By U. Kerth. Lyon College.
Kern responded to a regimen of 2 silagra 100mg without a prescription,000- whereas yohimbine increases it (18) best 100mg silagra. Chapter 129: Circadian Sleep and Mood Disorders 1881 Timing of Light The Light Phase Response Curve The next step in the course of our work was to address the circadian phase-shifting effects of light purchase silagra 50mg without a prescription. A phase advance (shift to an earlier time)results from light exposure between the middle of the night and morning. A phase delay (shift to a later time)results from light exposure between the evening and middle of the night. These phase shifts are greatest in the middle of the night. During the day there are decreased responses to light. Each point represents the mean concentration of melatonin ( stan- Wever, who previously was the driving force behind the dard error) for six subjects. A paired t-test, comparing exposure importance of social cues, published a study in 1983, dem- to 500 lux with exposure to 2,500 lux, was performed for each onstrating that continuous bright light during the day had data point. A two-way analysis of variance with repeated mea- sures and the Newman-Keuls statistic for the comparison of a more potent effect on the human circadian system than means showed significant differences between 0230 and 0400 (*, did ordinary-intensity light (30). Right: Effect of different light intensities on melatonin secretion. Symbols: (o) 500 lux; (x) 2,500 lux; ( ) 1,500 lux; and ( ) Phase-Typing Circadian Rhythm Disorders asleep in the dark. Science 1980; Our much less elegant anecdotal report the same year indi- 210:1267–1269, with permission. We proposed that there were two types of circadian disor- We exposed him to bright light at these times, because ani- ders, the phase-delayed and phase-advanced types (Table mals tell time of year by the interval between the twilight 129. Most white light sources have this Phase-Advanced Type Phase-Delayed Type wavelength, which is in the middle of the scotopic spectral distribution. Rods, not cones, are most sensitive at this wavelength; Adjusting to night work Readjusting to off-work however, the precise retinal photoreceptors that mediate Winter depression chronobiologic effects of light have not yet been identified. The following year we showed that—holding the man group (39). Morning light was shown to be more anti- sleep/wake cycle constant—we could shift the melatonin depressant than evening light; however, evening bright light rhythm (a biological marker that we had proposed would was shown to be more effective than evening dim light. It be ideal for assessing circadian phase position in humans) should be noted, though, that there was no control for the by shifting the light/dark cycle (31,32). Signifi- cantly, the Terman group made the important suggestion The Phase Shift Hypothesis for Winter that 10,000 lux could be used for a shorter duration than Depression the 2,000- to 2,500-lux light that had been the previous When we proposed 'phase typing' circadian disorders (29), standard. Accordingly, we hypothesized that the optimum light for most patients. Some studies have shown that morn- time for bright light exposure was in the morning, which ing light is more effective than evening light (40,41); would provide a corrective phase advance. We further hy- whereas other studies showed that they are equally effective pothesized that morning light would advance the circadian (42). We also expressed of the former compared to the latter. According to their 'photon counting' hy- with the amount of phase advance. We had previously pothesis, light at any time of day should be antidepressant, shown this relationship with patients exposed to 30 minutes as long as light of sufficient duration and intensity was used versus 120 minutes of morning light (50), which has the (38). As Charmane Eastman has shown, the pla- cebo response is a major component to light treatment (51). Whether or not a specific mechanism for this can be found (e. We further suggest that dim light begin 1 hour before patients in the winter compared to the summer, particularly blood sampling (61). A third hypothesis, suggested by Charles salivary collections. In the early 1980s, we thought that plasma melatonin sam- pled every 30 to 60 minutes might be able to show differ- ences in circadian phase position between individuals and Low Melatonin Producers to monitor the phase-shifting effects of bright light (31,32). When there is a the time when melatonin levels begin to increase. Circadian Amplitude Sighted People It is not clear if the overnight melatonin profile is a good marker for the amplitude of its endogenous circadian pace- In sighted people, we reduced the dose to. Furthermore, it is not clear if circadian amplitude produces melatonin levels of the same order of magnitude is as important as circadian phase, in that an amplitude that occur physiologically. As opposed to previous studies disturbance has yet to be shown. Moreover, no technique of melatonin (which used higher doses and gave melatonin has been shown to enhance circadian amplitude or to relia- in the late afternoon or evening), we administered melato- bly diminish it. The jury is out over whether or not sup- nin at different times. In each trial we gave melatonin on pressing amplitude is important for bright light to cause four consecutive days, and the results were the first unequiv- phase shifts (65,66). That melatonin causes phase shifts op- at least three types of blind people: normally entrained, posite to those of light should not be surprising, because entrained at an abnormal phase, and free-running [blind melatonin appears to be a chemical signal for darkness. Of the million or Circadian Time so legally blind in the United States, about 200,000 are totally blind. Because 'lights phase with their preferred sleep time. The clock times in the tonin in the afternoon/evening. The timing of light and melatonin administration is best done with reference to circadian time rather than clock a few hours later or earlier, depending on how much the time. The role of habitual wake time (not the wake time on a particular day) melatonin and light in the human circadian system. For example, a person who habitually Kalsbeek A, Romijn H, et al, eds.
He points to two example in Macbeth by William Shakespeare (circa quality 100 mg silagra, 1607) buy cheap silagra 50 mg line. The first is when Macbeth sees a ghost and his guests respond cheap 50 mg silagra with mastercard, “Gentlemen, rise, his highness is not well. The second occurs when Lady Macbeth walks and talks in her sleep. A physician is called who states “More needs she the divine than the physician”. The majority of psychiatrists working in public general hospitals lament the emergence of medicalization/psychiatricization, which has allowed the community (citizens, police, courts, and welfare agencies) to force clinical psychiatrists to accept responsibility for situations/problems over which they have no real influence. A good case can be made for the validity of psychiatric disorders such as schizophrenia, major depressive disorder, bipolar disorder and obsessive compulsive disorder. And, using “evidence based” protocols, the psychiatrist is capable of providing the best possible management for people suffering these disorders. Disorders of interest Critics raise doubts about the validity of some recently described “disorders”, many spawned by the medicalization of the difficulties of everyday life (distress). The following table lists some behaviours and potentially matching diagnoses. The intention is not to discredit these diagnostic categories, but to illustrate the potential for normal behaviour to be cast as a mental disorder. Behaviour Diagnosis Shyness Social anxiety disorder Naughtiness Conduct disorder, Childhood onset Conduct disorder, Adolescent onset Delayed language Expressive language disorder Active Hyperactivity disorder Promiscuity Sexual addiction (Schaeffer, 1997) Sexually disinterested Hypoactive sexual desire disorder Unsatisfactory erections Male erectile disorder Unsuccessful gambling Pathological gambling Amorality Antisocial personality disorder Violence Intermittent explosive disorder Apprehension Agoraphobia (specific places) Specific phobia (except places) Social phobia (social anxiety disorder) Worried Generalized Anxiety Disorder Stress at work Work stress (Wainwright & Calnan, 2002) Stress Acute stress disorder Dependent Dependent personality disorder Narcissistic Narcissistic personality disorder Attention seeking Histrionic personality disorder Factitious disorder Avoidant Avoidant personality disorder Isolative Schizoid personality disorder Excessive coffee use Caffeine intoxication Caffeine induced sleep disorder Caffeine induced anxiety disorder Smoking Nicotine dependence Excessive alcohol use Alcohol intoxication Alcohol abuse Excessive cannabis use Cannabis intoxication Cannabis abuse Pridmore S. Distress is frequently misclassified as Major depressive disorder or PTSD. Nevertheless, it is frequently medicalized by rd commentators, thus becoming a 3 topic of interest. Depression (Major depressive disorder) See Chapter 8 for additional details. Clinicians who work in psychiatric wards do not doubt the existence of Major depressive disorder. Episodes last months, but may be shortened by treatment. Early episodes may be triggered by undesired events (loss). Later episodes may occur spontaneously, without detected triggering events. Depressed (sad, unhappy) mood is one, but only one, of the symptoms of Major depressive disorder (and related psychiatrically recognised conditions such as bipolar disorder), but depressed mood alone, is not sufficient to justify the diagnosis. Other symptoms include vegetative symptoms such as changes in sleep, ability to concentrate, energy and appetite (food, sexual intimacy). A psychiatric diagnosis can only be made safely when a recognized constellation of symptoms has been present for a sufficient length of time. Medicalization and Major depressive disorder As The Buddha pointed out, many life experiences are painful (or sad, unhappy or distressing). The mistaken belief is now held by many (citizens, police, courts, and welfare agencies), that sadness/distress automatically indicates a psychiatric disorder, the need for psychiatric treatment, and the need for psychiatric services to “take responsibility” for the individual. AGE ADMIT UR DIAGNOSIS 30 15-Feb 224691 Mania 20 1-Mar 281297 Situational Crisis 1 35 26-Feb 279575 Schizophrenia 39 27-Feb 233388 Schizophrenia 30 1-Mar 327579 Situational Crisis 2 19 28-Feb 414102 Situational Crisis 3 49 27-Feb 655614 Mania 18 20-Feb 235999 Schizophrenia 56 1-Feb 209051 Schizophrenia 40 25-Feb 348912 Drug Psychosis 30 21-Feb 226554 MDD Poly sub 33 5-Mar 353365 MDD 21 30-Jan 371426 Mania 28 20-Feb 379737 Schizoaffective d/o Pridmore S. This is the “bed status” from a 36 bed psychiatric ward of an Australian teaching hospital one day in early March, 2007. Eight people had been admitted with the “diagnosis” of “situational crisis”. The DSM-IV (the system in use at the time) did not have a “diagnosis” of “situational crisis”, but was the term used in this particular hospital when patients were admitted because of complaints of distress in the absence of evidence of a psychiatric disorder, or threats by the individual that if they are not given a bed, they will self-injure. The diagnosis of “situational crisis” is a form of medicalization – in some instances because staff find it difficult to make a judgement, in other cases because the presenting individual resorts to black-mail. Other hospitals use other “diagnoses” in the same circumstances including, Depression NOS (not otherwise specified; meaning not meeting criteria of Major depressive disorder, or other depressive disorders), and Personality disorder NOS (not otherwise specified). Medicalization of distress into Major depressive disorder has been facilitated by well- meaning attempts to increase public awareness of this disorder. Non-psychiatrists have been handed puny checklists and invited to make diagnoses. They have happily co-operated, with disastrous over diagnosis of mood disorders. The World Health Organization (1996) claims there is a world-wide epidemic of depression (Ustun et al, 2004), and experts claim Major depressive disorder is frequently missed by general practitioners. A recent cross sectional study in Australia found depression and dysthymia (a mild form of depression) in 5. Arguments against the epidemiological studies which underpin the “epidemic” story include that the symptom checklists which have been used do not take into account the circumstances and the meaning of those circumstances to the individuals being examined (Jacob, 2006; Summerfield 2006a). Differentiating distress from Major depressive disorder can be difficult (Pilgrim & Bentall, 1999) and, distress is part of normal reaction to stress, a common feature of people facing the demands of life (Jacob, 2006). Progressive medicalization of distress has lowered the threshold of individuals to tolerate mild symptoms and encouraged the seeking of medical attention (Barsky and Borus, 1995). The social supports available to the individual have been reducing over the last century, and the mental health team in now providing the psychological and social support which was previously provided by the family and local community (Jacob, 2006). Antidepressants have become the panacea for loneliness, relationship difficulties, interpersonal conflicts, inability to cope with day to day stress. Given, 1) distress is ubiquitous, 2) differentiating distress from Major depressive disorder is a task requiring expertise, 3) traditional emotional supports are now less available, and 4) drug companies and at least some psychiatrists have promoted the medicalization of distress, it is not surprising that medicalization remains healthy. Nor is it surprising that the community (citizens, police, courts, and welfare agencies) is now binging/sending droves of distressed individuals to hospitals with lay-generated (inaccurate) diagnoses of “depression”. And, so-called “burnout” has been described as more closely related to demoralization than Major depressive disorder (Cannon, 2006). PTSD was first described in the USA following the Vietnam War (1965-73). It is the only condition in the DSM-5 for which an aetiological (causative event) must be identifiable. The individual must have been exposed to a traumatic event in which there was “actual or threatened death, serious injury or sexual violence”. Other diagnostic criteria include the re-experiencing the event, avoidance of reminders of the trauma, decreased ability for emotional warmth toward others and persistent increased arousal (or nervousness).
In Executive functioning/ Executive functioningrefers to volition quality silagra 100 mg, this type of analysis discount 50 mg silagra fast delivery, the combined sample sizes are large card sorting planning discount silagra 100mg amex, purposive action, and and the relationships between neurocognition and func- self-monitoring of behavior. The metaanalyses solving tests such as the WCST are demonstrate that these four neurocognitive constructs are frequently used to assess executive functioning. CPT, Continuous Performance Test; WCST, Wisconsin Card Sorting Most of the studies in this area have used rather specific Test. METAANALYSES: NEUROCOGNITIVE PREDICTION OF FUNCTIONAL OUTCOME Domain Total Sample Size Pooled Estimated ra Effect Size p Value Secondary verbal 727. Neurocognitive deficits and functional outcome in schizophre- nia: are we measuring the “right stuff”? Al- words, although negative symptoms covary to at least a though effect sizes for the individual constructs are mainly modest extent with neurocognition (17,104) and their rela- in the medium range, they can become quite large when tionship to function appears to be mediated through this global or composite measures of neurocognition are used overlap, in toto the results suggest that cognitive impair- instead of individual measures (48,104). Such composite ment, rather than symptoms, most strongly influences func- measures indicate that neurocognition can explain between tional outcome. Just as the neurocognitive deficits in schizophrenia are How do these relationships compare with those for clini- not fully specific to schizophrenia, the correlations with cal symptoms? In general, psychotic symptoms (hallucina- functional outcome are unlikely to be specific to schizophre- tions and delusions) fare rather poorly as predictors and nia. Based on the role of neurocognitive deficits in other correlates of functional outcome (43). Negative symptoms disorders, one would not one expect them to be. The func- are more highly correlated with functional outcome, but tional consequences of neurocognitive deficits have been across studies, the relationships are neither stronger nor observed in a variety of neurologic conditions, including more consistent than those for neurocognitive deficits (17, head injury, Alzheimer disease, multiple sclerosis, Parkinson 48,104). Little is known about disorganized symptoms, disease, and AIDS encephalopathy (51,87,103). In fact, which often constitute a separate syndromal dimension that neurocognitive deficits have been associated with activities includes formal thought disorder, although recent studies of daily living even in a nonclinical sample of elderly persons suggest that this type of symptom may be related to func- (74). The work so far has been aimed at determining whether The relative contributions of symptoms and neurocogni- neurocognition is related to functional outcome. At this tion to functional outcome have only rarely been tested with time, it can be concluded that it is related, and the effect appropriate statistical analyses, including multiple regres- sizes are generally medium for individual constructs and sion (48,71). These studies do, however, support the idea generally large for composite measures. However, rather lit- that the neurocognitive contributions to outcome are tle is known about how neurocognition is related to func- stronger than those of symptoms. It is likely that some cognitive domains phisticated path analyses were used to test the associations have direct, causal relationships, although others may be among positive symptoms, negative symptoms, cognition, related to functional outcome through mediators, such as and activities of daily living in two separate samples of social cognition or the application of knowledge and reason- schizophrenic patients. A global measure of cognition had ing to problem solving. Various causal models were tested in EFFECTS OF MEDICATIONS ON which certain pathways were omitted. The pathway from NEUROCOGNITIVE DEFICITS cognitive impairment to functional outcome was necessary in the model; the fit was poor when it was omitted. To One of the most surprising aspects of conventional antipsy- the extent that symptoms were correlated with functional chotic medications is that although they usually have a pro- outcome, the relationships seem to be indirect. In other found impact on psychotic symptoms, their effects on neu- Chapter 48: Neurocognitive Functioning in Patients with Schizophrenia 665 rocognitive deficits tend to be negligible (7,11,98). In many of these studies, a Occasionally, treatment with conventional antipsychotic single group was assessed at baseline while on a conventional medications has led to improvement in basic perceptual or medication and then assessed again after being switched to attentional processes (3,98). However, it can be concluded an atypical medication. Inferences from these types of stud- that changes in neurocognition, if they occur, are small ies are necessarily tentative because no control is made for compared with the changes in psychotic symptoms. A small num- terms of disability, this presents a rather unfortunate mis- ber of parallel group blinded studies are emerging for cloza- match in which the domain of illness most affected by con- pine (4,108), risperidone (44,62), and olanzapine (85). Anticholinergic medi- alternative explanations for treatment effects. For the most cations given for extrapyramidal side effects compromise part, studies have not been designed or analyzed in a way certain neurocognitive abilities. Although the range of ef- that allows one to rule out indirect effects. For example, if fects of anticholinergic medications is not well character- a newer antipsychotic medication has a better clinical effect ized, they may disrupt aspects of secondary verbal memory than a conventional medication, it may improve neurocog- that rely on rehearsal strategies (18). Other aspects of mem- nition as an indirect benefit of greater symptom reduction. Sev- less affected (4,38), and the effects on other neurocognitive eral studies have noted that changes in neurocognition ap- abilities, such as visual processing, are relatively unknown. An alternative explanation is that the neuro- appears to be more promising. Initial interest in the neuro- cognitive benefits of newer medications are mediated by a cognitive effects of new antipsychotic medications was stim- reduced need for anticholinergic medications. Although this ulated by a series of (mainly open-label) studies of clozapine may turn out be true in some instances, the differential use (4,38,47,53,67). The results of these studies were surprising of anticholinergic medications did not explain the effects in two respects: First, in most of the studies, clozapine treat- of risperidone on immediate and secondary verbal memory ment resulted in improvement in verbal fluency (i. The beneficial effects of newer medi- ability to generate words that begin with a certain letter or cations on neurocognition may be mediated by lower rates belong to a certain semantic category) and possibly psycho- of extrapyramidal symptoms. Second, the initiation of clozapine treatment effects will be seen in comparisons with very low doses of in some studies appeared to have at least short-term detri- conventional medications, when side effects are minimal. These studies (again, mostly transient D2 blockade remains a viable explanation of open-label) have generally shown that they have benefits for 'atypicality' (59). Thus, it is possible that the administra- neurocognition in comparison with conventional antipsy- tion of conventional neuroleptics in inappropriately high chotic medications. Indications of short-term detrimental doses resulted in a lack of improvement, although dose- effects, similar to those seen in some clozapine studies, have reduction studies do not support this explanation (93,97). A rather comprehensive review (72) and a met- mains obscure. In any event, a single neurotransmitter effect aanalysis (61) of the existing literature have both provided seems unlikely to account for the effects, which probably a basis for optimism about the beneficial neurocognitive involve a constellation of actions at serotonergic, adrenergic, effects of newer medications. The metaanalysis of Keefe et cholinergic, and dopaminergic receptors (72). The neuropsychological signature of cholinergic medications).
When chronically abused 50 mg silagra with amex, PCP ing events following stimulation of iGluRs order 50mg silagra with mastercard, and stabilizing produces a syndrome in normal individuals that closely re- the inactivated state of voltage-dependent sodium channels purchase silagra 50 mg without a prescription. Subanesthetic doses of keta- tor subtypes and the effect of chronic treatment with NBQX mine administered to normal subjects produces positive in the spinal cord of motor neuron disease (mnd) mice. These findings suggest that selective antagonism of characteristic of schizophrenia (214). When administered 82 Neuropsychopharmacology: The Fifth Generation of Progress to schizophrenic subjects, subanesthetic doses of ketamine nist at the glycine modulatory site with 60% efficacy and exacerbate delusion, hallucinations, and thought disorders readily crosses the blood–brain barrier (230). These effects are attenuated by ics and exhibiting prominent negative symptoms revealed the atypical antipsychotic clozapine but not haloperidol. Chronic PCP serine dose of 100 mg per day in a small open trial with treatment produced more perseveration and fewer nonspe- medication-free schizophrenics (232). D-cycloserine at 50 cific cognitive deficits in monkeys that persisted after dis- mg per day significantly improved negative symptoms when continuation. Notably, these memory deficits were pre- added to conventional antipsychotics in an 8-week fixed vented by clozapine treatment (220). Notably, full response for negative symptoms was 222), which was associated with impaired performance on a not achieved until after 4 to 6 weeks of treatment. Furthermore, administra- zapine responders because clozapine has substantial effects tion of a group I mGluR agonist blocked PCP-induced glutamate release without affecting dopamine release (223). To the contrary, two separate trials the rodent have been shown to be comparable to humans of D-cycloserine at 50 mg per day added to clozapine re- in a positron emission tomographic study in which [11C]- sulted in worsening of negative symptoms (234,235). In raclopride binding in striatum was used to measure dopa- contrast, trials in which the full agonists, glycine or D-ser- mine release; subanesthetic doses of ketamine cause in- ine, were added to clozapine yielded no additional change creased dopamine release in human subjects (224). A If the symptoms of schizophrenia result from hypofunc- plausible explanation for these findings is that clozapine tion of NMDA receptors, then agents that enhance NMDA may exert its effects on negative symptoms and cognitive receptor function would be predicted to reduce symptoms. Electrophysiologic studies in the hippocam- Support for this inference comes from electrophysiologic pal slice indicate that the glycine modulatory site is not fully studies in the hippocampal slice where clozapine enhances occupied because of efficient transport of glycine by the NMDA receptor currents (238). GLYT-1 transporter on astroglia so that the modulatory site As hippocampal interneurons appear more sensitive to is subject to pharmacologic manipulation (133). In most of NMDA receptor antagonists owing to the presence of the studies, the drugs were added to typical antipsychotics NR2C (239), hypofunction of these NMDA receptors be- in stable patients with prominent negative symptoms. Javitt cause of an excess of endogenous antagonists such as NAAG and colleagues have performed a series of placebo-controlled or kynurenic acid could account for many features of schizo- crossover trials in which high doses of glycine (30 to 60 g per phrenia. The disinhibition of cortico-hippocampal efferents day) were added to antipsychotic drugs. They demonstrated appears to increase subcortical dopamine release associated improvement in negative symptoms and cognitive function with positive symptoms (240). This would also interfere without effects on psychotic symptoms or extrapyramidal with the precision of cortical/hippocampal activations con- side effects (226–228). The effects of glycine modulatory site sin Card Sorting test), and psychosis (229). The more robust activation, particularly on negative symptoms and cognitive effect of D-serine may reflect the fact that it has better impairment, are consistent with this model. Finally, the penetrance of the blood–brain barrier, is a full agonist and fact that ketamine reproduces the eye tracking impairments has a higher affinity than glycine. Chapter 6: L-Glutamic Acid in Brain Signal Transduction 83 Age-Associated Memory Impairment CONCLUSION Glutamate receptors have also been implicated in the func- In closing, glutamate sits at the epicenter of signal transduc- tional decline seen in normal aging in the absence of neuro- tion in brain, not only mediating excitatory neurotransmis- degeneration. Spatial memory is particularly vulnerable to sion, but also modulating neuroplasticity at the genetic, syn- aging (243), and is also disrupted by pharmacologic block- aptic, and structural levels. Furthermore, insufficient ade of NMDA receptor function (244) or hippocampal glutamatergic signaling causes the degeneration of imma- knockout of NR1 (245). Electrophysiologic investigations ture neurons through apoptosis (254), whereas excessive ac- of aging in rat hippocampus have revealed that certain as- tivation of iGluRs kills neurons through necrosis and/or pects of excitatory synaptic transmission are unaffected or apoptosis. Dysregulation of glutamatergic neurotransmis- even compensatory, whereas others are compromised (246). In studying age-related changes in receptors, it is particu- Dr. Coyle serves as a consultant for Jansson, Abbott, and larly important to be able to take the analysis from the Prestwick and owns stock in Merck, Celera, Genzyme, and regional level to that of cell classes, circuits, individual neu- PESystems. NMDA promotes the survival´ fined to the outer molecular layer (OML), that is, the distal of cerebellar granule cells in culture. Neuroscience 1988;27: dendrites of granule cells; whereas other excitatory inputs 437–451. Glutamate modulation of dendrite out- growth: alterations in the distribution of dendritic microtubules. Modulation of neuronal migration by the fluorescence intensity for NR1 in the OML of the DG NMDA receptors. Excitotoxic neurodegener- ation in Alzheimer disease. New hypothesis and new therapeutic tion of these circuits, this pattern means that decreased NR1 strategies. Glutamate- the ERC input to the hippocampus as a key element in age- induced neuronal death: a succession of necrosis or apoptosis related changes, and suggests that the intradendritic distri- depending on mitochondrial function. Neuron 1995;15: bution of a neurotransmitter receptor is modified in an age- 961–973. Glutamate neurotoxicity and diseases of the nervous related and circuit-specific manner (251). Although these results suggest that age-related circuit- 8. Glutamate and related acidic excita- specific shifts in NMDA receptors might underlie memory tory neurotransmitters: from basic science to clinical applica- defects, they were not done in behaviorally characterized tion. In addition, the data on NR1 changes were limited to 10. Glutamate-operated chan- the dendrite and did not directly address the GluRs at the nels: developmentally early and mature forms arise by alternative synapse. Thus, these data need to be extended, particularly splicing. Glutamate receptor particularly relevant because in rat hippocampus decreases RNA editing in vitro by enzymatic conversion of adenosine to inosine. The role of RNA editing in controlling glutamate age-associated memory impairment more directly than do receptor channel properties. Early-onset epilepsy 84 Neuropsychopharmacology: The Fifth Generation of Progress and postnatal lethality associated with an editing-deficient 34.