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A functional down-regulation of receptor-mediated mechanisms are activated by alcohol (34 order discount kamagra gold line, 5-HT3 receptors in the NAC may contribute to cocaine 40) purchase 100mg kamagra gold overnight delivery. Chronic cocaine and (27) may relate to the finding that ethanol enhancement of alcohol administration also disrupts the endogenous opioid DA release in the NAC appears to require activation of system (20) cheap kamagra gold 100mg overnight delivery. Neuronal nicotinic acetyl- tion of nicotinic receptors in the VTA, ultimately leading choline receptors are structurally related to GABAAreceptors 1416 Neuropsychopharmacology: The Fifth Generation of Progress (41). Activation of these nicotinic receptors may enhance the development of alcoholism. One gene variant (allele) is ethanol reinforcement and voluntary intake (42). Alcohol Some studies have implicated involvement of the seroto- dehydrogenase (ADH) metabolizes ethanol to acetaldehyde, nin receptors 5-HT3 and possibly 5-HT4 in DA release a toxic intermediate, which is in turn converted to acetate in the NAC (31,43). Approximately half receptor that directly gates an ion channel and hence ethanol the population of Southeast (SE) Asian countries such as directly potentiates the effects of serotonin at this site (44). China, Japan, and Korea have functional polymorphisms at Chronic alcohol intake increases the sensitivity of 5-HT3 four different genes: ADH2, ADH3, ALDH1, and ALDH2. Across populations, the ALDH2-2 variant appears on a sim- The 5-HT3 antagonist ondansetron has been shown to re- ilar genetic background (haplotype) and thus has probably duce alcohol consumption in alcoholics (45). The most important variants are ALDH2-2 (Glu487–Lys487) and ADH2-2 GENETIC STUDIES OF ALCOHOLISM IN (Arg47–His47). ALDH2-2 dominantly inactivates ALDH2, HUMANS the ALDH that is mitochondrially localized and responsible for most acetaldehyde metabolism in cells. ADH2-2 is a In a heterogeneous disease such as alcoholism it is likely superactive variant. Allelic variation at ADH3 apparently that there are different environment-related thresholds and exerts no independent effect on the risk for alcoholism; different genes and gene variants. In addition there could however, ADH3-1 is in linkage disequilibrium with ADH2- be additive or nonadditive (epistatic) interactions between 2 (48,49) and is thus also predictive of vulnerability. Classic genetic analyses in ro- 2 and ALDH2-2 raise the levels of acetaldehyde by increas- dents show that certain alcohol-related phenotypes (e. On the other hand, lism, and by interacting additively, but not synergistically human data showing an approximately 2:1 MZ/DZ twin (50). The result is that ingestion of even small amounts of ratio of concordance for alcoholism and high recurrence ethanol produces an unpleasant reaction characterized by rates in first-degree relatives of alcoholics followed by a pro- facial flushing, headache, hypotension, palpitations, tachy- gressively decreasing risk in proportion to relatedness are cardia, nausea, and vomiting (51). In an analogous fashion, compatible with additivity of inheritance, and do not favor disulfiram, used in the treatment of alcoholism, and some multiple genes. The alcoholism genes identified so antiprotozoal drugs such as metronidazole, inhibit ALDH2 far—ALDH2 and ADH2—were discovered individually and thereby cause a flushing reaction after alcohol consump- but act additively when they co-occur (vide infra). Therefore, the protective effect of ALDH2 genotypes To dissect the multiple genetic influences on alcoholism can be regarded as analogous to protection with disulfiram, vulnerability, it may be necessary or useful to consider sev- as this flushing reaction, severe in homozygotes but milder eral phenotypes representing different aspects of the disease. The allele frequency of the homogeneous clinical groups by severity (dependence or dominantly acting ALDH2-2 is 0. Cloninger (46) divided alcoholics on flushing after alcohol consumption. Their risk of alcoholism a clinical and genetic epidemiologic basis into type 1 (mi- is reduced about four- to tenfold. Approximately 10% of lieu-limited, later onset) and type 2 (early onset, male domi- Japanese are ALDH2-2/ALDH2-2 homozygotes. Thus far, nated, associated with ASPD), thus linking premorbid per- only one alcoholic ALDH2-2/ALDH2-2 homozygote has sonality with alcoholism vulnerability and identifying an been observed across a series of studies in which several alcoholism subtype, type II, with a stronger genetic predis- hundred alcoholics have been genotyped, and that individ- position. This classification is supported by a study involv- ual is the focus of a report (52). Tu and Israel underlying dimensions of liability for alcoholism, drug dis- (53) found that acculturation accounted for some of the orders, ASPD, MD, and GAD that are familially transmit- variance (7–11%) in alcohol consumption for SE Asian ted with moderate specificity: (a) chronic dysphoric symp- males born in North America, although the ALDH2 poly- toms of anxiety and depression, and (b) acting-out behaviors morphism predicted two-thirds of the alcohol consumption and harmful substance use. Also, there are large differences in the prevalence of alcohol dependence in populations that GeneticsOf Alcohol Metabolism have similar ALDH2 allele frequencies. The frequencies of At the present time, the genes for alcohol metabolism are the ADH2 and ALDH2 variants are similar, but the preva- the only genes that are known to have a major impact on lence of alcoholism is 2. Such endophenotypes may be influenced by AND ADH2 GENOTYPES AND THE RISK FOR variation at fewer genes. The brain is relatively inaccessible, ALCOHOLISM IN SOUTHEAST ASIANS (48) so it has been more difficult to obtain biochemical and ALDH2 ADH2 Protective Factor physiologic measures that identify more specific genetic sub- types as was done decades ago for certain other common, ∗2/∗2 ∗2/∗2, ∗1/∗2, or ∗1/∗1 High ∗ ∗ ∗ ∗ ∗ ∗ broadly defined diseases (e. Association studies 2/ 1 2/ 2 or 2/ 1 ∗ ∗ of candidate genes, although laborious, have far greater 1/ 1 ∗1/∗1 ∗2/∗2 power for untangling the genetics of complex diseases than ∗2/∗1 linkage analysis (60). New approaches, including TDT ∗1/∗1 None (transmission disequilibrium test) analysis (61,62) and eth- nic matching using informative markers (63), have been ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase. Korea, suggesting that there are interactions with other ge- Rodent Models: Quantitative Trait Locus netic and environmental factors (54). Analyses The ADH2 genotype has been shown to be an indepen- Rodent strains are inbred to produce large numbers of ge- dent factor contributing to the risk of alcoholism (50) and netically identical animals that can be maintained under acts additively with the ALDH2-2 variant (Table 99. A controlled environmental conditions and intercrossed when pilot study found that the ADH2-2 allele accounts for 20% required. The neurobiology of reinforcement and reward to 30% of the alcohol intake variance between two groups of was elucidated largely through behavioral and anatomic light-drinking and heavy-drinking Israeli Jews, and suggests studies in rodents. Several behavioral traits in rodents are that the relatively high frequency of the ADH2-2 allele continuous and polygenic. Each of the multiple genes re- might contribute to the generally perceived lower levels of sponsible for such quantitative traits is termed a quantitative alcohol consumption and increased sensitivity to alcohol trait locus (QTL). Several QTLs may influence one trait, observed among Jews (55,56). In one report, The knockout of an individual gene in the mouse can reveal the presence of ADH2-3 in African-American mothers a potential role for the equivalent (homologous) gene in the drinking during pregnancy was associated with a lower rate human. Several QTLs for alcohol-associated behaviors have been identified in mice by using recombinant inbred strains that differ widely with respect to many alcohol-related traits, and DETERMINING THE GENETIC BASIS OF by follow-up studies using interstrain crosses and congenics. VULNERABILITY TO ALCOHOLISM The behaviors for which QTLs have been mapped include acute and chronic alcohol withdrawal sensitivity, alcohol Genetic analysis of complex disorders is complicated by the consumption, and alcohol-associated hypothermia. Buck et fact that any single gene is likely to account for only a small al. To detect subtle genetic effects, large genes influencing alcohol withdrawal severity can be as- samples are needed. The four methods (59) most widely signed to QTLs on mouse chromosomes 1, 4, and 11. The used are (a) linkage analysis: the inheritance pattern of phe- locus on chromosome 11 accounted for 12% of the genetic notypes and genotypes are elucidated in pedigrees; (b) allele variability in withdrawal liability and was near the genes for sharing methods: affected relatives are compared to detect the 2, 1, and 6 subunits of GABAA receptors. Further- excess genotype sharing; (c) association (case-control) stud- more, a 2 subunit polymorphism has now been found to ies: unrelated affected and unaffected individuals are com- be genetically correlated with alcohol withdrawal severity in pared; (d) analysis of inbred, transgenic, and gene-knockout mice (65). QTLs for alcohol-induced hypothermia, alcohol animals (principally mice and rats). An alternative approach is to employ an endopheno- ships between different phenotypes indicate that the same type as a trait specific marker, e. On Serotonin is involved in behavioral inhibition and is a target chronic exposure to alcohol they show less evidence of toler- for the pharmacologic treatment of alcoholism. These mice also work harder to self-administer cocaine serotonin reuptake inhibitors play a limited role in modify- and show an increased locomotor response, behaving as if ing craving for alcohol and also modify other comorbid already sensitized to the drug (69).

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Part of the behavioral these preliminary data support the notion that these com- profile of CRH2 knockouts is suggestive of increased stress- pounds represent an important new class of drugs that may like responding purchase kamagra gold in india, but other aspects of the behavioral profile offer great promise for the treatment of illnesses associated indicate either no alteration of stress-related responding with increased anxiety and stress generic 100mg kamagra gold with amex. The observed increases in anxiety-like behaviors in these genetically altered mice may be due to increased levels of The 5-HT System brain CRH and/or urocortin; in two of the three studies purchase kamagra gold online pills, Serotonin is a member of the monoamine family of trans- an elevation of baseline CRH or urocortin mRNA levels in mitters that also include dopamine and norepinephrine. As the CNS was seen in CRH2 knockout mice (118,119). It should be noted that 5-HT produces its effects through at least 15 different 5- acute blockade of CRH2 receptors results in a decrease in HT receptors that are differentially distributed throughout stress-induced defensive behaviors; thus the behavioral pro- the CNS; the principal mode of 5-HT inactivation is cellu- file of these animals is opposite to that of mice that are lar reuptake via terminal transporter proteins (129). Thus, the timing HT system has long been implicated in the regulation of of the gene deletion may critically influence the nature of mood states and anxiety, and selective serotonin reuptake the behavioral phenotype that ensues. Future studies utiliz- inhibitors (SSRIs) constitute a major class of antidepressants ing novel inducible-knockout technologies may help in clar- that have anxiolytic effects. As outlined below, 5-HT trans- ifying the developmental versus acute role of various genes mission also plays a critical role in the regulation of anxiety- 892 Neuropsychopharmacology: The Fifth Generation of Progress like behaviors. This proposed mechanism is consistent with the the paucity of highly selective ligands for these multiple increase in stress-related behaviors that are seen in certain target sites, several investigators have employed murine gene transgenic mice with mutations in the GABAA receptor (see targeting strategies to elucidate the roles of specific 5-HT below). Further work is necessary to determine the precise receptors in the regulation of stress and anxiety. In contrast to 5-HT1A knockout mice, mice that lack Studies of targeted gene deletions within the 5-HT system the 5-HT receptor show decreased anxiety-like behaviors 1B have revealed an important role for this system in the regula- in several tests of approach-avoidance conflicts. The knockout mice spend more time in the center of an open behavioral sequelae of disrupting 5-HT receptor gene field and more readily explore novel objects than their wild- expression have been elegantly summarized in several review type controls; this profile is opposite from that of 5-HT1A articles (89,130–132). Perhaps the best-characterized 5-HT knockout mice, and is suggestive of diminished neophobia mutant mice are the 5-HT1A and 5-HT1B receptor knock- (89,137). Consistent with this pattern of results is the find- outs. Mice with a mutation in the 5-HT1A receptor gene ing that as pups, 5-HT1B mice emit fewer ultrasonic vocali- have been found to display increased stress-like behaviors zations when separated from their mothers; separation- in multiple tests of approach-avoidance conflicts. These ani- induced vocalizations are thought to provide a measure of mals show decreased entries into and time spent in the more anxiety and distress in pups (138,139). It is interesting to aversive region in paradigms such as the open field, elevated plus maze, and the elevated zero maze; thus 5-HT knock- note, however, that no changes in contextual or cue-induced 1A out mice avoid the center of an open field, the open arms conditioned freezing are observed in 5-HT1B mutant mice, of a plus maze, and the unenclosed regions of a zero maze suggesting that approach-avoidance conflicts and condi- (133–135). It is worth noting that this 'increased anxiety' tioned fear may be differentially modulated by the 5-HT pattern of results was found consistently across three differ- system. The other main behavioral effect of constitutive ent research labs, indicating its robustness and reproducibil- 5-HT1B receptor deletion is a marked increase in aggressive ity. Consistent with this profile is the finding that these behavior (89,140,141). This increase in 5-HT1B knockout mice may also provide valuable informa- stress-like responding is not accompanied by changes in tion on the neural and genetic factors associated with stress overall locomotor activity or motor and spatial coordina- and anxiety-related functioning (89,142). It should be noted that mice with null mutations of other Curiously, 5-HT1A knockout mice display increased mobil- 5-HT receptor subtypes have also been generated, but these ity in response to an acute stressor such as forced swimming animals have not been found to display as robust an anxiety- or tail suspension (133–135). Taken together, these find- related behavioral profile as the 5-HT or 5-HT knock- 1A 1B ings indicate that 5-HT1A knockout mice may represent out mice. It has been found that 5-HT receptor knockout 5A another animal endophenotype of increased anxiety. These knockout mice also do not respond ingly, a recent report indicates that this mutation alters differently from control subjects in tests of startle reactivity GABA system expression and function (136). It has been or in burying a probe that delivered a brief electric shock. Anal- ysis of brain tissue from these animals indicates that GABA profile from that of the 5-HT1A or 5-HT1B knockout mice. A receptor binding is reduced and that the expression of An initial report indicates that 5-HT6 receptor deficient 1 and subunits of the GABA receptor are decreased in the mice may exhibit increased avoidance of aversive environ- 2 A amygdala. The anxiolytic actions of benzodiazepines may in ments; although these preliminary findings are interesting, part be mediated by GABAA receptors within the amygdala; further work is needed to fully characterize the phenotype the profile of results in 5-HT1A knockout mice has led to of these mutant mice (144,145). Mice lacking either the the intriguing speculation that the anxiety-like endopheno- 5-HT2A or 5-HT2C receptors have also been created; to the type in these mice may actually in part derive from a de- best of our knowledge, the stress-related behavioral func- crease in the expression and function of the GABAA recep- tioning of these animals has yet to be reported (146,147). Chapter 62: Animal Models and Endophenotypes of Anxiety and Stress Disorders 893 Clinically Effective 5-HT System Drugs for Stress- shorter form GAD65 (149). Whereas GAD67 is thought Related Disorders to maintain basal GABA levels, GAD65 is thought to regu- late the synthesis of GABA at nerve terminals in response As mentioned above, one of the most commonly prescribed to high GABA demand (150). Given the important role and effective classes of drugs that is used in the treatment of GABA in inhibitory neurotransmission associated with of depression and anxiety is the SSRIs, which block the anxiolysis, several investigators have evaluated the behav- reuptake of 5-HT by its transporter and thereby increase ioral profile of genetically altered mice that lack the GAD65 serotoninergic transmission. Two separate groups have reported that GAD65 clinical studies including those obtained from 5-HT recep- mice display an increase in stress-like behaviors in numerous tor knockout mice, 5-HT1A agonists have been developed behavioral paradigms (151,152). The clinical utility of this class had fewer entries into and time spent in the center of an of compounds, however, remains to be determined. As these open field or the open areas of an elevated zero maze (similar transgenic approaches develop and become more refined, to an elevated plus maze), indicating that they were more they will undoubtedly aid in clarifying the roles of the many avoidant of inherently aversive areas. Similarly, these mice other 5-HT receptor subtypes in processes related to stress had lower levels of activity in the bright portion of a light- and anxiety and will aid in drug development. It should be mentioned that GAD65 / mice also displayed an elevation in the occur- The GABA System rence of spontaneous and stress-induced seizures, and that these mice had a dramatically increased mortality rate start- The primary inhibitory neurotransmitter in the CNS is ing at 4 to 5 weeks after birth (151). Thus, although the GABA; GABA-synthesizing cells are distributed throughout behavioral profile of GAD65 knockout mice is suggestive the brain (128). The actions of GABA are mediated by two of increased anxiety-like responses, it is possible that these major classes of receptors, GABAA and GABAB, both of effects are secondary to the occurrence of seizures and to which modulate the activity of ion channels. The principal the factors leading to early lethality. The usefulness of this mode of inactivation of GABA transmission is the presynap- knockout as a model for anxiety-related deficits may there- tic reuptake of GABA by its transporter protein. Given that benzodiazepines and barbiturates both types of GABA receptors are widely distributed act as positive modulators of GABA transmission at the through the CNS, several important differences exist be- GABA receptor by enhancing GABA-induced chloride A tween the two. Relevant to psychopharmacology is the find- channel opening, it is of interest to note that GAD65 / ing that traditional anxiolytics (benzodiazepines) do not mice were not sensitive to the effects of either benzodiaze- bind to GABAB receptors, but rather mediate their effects pines or barbiturates, but did respond to the direct GABA A through GABAA receptors. GABAA receptors consist of a agonist muscimol, which binds directly to the GABA site of chloride channel formed by the pentameric arrangement of the GABA receptor and increases opening of the chloride A at least 18 different protein subunits ( 1–6, 1–4, 1-3, , channel in the absence of GABA (152). This pharmacologic , , 1–3), thus allowing for considerable heterogeneity of profile is consistent with the finding that GABA synthesis the GABAA receptor isoforms (148). Typically, benzodiaze- is blocked by the GAD65 null mutation, but that GABA A pine-responsive GABAA receptors consist of , , and receptor binding is unaffected by this change. Furthermore, subunits; in addition to the benzodiazepine site, these recep- this mutation does not seem to alter the functioning of tors also contain distinct sites for the binding of GABA, GABA receptors because direct agonists stimulate the recep- barbiturates, and ethanol. These various regions act as allo- tor but indirect modulators of GABA do not.

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Derivation of a phar- by cannabinoids is absent in mice deficient for the cannabinoid macophore model for anandamide using constrained conforma- CB(2) receptor kamagra gold 100 mg otc. Localization of cannabinoid receptors in brain Chem 1998;41:4207–4215 purchase 100mg kamagra gold with mastercard. Cannabinoid re- donoylglycerol but not N-palmitoylethanolamine or ananda- ceptor localization in the brain order kamagra gold 100mg amex. Proc Natl Acad Sci USA 1990; mide is the physiological ligand for the cannabinoid CB2 recep- 87:1932–1936. J Biol Chem 2000;275: endogenous cannabinoid receptor ligands with neuromodula- 605–612. Localization of cannabinoid of anandamide, a cannabinoid receptor agonist. Biochem Phar- CB(1) receptor mRNA in neuronal subpopulations of rat stria- macol 1993;46:791–796. Cannabinoid receptor agonist efficacy for stimulating [35S]GTPgS binding to rat cere- 37:71–80. Localization of central canna- bellar membranes correlates with agonist-induced decreases in binoid CB1 receptor messenger RNA in neuronal subpopula- GDP affinity. Pharmacology of cannabinoid CB and CB recep- by delta-9-tetrahydrocannabinol or anandamide. Cardiovascular effects of endocannabinoids: the plot thickens. Prostaglandins Other Lipid of the effects of anandamide, the putative endogenous canna- binoid receptor ligand, on extrapyramidal function. Cannabinoid transmission and pain binoid CB(1) receptor expression in rat spinal cord Mol Cell perception. Cannabinoid receptors undergo tion of endogenous cannabinoid anandamide in central neu- axonal flow in sensory nerves. Annu Rev zation of an enzyme that degrades neuromodulatory fatty-acid Pharmacol Toxicol 1995;35:607–634. Brain regional cannabinoid, inhibits calcium currents as a partial agonist in distribution of endocannabinoids: implications for their biosyn- N18 neuroblastoma cells. Enhancement of type calcium currents in AtT20 cells transfected with rat brain anandamide formation in the limbic forebrain and reduction cannabinoid receptor. J Biol Chem 1996;271: endogenous cannabinoids in the globus pallidus are associated 19238–19242. Proc Natl Acad Sci USA 1997;94: pathway associated with stimulation of CB2 peripheral canna- 4188–4192. Activation of peripheral kinase and induction of krox-24 expression. Eur J Biochem 1996; CB1 receptors by an endogenous cannabinoid contributes 237:704–711. Platelet- and macro- Chapter 106: Marijuana 1531 phage-derived endogenous cannabinoids are involved in endo- of sucrose and ethanol intake by SR 141716, an antagonist of toxin-induced hypotension. Cannabinoid transmission and reward- Pharmacol 1997;334:R1–R2. Pain modulation binoid CB(1) receptor knockout mice. Eur J Pharmacol 1999; by release of the endogenous cannabinoid anandamide. An analgesia circuit acyl-phosphatidylethanolamines and N-acylethanolamines. J Nat Prod hyperalgesia and inflammation via interaction with peripheral 1980;43:169–234. Antinociceptive, subjective and delta9-THC and other cannabinoids in confiscated marijuana behavioral effects of smoked marijuana in humans. Dynorphin B and spinal water-soluble cannabinoid receptor agonist with antinociceptive analgesia: induction of antinociception by the cannabinoids properties. Inhibition of deoxy- 8-THC and related compounds: synthesis of selective long-term potentiation in rat hippocampal slices by anandamide ligands for the CB2 receptor. Bioorg Med Chem 1999;7: and WIN55212-2: reversal by SR141716A, a selective antago- 2905–2914. J Pharmacol Exp Ther 1999;289: potentiation in mice lacking cannabinoid CB1 receptors. D(2) dopamine receptors high-affinity anandamide transport, as revealed by selective inhi- enable delta(9)-tetrahydrocannabinol induced memory impair- bition. Fatty acid sulfonyl fluo- J Pharmacol 1993;231:313–314. BENOWITZ About 25% of adults in the United States smoke tobacco pies for less common addictions to stimulants such as cigarettes. Most continue smoking because they are addicted cocaine and amphetamines or to other drugs. That nicotine is central to maintaining tobacco diction resulting from tobacco cigarette smoking is empha- use is well established (49). Other routes for nicotine delivery, chewing tobacco, smokers report that they would like to quit. Each year, less buccal and nasal snuff, and smoked pipes and cigars, deliver than 1% will actually succeed without any therapeutic inter- substantial amounts of nicotine but with different pharma- ventions. Few other conditions in medicine present nicotine cokinetics, although the pharmacology is otherwise similar. Health care providers too often fail systems warrant special attention. Worldwide potential benefits of prevention and adequate treatment are staggering (96). During the twentieth century, to sustaining tobacco smoking, the beginnings of tobacco only approximately 0. If current smoking patterns continue, tioned factors, social settings, personality, and genetics (4). Smoking is an ex- 4 million people died of tobacco-related disease in 1998. Nicotine yearly by the year 2030, with 70% of those deaths in devel- smokers appear able to discriminate small, rewarding effects oping countries. Reducing the number of current smokers from each individual puff and to titrate nicotine dose from by 50% would avoid 25 million premature deaths in the each cigarette. From the typical 10 puffs per cigarette, a first quarter of this century and about 150 million more by one pack-per-day smoker receives 73,000 distinct drug rein- midcentury (96). Although nicotine can enhance mood Understanding the role of nicotine in sustaining tobacco directly, what is even more important for understanding addiction offers a basis for optimal and rational treatments nicotine addiction therapeutics is that when nicotine is for preventing or stopping smoking (49).

AK also induces nociceptive responses at local sites of adminis- inhibitors buy kamagra gold 100mg on-line, such as CP 3269 and ABT-702 (Fig order 100 mg kamagra gold free shipping. P2 receptor antagonists that can be blocked by xanthine adenosine antagonists cheap kamagra gold 100mg. ATP is CHALLENGES IN THE DEVELOPMENT OF released from certain cell types (e. P2X3-receptor knockout mice through which ATP, ADP, AMP, and adenosine (and UTP) have reduced nociceptive responses (61). The effects of produce their effects on mammalian tissues. A clear histori- adenosine are opposite effects to those of ATP (80), a find- cal delineation between the P1 and P2 fields is that in the ing suggesting that the nociceptive effects of ATP can be former, more than 20 years of pharmacology and medicinal autoregulated by adenosine production from the nucleotide. In contrast, defini- inhibit nociceptive processes in the brain and spinal cord. 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C: An alternative model for neuronal glutamate repletion in which the astrocyte repletes the lost neuronal glutamate by providing the neuron with -ketoglutarate [or equivalently other tricarboxylic acid cycle (TCA) intermediates] (32–34) purchase kamagra gold toronto. Glc order kamagra gold without a prescription, glucose; a-KG purchase cheap kamagra gold on line, -ketoglutarate: Vtrans, net rate of net ammonia transport into the brain (VNH4 in the text); Vefflux, rate of glutamine efflux from the brain; Vana, anaplerotic flux; V , rate of the glutamate/glutamine cycle; V , rate of glutamine synthesis. Using [2-13C] cycle gln glucose (27) and [2-13C] acetate precursors these pathways may now be distinguished. The natural abundance of the 13C isotope is This chapter reviews these findings and discusses some of 1. Substrates labeled with for studying neurotransmitter systems of approximately 1 13 to 4 mm3 in animal models and 7 to 40 mm3 in human the nonradioactive, stable, C isotope have been employed in vivo to study metabolic flux, enzyme activity, and meta- brain. Even in the best case the MRS signal is the sum of bolic regulation in the living brain of animals and humans the signal from a large number of neurons and glia including (6–39). Enhanced sensitivity may be achieved by measuring many different subtypes. Fortunately, nature has localized the 13C enrichment of a molecule through indirect detection key enzymes and metabolites involved in neurotransmitter through 1H MRS. From these measurements the flux cycling in specific cell types, which greatly simplifies the through specific metabolic pathways may be calculated (17, interpretation of the MRS measurements. As with any new tech- and the relationship of amino acid metabolism to functional nique there are still uncertainties due to methodologic is- neuroenergetics. Studies performed to validate the MRS measurements glutamine have been shown to be localized within gluta- will be reviewed, and present limits in measurement accu- matergic neurons, GABAergic neurons, and glia, respec- racy and interpretation delineated. Under nonfasting conditions glucose is the almost exclusive source of energy for the brain. By following the flow of 13C label from glu- 13 IN VIVO C MRS MEASUREMENTS OF THE cose into these metabolites, MRS has been used to deter- PATHWAYS OF GLUCOSE OXIDATION: mine the separate rates of glucose oxidation in these cell FINDINGS AND VALIDATION types. The metabolism of glutamatergic neurons, GABAer- gic neurons, and glia is coupled by neurotransmitter cycles. This section reviews studies in which MRS was used to In the glutamate/glutamine cycle, glutamate released from measure the pathways of glucose oxidation in the cerebral nerve terminals (by either vesicular release or transport re- cortex. Glucose oxidation under nonfasting conditions is versal) is transported into surrounding glial cells, and con- almost the exclusive source of energy for the brain. Glutamine in then transported out of localization of key enzymes involved in GABA and gluta- the glia and into the neurons, where it is converted back mate metabolism in specific cell types provides the capabil- to glutamate, thereby completing the cycle (Fig. By ity for MRS to study their separate neuroenergetic require- following the flow of 13C label from glutamate into gluta- 13 ments. Through a similar strategy the cal specificity of MRS allows the flow of 13C label from GABA/glutamine cycle may be measured. The major finding of these stud- cycling to neuroenergetics have provided several new and ies is that in normal conditions in nonactivated human cere- controversial insights into the relationship of brain metabo- bral cortex and in rodent models, glucose oxidation in gluta- lism and function. Contrary to the previous view of a sepa- matergic neurons accounts for between 60% and 80% of rate metabolic and neurotransmitter pool of glutamate, glu- cerebral cortex energy consumption. The remaining 20% tamate release and recycling have been shown to be a major to 40% is primarily distributed between GABAergic neu- metabolic pathway. Another key finding is that the gluta- mate/glutamine cycle in the cerebral cortex is coupled in a Oxidation in Glutamatergic Neurons close to 1:1 ratio to neuronal (primarily glutamatergic) glu- The initial use of MRS to study brain metabolism was to cose oxidation above isoelectricity. This finding, in combi- measure glucose oxidation by following the flow of 13C nation with cellular studies, has led to a model for the coup- isotope from [1-13C] glucose into the C4 position of gluta- ling between functional neuroenergetics and glutamate mate (2,6). The coupling between neurotransmis- a [1-13C] glucose precursor to C4-glutamate and subse- sion and neuroenergetics provides a linkage between the quently C4-glutamine. Glucose is metabolized to pyruvate functional imaging signal and specific neuronal processes. The 318 Neuropsychopharmacology: The Fifth Generation of Progress The rate of neuronal glucose oxidation has been deter- mined in several studies from 13C MRS and 1H-13CMRS measurements of cerebral cortex glutamate turnover from a [1-13C] glucose precursor in animal models (2,14–17, 21,22,25–27) and humans (12,13,18,19,29,31,35,43,44). Comparison of the rates of neuronal glucose oxidation mea- sured in these studies with conventional arteriovenous (AV) difference and PET measurements of total glucose con- sumption found that the majority (between 70% and 90%) of total glucose oxidation in the rat and human brain is associated with the large glutamate pool, believed to reflect glutamatergic neurons, measured by MRS. In two recent 13C MRS studies of resting awake human occipital parietal FIGURE 25. The figure shows a 50- cortex, in which other pathways of glucose metabolism were minute accumulation 13C MRS spectrum obtained at 4 T approxi- directly measured, a similar range of between 60% (35) and mately 60 minutes after the start of a 1-13C glucose infusion. The 80% (29) of total glucose oxidation was calculated for the spectrum was obtained from a 72-mL volume centered on the midline in the occipital/parietal lobe. The large percentage of cortical syn- sion of regions of the bottom trace. Labeled resonances include apses that are glutamatergic and the high electrical activity the C2, C3, and C4 positions of glutamate, glutamine, aspartate, of glutamatergic pyramidal cells (4,45) may explain why and -aminobutyric acid (GABA) and the C3 position of lactate. As described in the text (see In Vivo 13C MRS Measurements of such a large fraction of total glucose oxidation is associated the Pathways of Glucose Oxidation: Findings and Validation), the with glutamatergic neurons. Local- ized in vivo 13C-NMR of glutamate metabolism in the human other neuron types, particularly GABAergic, the assignment brain: initial resultsat 4 tesla. DevNeurosci 1999;20:380–388, with of the fraction of glucose oxidation occurring in gluta- permission. In the future, the fraction of glutamate in glia may be measured more accurately through dynamic 13C MRS measurements of glutamate and glutamine labeling during the infusion of label is then transferred to the tricarboxylic acid cycle (TCA) labeled acetate that is incorporated into the brain selectively by the actions of pyruvate dehydrogenase (PDH) and citrate in the glia (28,38,39). When the label reaches C4- -ketoglutarate it is transferred to the large neuronal glutamate pool by the high MRS Measurements of the Rate Glucose activity exchange reactions of the amino acid transaminases Oxidation in GABAergic Neurons and mitochondrial/cytosolic transporters. The large gluta- mate pool was first identified in 14C tracer studies (40). GABA is the major inhibitory neurotransmitter and may Based on kinetic and immunohistochemical staining stud- represent over 30% of the synapses in the cerebral cortex (4, ies, it is believed to correspond to the glutamate pool of 46,47). GABA is synthesized from glutamate in GABAergic glutamatergic neurons (18,41,42). Due to the rate of these neurons by the enzyme glutamic acid decarboxylase (GAD). Almost all of the brain GABA pool tion of 13C label into the trapping glutamate pool, and the is localized to GABAergic neurons under normal condi- kinetic curves analyzed by metabolic modeling to calculate tions. The labeling of the GABA pool from [1-13C] glucose the rate of the neuronal TCA cycle (18). The trapping pool provides a minimum estimate of the rate of glucose oxida- assumption is not essential to determine the rate of the tion in the GABAergic neuron. The estimate is a minimum TCA cycle because subsequent labeling in the C3 position because label may bypass GABA and continue from -keto- of glutamate can be measured to allow calculation of the glutarate/glutamate into the TCA cycle directly. Because glucose is the primary MRS analysis of cerebral cortex from extracts of rats infused fuel for neuronal oxidation, the measurements of the TCA with [1-13C] glucose has been used to measure the time cycle may be converted to measurements of glucose oxida- course of labeling in the GABA and glutamate pools (24, tion using known stoichiometries (17,18). Isotopic labeling of C4-glutamine by the glutamate/glutamine cycle from a [1-13C] glucose precursor. Infused [1-13C] glucose labels neuronal C3-pyruvate. This label is then incorpo- rated via the combined action of pyruvate dehydrogenase and the TCA cycle into -ketoglutarate, which is in rapid exchange with glutamate due to the action of several transaminases.

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