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Several lines of evidence suggest that multiple central tion order aspirin 100pills with mastercard. FG7142 (20 mg/kg) significantly elevated prefrontal nervous system structures cheap 100 pills aspirin, including the medial septum/ cortical ACh release in vivo (measured in parallel studies) aspirin 100 pills without prescription, diagonal band region, are critical in mediating the effects and FG7142 on its own impaired delayed alternation per- of muscarinic drugs on mnemonic functions (80). Interestingly, the fact that coadministration of of muscarinic-receptor antagonists into a variety of cortical FG7142 and scopolamine did not affect the slope of the regions, including the hippocampus, prefrontal cortex, and dose–response curve for scopolamine suggests that these amygdala, can impair the cognitive functions associated two drugs act on different mechanisms to impair delayed with these respective regions (81). The additivity of these effects indi- systemic muscarinic antagonists are attenuated by intrasep- cates that supranormal ACh transmission produced by tal injections of muscarinic agonists, and intraseptal applica- FG7142 likely does not contribute to the working memory tions of muscarinic antagonists mimic the amnesic effects deficits produced by this drug; moreover, the data indicate of systemic treatment with muscarinic antagonists in experi- that the impairments produced by scopolamine are inde- mental animals (82). These results suggest that activation pendent of the level of ongoing cortical cholinergic trans- of muscarinic receptors by ACh at multiple forebrain sites, mission. Thus, it is possible that the cognitive effects of including within the somatodendritic regions of the cholin- muscarinic antagonists may not be solely the consequence ergic neurons, may be involved in the behavioral dysfunc- of changes in cortical cholinergic transmission. The septohippocampal pathway was first believed to con- Figure 1. Scopolamine was administered sys- limb of the septohippocampal GABA pathway has suggested temically to rats performing a test of working memory, the that the septohippocampal GABA and cholinergic pathways spatial delayed alternation task, both alone and in combina- may both be critical for the effects of septal efferents on tion with FG7142, an anxiogenic -carboline that acts as cognitive functioning (85). In support of this hypothesis, an inverse agonist of the benzodiazepine site of the GABAA agents that increase impulse flow in the septohippocampal receptor. Consistent with previous findings, scopolamine GABA pathway, including muscarinic agonists, augment FIGURE 1. The cognitive effects of scopolamine administration are insensitive to phasic changes in cortical acetylcholine (ACh) release. Scopolamine dose-dependently impairs performance on a test of spatial working memory, the delayed alternation task, in control rats and rats treated with FG7142, an inverse agonist of the benzodiazepine site of the -aminobutyric acid subtype A (GABAA) receptor (left). Although FG7142 increases prefrontal cortical ACh release in vivo (right) and produces performance deficits on its own (left), it does not alter the slope of the dose– response curve for scopolamine. Interestingly, impulse flow in the septohippo- mediated via the M1 subtype of muscarinic receptor, partly campal GABA pathway is maintained by ACh released via as a result of closing of M-type potassium channels, so that the tonic firing activity of septohippocampal cholinergic specific M1-receptor agonists were developed. This release occurs via local axon collaterals of M1-receptor agonists were found to be of limited use in septohippocampal neurons, which then synapse on septohi- improving cognition. This might not be surprising because ppocampal GABA neurons within the medial septum/diag- studies of knockout mice lacking M1 receptors show no onal band (Fig. Thus, interaction between the septohi- change in muscarinic enhancement of potassium currents ppocampal GABA pathway and muscarinic mechanisms in the hippocampus (30). The finding that non-M1 recep- within the medial septum/diagonal band may be crucial for tors (M3 and possibly M5) mediate the effects of ACh in learning and memory (86). In contrast, septohippocampal GABA neurons are very selective in their innervation pattern, do not inner- Nicotinic Mechanisms vate the pyramidal cells at all, but innervate almost every Nicotinic systems are also involved in several important as- type of hippocampal interneuron (89). Septohippocampal pects of cognitive function, including attention, learning, GABA neurons are able to produce a powerful disinhibitory and memory (60). Nicotinic ACh receptors are expressed effect on pyramidal cells via this connectivity and so enhance throughout the brain, including areas involved in cognitive their excitability (90). Loss of cholinergic neurons severely function, such as the hippocampus and frontal cortex (91). A restoration of cholinergic function within the me- working memory function (60). The nAChR subtypes in- dial septum/diagonal band, not just in the hippocampus, volved in cognitive function are under investigation, and could therefore be critical for the treatment of cognitive different subtypes may be involved in the performance of deficits associated with the septohippocampal pathway. As mentioned above, experiments on knockout mice have implicated nAChRs containing the 2 subunit in both passive avoidance learning (11) and maintenance of spatial learning during aging (32). Although the cellular basis for the effects of nicotine are likely to be diverse, one site of action for nicotine, excitation of hippo- campal GABAergic interneurons through both 7 and non- 7 subtypes of the nAChR, has been demonstrated by sev- eral groups (see ref. Further, although theta rhythm in the hippocampus, a mechanism that appears to facilitate the induction of synaptic plasticity, is abolished by atropine (93), it is converted to burst-mode activity by nicotinic antagonists (94). Schematic representation of the septohippocampal progressive supranuclear palsy, and several other disorders pathway. The medial/septum diagonal band region is composed primarily of cholinergic and GABAergic neurons, and the activity (96), although not all studies have reported losses in cholin- of both neuronal populations is regulated by locally released - ergic neurons (97). In those that have reported losses, the aminobutyric acid (GABA). The cholinergic neurons and a subpo- greatest reduction in numbers, of the order of 50% to 65%, pulation of GABA neurons, containing the calcium-binding pro- tein parvalbumin (parv), project to the hippocampus via the fim- has been observed in cholinergic neurons of the nucleus bria/fornix. Similarly, muscarinic antagonists disrupt impulse flow in the septohippo- (96). Loss of high-affinity nAChRs has also been seen in campal GABA pathway. ROLE FOR CHOLINERGIC NEURONS IN CONCLUSIONS STIMULUS PROCESSING Recent studies using new physiologic techniques, choliner- Several lines of evidence suggest that cholinergic neurotrans- gic-selective toxins, and molecular genetic techniques have mission through nAChRs can affect stimulus processing. In refined our ideas about the role of ACh in the brain. In support of this notion, nicotine has been reported to allevi- particular, it is clear that cholinergic and GABAergic path- ate some sensory gating deficits in schizophrenic patients ways are intimately connected in the hippocampus and basal (99), and animal studies also suggest that nicotine may act forebrain complex and may combine to exert their effects to facilitate sensory inhibition, such as prepulse inhibition on cognition, attention, and arousal. Further, the subtypes of startle in mice (100) and rats (101). In another animal of cholinergic receptors that mediate these effects of ACh model of sensory processing, latent inhibition, nicotine can are beginning to be elucidated with the use of knockout either enhance or disrupt sensory habituation, depending mice that lack specific receptor subunits. These techniques on the preexposure parameters (102). Lesions of the nucleus have contributed to a minirevolution in our views of how accumbens or the pedunculopontine nucleus have been ACh contributes to cognitive processes. Research in this shown to block prepulse inhibition (103), whereas lesions area is moving very quickly, and it is likely that these ideas of the hippocampus, septum, medial raphe, and nucleus will continue to be refined as the new techniques are applied accumbens disrupt latent inhibition (104), observations to previously described behavioral paradigms. Improve- suggesting that nicotine may act in one or more of these ments in existing techniques—for example, through the de- brain areas to affect sensory processing. Another brain area velopment of inducible and site-specific mutations in cho- that is likely to mediate the effect of nicotine on sensory linergic-receptor subtypes—will also contribute to further gating in schizophrenia is the hippocampus. Postmortem refinements in our view of cholinergic functions in the studies have shown a reduced number of -bungarotoxin- brain. Further, pharmaco- logic (106) and genetic (107) studies have suggested a role SUMMARY for the 7 nAChR in prepulse inhibition in rodents.

Stud- or CBF in patients with alcoholism order 100 pills aspirin free shipping, multiple studies have ies comparing the response to benzodiazepines between con- been done comparing regional brain metabolic and CBF trol subjects and patients with alcoholism showed a signifi- responses to various pharmacologic challenges between con- cantly lower response in the orbitofrontal cortex in patients trol subjects and patients with alcoholism cheap aspirin 100pills on-line. Because most of with alcoholism than in controls (46 discount 100 pills aspirin with visa,53). The blunted re- the pharmacologic interventions were chosen to target a sponse to lorazepam in orbitofrontal cortex persisted after specific neurotransmitter system, we will discuss the find- detoxification, a finding suggesting that it was not the result ings from these studies under the neurotransmitter heading. Such studies showed that acute alcohol ad- in benzodiazepine receptors using PET and [11C]flumazenil ministration decreased brain glucose metabolism (Fig. When compared with controls, patients with alco- though there were no changes in the levels of receptor be- holism showed a significantly larger reduction in metabo- tween controls and patients with alcoholism, the latter had lism despite showing less subjective response to the intoxi- a significantly larger variability for Bmax (receptor concentra- cating properties of ethanol (55). In control subjects but tion) measures than controls (63). However, more recent not in patients with alcoholism, the subjective response to studies have consistently reported significant decreases in Chapter 103: Application of Imaging Technologies in Drug Addiction 1483 benzodiazepine receptors in patients with alcoholism, pre- trols. This study showed that mCPP-induced activation in dominantly in frontal brain regions including cingulate thalamus, orbitofrontal cortex, caudate, and middle frontal gyrus and orbitofrontal cortex (64,65), but also in cerebel- gyrus was significantly blunted in patients with alcoholism lum (66). The reductions in benzodiazepine receptors in when compared with controls (74). This finding was inter- patients with alcoholism reported by these imaging studies preted as reflecting a hyporesponsive striatothalamoorbito- are consistent with postmortem studies and may indicate frontal circuit in patients with alcoholism. The abnormal either a toxic effect of alcoholism on benzodiazepine recep- response to mCPP suggests an involvement of the serotonin tors or a vulnerability factor for developing alcoholism. The system in the abnormalities seen in this circuit in patients reductions in benzodiazepine receptors in the orbitofrontal with alcoholism. This study showed a significant reduction in the availability of brainstem serotonin transporters in patients with alcoholism Dopamine System that was significantly correlated with lifetime alcohol con- DA D2 receptors were evaluated in patients with alcoholism sumption and with ratings of depression and anxiety during with PET and [11C]raclopride and showed significant re- withdrawal (75). As for the prior study, this finding provides ductions in DA D2 receptor availability when compared evidence of a role for serotonin in alcoholism and in its with controls (67,68). No significant correlations were involvement with depressive symptoms during withdrawal. One of these studies also Opioid System measured DATs in a subgroup of the alcoholics in whom reductions in DA D2 receptors were detected and reported The effects of an oral naltrexone challenge on CBF in pa- no changes in DAT availability (68). This finding was inter- tients with alcoholism during detoxification was studied preted as evidence of GABAergic involvement in patients with SPECT and HMPAO. At baseline, patients with alco- with alcoholism because DA D2 receptors in striatum are holism showed lower CBF in left orbitofrontal cortex and mainly localized in GABA cells. After naltrexone, a signifi- DAT availability in patients with alcoholism has been cant regional CBF decrease was found in basal ganglia and measured by various PET and SPECT studies. The results the left mesial temporal region, which are structures rich in have not been consistent. These results were interpreted as support- reported that a group of violent patients with alcoholism ing the involvement of the opioid system in alcohol depen- had increases (8%) and nonviolent patients with alcoholism dence (76). SPECT studies in nonviolent patients with late-onset Spectroscopic Studies alcoholism have also reported a reduction in DATs (70). However, a PET study done with [11C]D-threo-MP and a Patients with alcoholism had a significant reduction of the SPECT study done with [123I] -CIT showed no changes cerebellar N-acetylaspartate–to-creatine ratio, which was in- in DATs in patients with alcoholism (71,68). These discrep- terpreted as reflecting neuronal loss and a reduction of the ancies are likely to reflect in differences in the time since choline-to-creatine ratio, which was interpreted as reflecting detoxification. One SPECT study showed that whereas cell membrane modification or myelin alterations (77). DAT levels were significantly reduced in patients with alco- holism within the first few days of last alcohol use, the levels Subjects at Risk of Alcoholism returned to normal 4 weeks after detoxification (72). PET studies with 6-[18F]-FDOPA (a marker for the DA synthesis The regional brain metabolic response to lorazepam was in the DA terminal) in patients late-onset (type 1) alcohol- evaluated in subjects with a positive family history of alco- ism showed higher striatal 6-[18F]-FDOPA uptake in the holism (FHP) and was compared with that of subjects with- patients with alcoholism than in the controls, a finding that out a family history of alcoholism (FHN) (78). At baseline, was interpreted as a compensatory mechanism to low post- FHP subjects showed lower cerebellar metabolism than synaptic DA function (73). FHN, and when challenged with lorazepam, they also showed a blunted response in cerebellum and in anterior cingulate gyrus. Lorazepam-induced changes in cerebellar Serotonin System metabolism were significantly correlated with motor impair- The effects of m-chlorophenylpiperazine (mCPP), a mixed ment. The blunted cerebellar sensitivity to benzodiazepines serotonin agonist-antagonist drug, on brain glucose metab- in FHP could account for the decreased sensitivity to the olism was compared in patients with alcoholism and in con- motor effects of alcohol and benzodiazepines in FHP sub- 1484 Neuropsychopharmacology: The Fifth Generation of Progress jects. The decreased cerebellar baseline metabolism in FHP in cerebral high-energy phosphates and in phospholipid me- subjects as well as the blunted cerebellar response to lora- tabolites. Marijuana Opiates Marijuana is the most widely used illicit drug of abuse in the United States. Despite its widespread use, the mecha- The effects of morphine on brain glucose metabolism were 9 nisms by which -tetrahydrocannabinol (THC) (the main evaluated in polydrug abusers (79). This study showed that psychoactive substance of marijuana) exerts its psychoactive morphine reduced glucose metabolism by 10% in whole effects are still not known. Relatively few imaging studies brain and by about 5% to 15% in telencephalic areas and have been done to assess the effects of acute and chronic the cerebellar cortex. Morphine-induced metabolic decre- marijuana use in the human brain. The effects of acute fentanyl, a synthetic opiate, on CBF were measured with PET and [15O]water. Fentanyl Brain Metabolism and Cerebral Blood Flow administration was associated with significant increases in regional CBF in cingulate, orbitofrontal, and medial pre- SPECT studies assessed the effect of THC intoxication on frontal cortices, as well as caudate nuclei, areas known to CBF in chronic marijuana users (84,85). Acute marijuana be involved in reward and addiction (80). In a more continuation and then retested 2 weeks later (81). The recent study, these investigators extended these findings to initial scans demonstrated significant CBF defects in the a larger groups of subjects and documented increases in frontal, parietal, and temporal cortices. Two weeks later, CBF in anterior cingulate gyrus and in the insula in mari- the SPECT scans showed improvement. Interpretation of the effects of THC on this study provide evidence that long-term use of opiates CBF is confounded by the vasoactive properties of THC results in perfusion abnormalities that are partially reversible (87). Thus, it is difficult to separate the effects of THC that with short-term abstinence. This problem is obviated when using deoxyglucose to measure brain glucose metabo- Dopamine System lism because this agent is insensitive to fluctuations in CBF Using PET and [11C]raclopride, opioid-dependent subjects (88).

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In all these models except one (126) discount aspirin 100pills free shipping, the N-terminal and the C-termi- 1204 Neuropsychopharmacology: The Fifth Generation of Progress TABLE 83 generic 100 pills aspirin overnight delivery. MISSENSE MUTATIONS IN THE PRESENILIN 1 GENE PRESENILIN 2 GENE Age of Age of Mutation Onset (y) References Mutation Onset (y) References V82L 55 Campion et al buy aspirin 100pills overnight delivery. George-Hyslop, 1998 (78) E120K Hardy, 1997 (106) nal domains were shown to protrude into the cytoplasm. In this Group, 1995 (109) model, HR7 and HR10 do not pass through but are associ- M139K Dumanchin et al. Alternative topologies have also I143F Hardy, 1997 (106) been suggested. George-Hyslop, 1998 (78) Presenilins are neither glycosylated nor modified by sul- H163R 50 Sherrington et al. The most prominent post-translational G209V Kamino et al. PS1 is rapidly cleaved into a 27- to 28-kd N- A231T 52 Campion et al. These findings are consistent R269G Hardy, 1997 (106) with the demonstration that the FAD-linked PS1 E9 var- R269H Hardy, 1997 (106) iant, which lacks exon 9 encoded sequences (amino acids E273A Kamimura et al. A426P Hardy, 1997 (106) It appears that endoproteolysis of the presenilins is not P436S Hardy, 1997 (106) needed for activation of their putative activities but may be required to convert unstable presenilins into stable com- plexes (134). Chapter 83: Molecular Genetics of Alzheimer Disease 1205 Various C-terminally truncated and chimeric PS poly- Studies with progressive deletion of presenilin showed peptides were used to characterize the interaction between that the hydrophilic N-terminal of PS2 (1-87) is sufficient NTF and CTF. It was observed that transgene-derived for the interaction with APP (127). Two different domains human PS1 NTF expressed in mouse N2a cells neither as- of APP appear to be involved in the APP-PS interaction. Fur- passing A and the TM region are able to interact with thermore, in cells coexpressing PS1 and PS2, PS1-and PS2- PS1 and PS2 (142,143). However, deletion of the cyto- derived fragments did not form mixed assemblies. In con- plasmic C-terminus domain does not abrogate PS1 binding trast, cells expressing a chimeric PS1/PS2 polypeptide (143). In addition, two APP constructs representing physio- formed PS1 NTF. These studies pro- logically secreted forms of APP (sAPP and sAPP ) were vide strong evidence that intramolecular associations be- shown to coprecipitate with PS2 in transfected COS cells tween PS domains precede endoproteolytic processing (127). Taken together, these result suggest presenilin binds (136). Full maturation of cleavage by the yet hypothetical presenilinase, presenilins APP does not seem to be required for the interaction, be- also undergo additional cleavage, termed alternative cleav- cause the APP form detected in precipitated complexes is age, within the hydrophilic loop domain (133). PS1, as well as PS1- or PS2 derived CTFs, can be cleaved by caspases in transfected cells and cells induced to undergo apoptosis. Several members of the caspase family of pro- Role in APP Processing teases, including caspases 1, 3, 6, 7, 8, and 11, are capable of cleaving PS1 and PS2 in vitro (138). Pathogenic mutations in PS modify APP processing, thereby leading to an augmentation of A 42 secretion. Pa- tients with AD who carry PS1 or PS2 mutations have signifi- Localization cant increase of plasma A 42 levels (145) together with deposition of A 42 in the brain (146,147). In fibroblasts Endogenous presenilins have a relatively limited subcellular from such patients, the APP metabolism is shifted toward distribution; they are found in the early compartments of an increase of A 42 production. Presenilin proteins have been local- mutated PS1 increases A 42 in transfected cells (148–151), ized to the endoplasmic reticulum (ER) and the Golgi sub- as well as in transgenic mice (148–150). Confocal and electron micros- PS influences the production of A 42 peptides remains un- copy, combined with subcellular fractionation experiments, certain, but these PS mutations appear to cause aberrant show that presenilins in neurons reside in the smooth and gain, rather than loss, of function. In neurons of PS1-knock- rough ER, the ER Golgi intermediate compartments, and, out mice, secretion of A is drastically reduced, leading to to a limited extent, in the cis-Golgi, but not beyond (139). This gives evidence that PS1 is obligatory Golgi compartments should, however, be interpreted with for proteolysis of APP at the -secretase cleavage site. Either mutation, when expressed in various mamma- (140). Studies provide convincing evidence that some mam- lian cell types, prevented both the normal endoproteolysis malian PS1 can be found at the cell surface, where it can be biotinylated (141). Conservative substitution of aspartate by glutamate still abrogated the -secretase Interaction with APP cleavage of APP, a finding indicating a specific requirement There is strong evidence that presenilins are able to interact for the two TM aspartates. These results are consistent with directly with APP. Complex formation between APP and one of two mechanisms: a role for presenilin as a unique presenilins has been demonstrated by coimmunoprecipita- cofactor for -secretase that could play a role in protein tion of both proteins in cells either transfected or with en- trafficking or a role as a functional -secretase, making it an dogenous proteins as well as with the yeast two-hybrid sys- unprecedented intramembranous aspartyl protease. Thinakaran and colleagues, in contrast to evidence for and against both possibilities. Presenilin proteins 1206 Neuropsychopharmacology: The Fifth Generation of Progress have been localized to early transport compartments, of PS1 not only prevented APP processing by -secretase, whereas abundant -secretase activity is restricted to late but also prevented the cleavage of the Notch C-terminus transport compartments and the endosomal pathway (55, in the membrane. The same holds true for the release of the Notch intra- either presenilins are directly involved in cleaving both cellular domain (see later), which occurs after ligand binding Notch and APP or mediate both cleavages in a more indirect by Notch at the cell surface (154,155). Processing of Notch resembles in some aspects the cellular localization of presenilin proteins in ER and early processing of APP. Notch is processed by a furin-mediated Golgi overlaps to some degree with the intracellular site of cleavage during its passage through the Golgi system. An addi- resultant two fragments remain in the same protein complex tional concern is that the presenilin sequences have no ho- and localize in the cellular membrane to form the functional mology to any of the proteases identified so far. The binding of the ligand to the receptor stimu- tion that PS is -secretase will require reconstitution of the lates the cleavage of one of the subunits at a specific extracel- -secretase/presenilinase activities in artificial lipid bilayers lular site close to the membrane. A subsequent intramem- using appropriate substrates and cellular factors. Partial branous cleavage liberates an intracellular fragment that characterization of detergent-solubilized -secretase activity translocates into the nucleus. This peptide forms an active shows that -secretase activity is catalyzed by PS1-contain- transcription complex, which activates transcription of ing macromolecular complex (156).

This combination reduces peripheral dopaminergic Adverse Effects of Dopamine Agonists side effects associated with the administration of levodopa The acute side effects of dopamine agonists are similar to alone buy 100pills aspirin with mastercard, and increases the amount of levodopa that is available those observed with levodopa and include nausea buy aspirin 100 pills low cost, vomiting discount aspirin 100 pills mastercard, to access the brain. However, even in the presence of a and postural hypotension (84). These side effects tend to decarboxylase inhibitor, the bulk of levodopa is still metabo- occur when treatment is initiated and abate over days or lized by COMT and only 10% of a given dose is transported weeks as tolerance develops. Introducing the agonist at a into the brain (17,89). Two new drugs that inhibit COMT, low dose, and slowly titrating to the desired effect reduces tolcapone (Tasmar) and entacapone (Comtan), have re- the probability that they will occur. Dopamine agonists can cently been introduced to the market as an adjunct to levo- acutely cause or intensify dyskinesias, but in the long term dopa therapy. Both drugs inhibit COMT in the periphery, they have the potential to lessen dyskinesias and motor fluc- although tolcapone has mild central effects as well. Entaca- tuations because of their long duration of action (see above). The ergot-derived dopamine ag- reach peak plasma concentration (Tmax) and effects are seen onists, bromocriptine, pergolide, and cabergoline, may have with both immediate and controlled release formulations ergot-related side effects including pleuropulmonary and (90–93). COMT inhibitors thus modulate peak and trough retroperitoneal fibrosis, erythromyalgia, and digital vaso- plasma levodopa concentrations, leading to a smoother spasm, although these are rare (84). The newer non-ergot plasma curve with reduced fluctuations in levodopa level dopamine agonists are less likely to induce these problems, (94). These pharmacokinetic effects have been shown to although there is anecdotal suggestion that they may still translate into enhanced levodopa entry into the brain on occur. Dose-related sedation may occur with dopamine ago- positron emission tomography (PET) (95) and clinical ben- nists (69,78), as with other dopaminergic agents including efits particularly for patients experiencing mild to moderate levodopa. More recently, sudden episodes of unintended motor fluctuations. Double-blind placebo-controlled clini- sleep while at the wheel of a motor vehicle have been de- cal trials in fluctuating PD patients demonstrate that scribed in PD patients and attributed to dopamine agonists COMT inhibitors increase the duration of beneficial effect (85). The episodes were termed 'sleep attacks' because they following a single levodopa dose (96). They also provide an occurred suddenly, although others have argued that there increase daily 'on' time of 15% to 25%, a decrease in is no evidence to support the concept of a sleep attack even 'off' time of 25% to 40%, improvement in UPDRS motor in narcolepsy. They have suggested that it is more likely scores, and a reduction in levodopa dose requirement of that these patients have unintended sleep episodes as a mani- 15% to 30% (97–100). Benefits with COMT inhibitors festation of excess daytime sedation due to nocturnal sleep have also been observed in nonfluctuating PD patients with disturbances that occur in 80% to 90% of PD patients and a stable response to levodopa. Two placebo-controlled trials to the sedative effect of dopaminergic medications (86). It showed improved motor scores and reduced levodopa dose is now apparent that these types of episodes can be associ- requirements in the group receiving the COMT inhibitor ated with all dopaminergic agents including levodopa (87). Physicians should be aware of the potential of dopaminergic There has also been interest in using COMT inhibitors agents to induce sleepiness, and that patients themselves from the time levodopa is first initiated in order to reduce may not be aware that they are sleepy. To detect excess the risk of developing motor complications (103). As de- sleepiness and to thereby introduce appropriate manage- scribed in the section on motor complications, laboratory ment strategies, it is necessary to employ sleep question- evidence supports the notion that treatment for PD patients naires such as the Epworth sleepiness scale, which inquires should be employed in such a way as to try and avoid pulsa- into the propensity to fall asleep and does not rely upon tile stimulation of dopamine receptors (51). Indeed, there subjective estimates of sleepiness (88). However, these patients Catechol O-Methyltransferase (COMT) eventually require levodopa, and when levodopa is adminis- Inhibitors tered the frequency of motor complications increases. It Orally ingested levodopa is massively transformed in the therefore has been postulated that administering levodopa periphery by two enzymatic systems—AADC and from the time it is first introduced with a COMT inhibitor 1802 Neuropsychopharmacology: The Fifth Generation of Progress to extend its half-life and deliver levodopa to the brain in data indicate that tolcapone is the more potent agent. How- a more continuous fashion might further reduce the risk of ever, because of the greater risk of hepatotoxicity and diar- motor complications. Based on a similar hypothesis, studies rhea, entacapone has become the more widely employed comparing controlled-release levodopa to regular levodopa COMT inhibitor. It should be emphasized that COMT failed to demonstrate any difference between the two formu- inhibitors provide antiparkinsonian benefit only when used lations (104,105). However, controlled-release formula- as an adjunct to levodopa. Further, the drug was prescribed advance in the medical treatment of PD and may be useful twice daily in these studies, and that may not have been in all stages of the illness (110). Used in combination with frequent enough to prevent fluctuations in plasma levodopa levodopa, they extend the half-life of levodopa, smooth the concentrations. Clinical trials to test this hypothesis using plasma levodopa concentration curve, and enhance clinical entacapone as an adjunct to levodopa are currently being dopaminergic benefits. Dyskinesia is the most common, but best left to the Parkinson specialist. There are preliminary nausea, vomiting, and psychiatric complications may occa- data suggesting that they enhance motor function in the sionally occur. Both the benefits and dopaminergic adverse milder patient with a stable response to levodopa, and this effects develop within hours to days after initiating treat- is being further evaluated. In general, they are easy to manage by simply reduc- to suggest that administering levodopa with a COMT in- ing the dose of levodopa (by approximately 15% to 30%), hibitor from the time it is first introduced may prevent not the dose of the COMT inhibitor. Dyskinesia is more pulsatile stimulation of dopamine receptors and minimize likely to be a problem in patients who already experience the risk of developing motor complications. The drugs are dyskinesia, and the need for a levodopa dose reduction can easy to use and require no titration. Dopaminergic side ef- be anticipated in these patients. An explosive diarrhea has fects tend to occur within days and can be managed by been seen in 5% to 10% of tolcapone-treated and necessi- tapering the levodopa dose. Because of the restrictions in tates discontinuing the drug. This has been much less of a the use of tolcapone due to liver toxicity, entacapone is now problem with entacapone and rarely requires stopping the the COMT inhibitor of choice.