June Corwin

Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer's disease.

Abstract To explore further the potential for cognitive enhancement utilizing nicotinic stimulation in Alzheimer’s disease (AD), six otherwise healthy subjects with moderate AD received placebo and three doses (6, 12, and 23 mg) of the novel selective cholinergic channel activator (ChCA) (nicotinic agonist) ABT-418 over 6 h in a double-blind, within-subjects, repeated-measures design. Subjects showed significant improvements in total recall and a decline in recall failure on a verbal learning task. Qualitatively similar improvements were seen in non-verbal learning tasks such as spatial learning and memory, and repeated acquisition. No significant behavioral, vital sign, or physical side effects were seen. These results confirm that stimulating central nicotinic receptors has acute cognitive benefit in AD patients. These findings suggest that selective ChCAs have a potential therapeutic role in dementing disorders, and that further studies with this or similar agents in AD and/or Parkinson’s disease are warranted.

Early pharmacokinetics and clinical effects of oral d-amphetamine in normal subjects

Seven normal subjects received 0.25 mg/kg D-amphetamine orally, both after an overnight fast and again after a standard breakfast. Plasma levels, subjective and cardiovascular effects, and observer-rated activation were assessed hourly for 5 hr. Food did not affect amphetamine levels. Plasma levels peaked at 2-3 hr. Maximum cardiovascular effects generally occurred at 1 hr, whereas maximum behavioral and subjective effects occurred at 2 hr. Subjective and behavioral effects declined thereafter, in spite of substantial amphetamine levels. A separate group of 8 subjects received 0.5 mg/kg D-amphetamine orally. Plasma levels, subjective and cardiovascular effects, and activation ratings were assessed hourly for 4 hr. Maximum plasma levels were approximately twice those seen in the first group. In this case, plasma levels peaked at 3-4 hr; blood pressure and subjective and behavioral effects were all maximal at 2-3 hr and were declining by 4 hr, in spite of stable or rising plasma levels.

Perceptual Identification Thresholds for 150 Fragmented Pictures from the Snodgrass and Vanderwart Picture Set

This paper reports perceptual identification thresholds for 150 pictures from the 1980 Snodgrass and Vanderwart picture set. These pictures were fragmented and presented on the Apple Macintosh microcomputer in a picture-fragment completion task in which identification thresholds were obtained at three phases of learning: Train (initial presentation), New (initial presentation after training on a different set), and Old (repeated presentation of the Train set). Pictures were divided into five sets of two subsets of 15 pictures each, which served alternately as the Train and New sets. A total of 100 subjects participated in the task, with 10 subjects assigned to each subset. Individual thresholds for each picture at each phase of learning are presented, along with the fragmented pictures identified by 35% of the subjects across the Train and New learning phases. This set of fragmented pictures is provided for use in experiments in which a single level of fragmented image is presented for identification after a priming phase. Correlations between the Snodgrass and Vanderwart norms and identification thresholds at the three phases of learning are also reported.

Nicotinic treatment of Alzheimer’s disease

Approximately 20 years after the formulation of the cholinergic hypothesis to explain the cognitive symptoms of Alzheimers disease, cholinesterase therapy remains the mainstay of treatment for this disorder, Although partially effective, currently available agents have limited effects on cognitive function and long-term efficacy appears modest. Direct or indirect stimulation of nicotinic cholinergic receptors may offer an additional therapeutic strategy. Ongoing investigations of the molecular substructure of central nervous system nicotinic receptors, their accompanying pharmacology, and the effects of nicotinic agents on cognitive function have suggested the possibility that nicotinic stimulation may have beneficial effects in Alzheimers disease and other neuropsychiatric disorders. Studies from our laboratory and others have explored the role of central nervous system nicotinic mechanisms in normal human cognitive and behavioral functioning as well as their role in Alzheimers disease. Results from acute therapeutic trials with nicotine arid novel nicotinic agents suggest that nicotinic stimulation in Alzheimers disease patients can improve the acquisition and retention of verbal and visual information and decrease errors in cognitive tasks, as well as improve accuracy and response time, Whether such results will translate into improved clinical functioning remains to be fully tested. Development of subtype-selective nicotinic agonists with an improved safety profile will enable long-term testing of the efficacy of nicotinic stimulation on cognitive performance as well as potential cytoprotective effects. Direct or indirect (allosteric) modulation of nicotinic receptor function offers a new opportunity for Alzheimers disease therapeutics.

Age-Related Effects of the Nicotinic Antagonist Mecamylamine on Cognition and Behavior

Studies of the neurochemical pathology of Alzheimers disease and Parkinsons disease reveal a severe and specific loss of central nicotinic cholinergic receptors. We have investigated the functional significance of this finding for cognitive functioning by studying the effects of the centrally active nicotinic antagonist mecamylamine. Single oral doses of mecamylamine were administered to 12 healthy young males and 15 healthy elderly subjects in doses of 5, 10, and 20 mg in a placebo-controlled, double-blind study. In both groups, the 20-mg dose caused a significant increase in errors in the learning condition of the Repeated Acquisition Task, producing a slower acquisition curve. There was no effect of drug on the performance component (retrieval of previously learned information). However, elderly subjects showed enhanced sensitivity to mecamylamine, with lO-mg dose producing significant impairment of learning not seen in the young normals. On a recognition memory task, there was an age-associated shift in response bias, with the elderly subjects becoming more liberal with increasing dose. Reaction-time measures suggested a dose-related slowing of reaction time on several tasks. Behavioral effects were minimal and physiologic effects were consistent with dose-related ganglionic blockade. These results indicate that acute blockade of nicotinic receptor function can produce measurable and significant cognitive impairment similar to some deficits seen in dementing illnesses, and that there is an age-related increase in sensitivity to nicotinic blockade.

Fragmenting pictures on the apple macintosh computer for experimental and clinical applications

A set of procedures implemented in Microsoft BASIC is described that creates fragmented versions of pictures scanned into the Apple Macintosh, stores them as resource files, and presents them in a computerized perceptual memory test. A total of 150 pictures were selected from the Snodgrass and Vanderwart (1980) set for fragmentation. The perceptual memory test provides for five forms of 30 pictures each, divided into two sets of 15 that serve alternately as the training or old set and the new set. A training set of 15 pictures is presented for identification during the first (training) phase of the test. The second (test) phase presents the training pictures again, randomly mixed with 15 new pictures for identification. The performance of 100 subjects on the memory test is presented, along with results for each form. Overall, subjects showed improvement on the task with practice (skill learning), indexed by a decrease in thresholds from the training set to the new set. Subjects also showed large savings for the repeated pictures (perceptual learning), indexed by a decrease in thresholds from the new to the old set.

Effects of d-cycloserine on negative symptoms in schizophrenia

INTRODUCTION The negative and cognitive symptoms of schizophrenia are poorly responsive to neuroleptic treatment. Glutamatergic dysfunction may mediate some of these symptoms. Low dose D-cycloserine (DCS) is a partial agonist at the glycine site of the NMDA-associated receptor complex, noncompetitively enhancing NMDA neurotransmission. Prior studies suggest a beneficial effect of DCS on negative symptoms and cognition. This treatment trial was initiated to confirm and extend these findings. METHODS Twenty-two male schizophrenic subjects displaying prominent negative symptoms who were stabilized on typical neuroleptics completed the study. A randomized double-blind parallel group design was used to compare the effects of 50 mg p.o. QD of DCS to placebo over 4 weeks. The two subject groups did not differ significantly in age, age of onset of illness or time on current neuroleptic treatment. Symptoms were rated by means of the SANS, BPRS and Abrams and Taylor rating scale. Cognition was assessed with the Sternberg Memory Test and the Continuous Performance Test. RESULTS Both medication groups improved over the 4 weeks of treatment. However, there were no significant differences between the DCS and placebo group on any symptom rating. DCS effects on cognition did not differ from placebo. DISCUSSION This study did not detect improvement in negative symptoms or cognitive performance with DCS treatment that has been found in some prior studies. This negative finding may be attributed to small sample size, relatively short duration of treatment and the overall modest effect of DCS. Future studies of DCS should be adequately powered to detect a small to medium effect size and should provide for a longer treatment phase than was used in this study in order to avoid a type II error.

Double blind controlled trials of cholecystokinin octapeptide in neuroleptic-refractory schizophrenia.

A group of 14 schizophrenics who remained symptomatic after neuroleptic treatment received either 0.02 mcg/kg CCK-8 or saline placebo intravenously. Thereafter, 13 received the alternative infusion as a crossover treatment. A second group of 16 such patients received 0.04 mcg/kg CCK-8 or saline intravenously and, thereafter, 14 of these received the alternative infusion as a crossover treatment. Psychopathology was rated prior to, 2–3 h post, and on days 3, 5 and 7 after each infusion. Ratings consisted of the BPRS, the Abrams and Taylor Scale for Emotional Blunting, the Hamilton Anxiety Scale and a Schneiderian “Positive” symptom scale abstracted from the Present State Examination. Parallel groups and cross over design analyses failed to show efficacy for CCK-8.

Disappearance of memory deficits in outpatient depressives responding to imipramine

We evaluated learning and memory in 50 depressed patients prior to and following 4 week treatment with imipramine compared to 21 normal controls tested at corresponding times. At baseline, the depressives did worse than normals on most memory tasks with the difficult memory tasks, regardless of store, modality or type of task best distinguishing between depressive and normal memory. Following imipramine treatment, responders performed better than nonresponders on the difficult memory tasks, and not significantly differently from controls on most tasks. This, as well as the fact that the responders improved to a greater degree than controls on most measures (in a few cases the difference was statistically significant) and the fact that at 4 weeks complete responders to imipramine did significantly better than partial responders to imipramine, indicates that relief from depression is highly related to improved memory functioning. The finding that complete responders to imipramine were not significantly worse than normal controls suggests that imipramine did not have significant adverse effects on memory.

Effects of nicotinic cholinergic agents on cognitive functioning in Alzheimer's and Parkinson's disease

The loss of central nicotinic receptors is a neurochemical hallmark of several degenerative brain disorders, notably Alzheimers (AD) and Parkinsons Disease (PD). Investigation of the effects of nicotinic agents in both normal and diseased individuals has produced strong evidence of the importance of the integrity of these systems for normal cognitive functioning. Studies in our laboratory utilizing the nicotinic antagonist mecamylamine show that blockade of nicotinic receptors produces measurable and significant cognitive impairment similar in nature to deficits seen in dementing illnesses. This work suggests that symptoms of impaired acquisition of information and short‐term storage, impaired memory consolidation, attention, visual perception, and speed may reflect nicotinic lesions. These studies and others have suggested that nicotinic systems may be involved in the modulation, partitioning, and maintenance of attention, especially for tasks involving working memory, e.g. nicotinic systems may help constrain the focus of attention. Recent studies with nicotine in AD patients reviewed here suggest that nicotinic stimulation can improve the acquisition and retention of verbal information and decrease errors. Finally a review of attentional deficits in AD and PD is presented as a suggested target for nicotinic intervention. Further work will attempt to examine whether nicotinic augmentation effects attentional systems, mnemonic systems, or both as well as whether chronic stimulation with nicotine or novel agonists will produce clinical benefit. Drug Dev. Res. 38:278–289