anxiety response α9 Viable Involved in cochlear efferent (10) innervation development and function β2 Viable Lack nicotine-induced increases in (7,11,24,31,32) passive avoidance, reinforcement, antinociception; show increased neurodegeneration during aging β3 Viable Altered locomotor activity (12) β4 Viable Viable, but lethal when combined (13) with β2 subunit knockout MLA, methyl-lyaconitine, a β7 antagonist. Chapter 1: Acetylcholine 5 the M2 muscarinic-receptor subtype do not show carba- lacking individual nAChR subunits should allow a finer chol-induced bradycardia, confirming that the effect of ACh definition of these receptor classes. In addition, knockout animals have receptor function has been the idea that nicotine exerts been very useful in determining which subtypes of musca- many of its functions in brain through the regulation of rinic receptors are responsible for the effects of ACh on neurotransmitter release, at least partly through terminal modulation of calcium channels in sympathetic neurons and preterminal nAChRs (25,26). A slow, voltage-independent modulation is mediated somes (nerve terminals) isolated from mice lacking the 2 by M1 receptors, whereas a fast, voltage-dependent modula- subunit of the nAChR have shown that presynaptic regula- tion is mediated through M2, and neither is affected in M4 tion of GABA release by nicotine is mediated through 2 knockout mice. This The function of ACh in the brain has also been examined is also likely to be the case for other neurotransmitters be- in electrophysiologic experiments with mice lacking cholin- cause the efflux of rubidium, a radioactive tracer that serves ergic-receptor subtypes. For example, a rapidly desensitizing as a marker of neurotransmitter vesicle fusion, is mediated nicotinic current in the hippocampus is mediated through through 2 subunit-containing receptors in most brain an 7-containing receptor (9). More recently, dopamine release from striatal appear grossly normal in behavioral experiments (22), but synaptosomes has been shown to be disrupted in 2-subunit future experiments should determine whether these currents knockout mice, while ACh release in the interpeduncular contribute to nicotine-induced improvements in cognitive nucleus is preserved (29). This suggests that a distinct function or to nicotine-induced seizure activity. Antisense nAChR subtype, most likely containing the 4 subunit, experiments have also demonstrated that the 5 nAChR mediates nicotine-elicited ACh release in the interpeduncu- subunit can alter the electrophysiologic properties of lar nucleus. Systems-level function and behavioral effects of ACh Mice lacking the 2 subunit have been used to characterize have also been examined in knockout mice. Muscarinic ago- four classes of nAChR in the brain by means of pharmaco- nist-induced seizures are dependent on the presence of the logic and electrophysiologic techniques (24) and to extend M1 receptor because M1 knockout mice are resistant to the existing pharmacologic characterization of nicotinic-re- pilocarpine-induced seizure activity (14). Future experiments using mice though the M1 receptor has been implicated in the modula- wild type β2 +/- β2 -/- FIGURE 1. Nicotinic ligand binding in brain slices from wild-type and 2-subunit knockout mice. Mice lacking individual subunits of the nicotinic acetylcholine receptor (nAChR) can be used to distinguish between subclasses of receptors. For example, although 2-subunit knockout mice lack the highest-affinity subclass of nicotine binding sites, the frog toxin epibatidine, shown here, still reveals 4 subunit-containing nAChRs in the medial habenula (remaining binding shown in panel at top, far right). Binding of epibatidine in brain slices through thalamus (top) or striatum (bottom) is shown in wild-type heterozygous ( 2 / ) and homozygous ( 2 / ) 2-subunit knockout mice. Stimulation of teg- channels is unchanged in the hippocampus of M1 knockout mental brainstem cholinergic neurons can evoke cortical mice (30). In contrast, the pharmacologic effects of musca- ACh release and EEG desynchrony, and these effects are rinic agonists on movement, temperature control, and anti- blocked by reversibly decreasing the activity of the basal nociception appear to be mediated through the M2 receptor forebrain (35). Moreover, application of cholinergic ago- because these responses are absent in M2 knockout mice nists to the basal forebrain produces behavioral activation (15). M4 receptors are also involved in locomotion; these and EEG desynchrony (33). Although the brainstem cholin- knockout animals exhibit increased basal locomotor activity ergic projections to the thalamus undoubtedly also contrib- and a potentiated locomotor response to D1-selective dopa- ute to EEG regulation (36), these findings suggest that cho- minergic agonists (16). In behavioral experiments, the 2 projections largely formed connections with noncholinergic nicotinic subunit mediates the ability of nicotine to improve neurons within the basal forebrain (37). This finding is avoidance learning and may also be involved in the circuitry critical because it could explain why stimulation of the hori- underlying this form of associative learning in wild-type zontal diagonal band, preoptic area, and substantia innomi- mice (11). In addition, this subunit appears to be necessary nata, but not of the septal nucleus and nucleus basalis, pro- for the mouse to experience the reinforcing properties of duces sleep in the cat (33). The ratio of cholinergic to nicotine because animals without the 2 subunit will not noncholinergic neurons in the horizontal diagonal band, self-administer nicotine (31). Extensions of these experi- preoptic area, and substantia innominata is significantly ments to mice lacking other subunits of the nicotinic recep- lower than in the septum and nucleus basalis. This observa- tor should allow identification of the receptor subtypes that tion has led to the hypothesis that activation of primarily are activated by smoking in humans and result in tobacco noncholinergic neurons is responsible for producing sleep addiction. An interesting effect of ACh on neuronal survival after basal forebrain stimulation (33). These noncholinergic was demonstrated in mice lacking the 2 nAChR subunit neurons are believed to be GABAergic and achieve their (32). Mice that lack this cholinergic-receptor subtype show effects through inhibition of cholinergic basal forebrain progressive neuronal loss with age in cortical and hippocam- neurons and neurons within the brainstem reticular forma- pal brain areas, which appears to lead to age-related impair- tion. In contrast, stimulation of the nucleus basalis or septal ments in spatial learning. These experiments demonstrate nucleus produces behavioral activation and cortical ACh that the effects of ACh on cognition, antinociception, loco- release, and this is consistent with the notion that basal motion, and overall neuronal activity are differentially me- forebrain cholinergic neurons are involved in behavioral diated through the various subtypes of muscarinic and nico- arousal (activation), whereas noncholinergic basal forebrain tinic receptors, and that the various roles of ACh may be neurons are involved in regulating the sleep state. These separated pharmacologically, suggesting new targets for ra- two effects are related (sleep vs. ROLE FOR CHOLINERGIC NEURONS IN AROUSAL AND SLEEP ROLE FOR CHOLINERGIC NEURONS IN MOTIVATION AND REWARD Traditionally, the basal forebrain complex, the primary source of cholinergic innervation to the telencephalon (Fig. Cholinergic neurons have also been implicated in motiva- 1. Either lesions or electric stimulation of subregions of that nAChRs are involved in motivation and reward is that the basal forebrain can facilitate sleep and synchronize the nicotine is abused by humans and is reinforcing in animals EEG, and cholinergic drugs regulate EEG synchrony (33). The effects of nicotine on tests Moreover, 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).

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