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Biomedical subjects

S D Iversen

Publications and source records attributed to S D Iversen.

At least 37 records · Page 2Linked to original sources
PubMed1997

Behavioural evaluation of cholinergic drugs.

Alzheimer's disease involves progressive degeneration of the cortex and the limbic system. Loss of afferent forebrain neurochemical modulatory systems is also seen, most significantly of the basal forebrain cholinergic system. Drug discovery programmes have pursued enhancement of forebrain muscarinic function as a therapeutic target. The most promising muscarinic agonists described achieve functional selectivity as agonists as the M1/M3 receptors in the CNS and M2 antagonists. These compounds have fewer cardiac and other cholinergic side effects. In rodent and monkey models of reference and working memory, these compounds reverse the cognitive impairment induced with plopolamine. Acetylcholinesterase inhibitors are even more efficacious in these models.

Alzheimer Disease↗
PubMed1997

Hemifield-specific visual recognition memory impairments in patients with unilateral temporal lobe removals.

Recent evidence on visual neglect suggests that each hemisphere maintains a retinotopically organized representation of the visual world contralateral to the current fixation point and that this representation is based not only on analysis of the current retinal input but, equally importantly, on information retrieved from memory. This idea predicts that unilateral damage to memory systems should produce a lateralized impairment of memory for the retinotopically contralateral visual world. To test this prediction we examined visual recognition memory performance in the left and right visual hemifields of patients who had undergone partial unilateral temporal lobe removals for the relief of epilepsy, either in the left hemisphere (n = 5) or the right (n = 5). The patients were given complex artificial scenes to remember, constructed of independent left and right halves, and were then tested for recognition of the left and the right halves separately. Stimuli were exposed tachistoscopically throughout and fixation was maintained on a central position. Patients made significantly more errors with half-scenes in the hemifield contralateral to their removal than in the ipsilateral hemifield, an increase of 50% in the error rate on average. The effect was seen equally in patients with left and right removals. This finding supports the idea that visual memory retrieval is retinotopically organized.

Adult↗
PubMed1995

Lack of effect of CCKB receptor antagonists in ethological and conditioned animal screens for anxiolytic drugs.

The effects of the CCKB receptor antagonists L-365,260, CI-988 and L-740,093, a new compound with improved bioavailability and CNS penetration, were assessed for anxiolytic-like effects in three rat anxiolytic screens sensitive to benzodiazepines, the elevated plus maze (EPM), conditioned suppression of drinking (CSD) and conditioned emotional response (CER) tests. In the EPM, L-740,093 (0.1-1.0 mg/kg), L-365,260 (0.00001-10.0 mg/kg), and CI-988 (0.01-1.0 mg/kg) did not increase the time spent on the open arms of the maze or the number of entries onto the open arms. In contrast, the benzodiazepine receptor partial agonist, bretazenil (0.3-10.0 mg/kg), significantly increased both the time spent on the open arms and the number of open arm entries. In the CSD and the CER tests, L-740,093 (0.1-1.0 mg/kg) L-365,260 (0.0001-0.1 mg/kg) and CI-988 (0.01-10.0 mg/kg) failed to increase suppression ratios compared to the vehicle-treated control rats, whereas, the benzodiazepine receptor partial agonist FG 8205 (10.0 mg/kg) (CSD) and bretazenil (0.3-3.0 mg/kg) (CER) both significantly increased suppression ratios compared to vehicle-treated control rats. In addition, L-365,260 (1.0-50.0 mg/kg), CI-988 (0.1-10.0 mg/kg) and diazepam (0.1-1.0 mg/kg) were assessed in a squirrel monkey conflict procedure. Although diazepam significantly increased suppressed lever pressing rates, L-365,260 and CI-988 were without effect. The present findings provide little support for the hypothesis that CCKB receptor antagonists have anti-anxiety effects in animals.

Animals↗
PubMed1995

Evidence that the anxiolytic-like effects of chlordiazepoxide on the elevated plus maze are confounded by increases in locomotor activity.

In exploratory animal models of anxiety, such as the elevated plus maze, the anxiogenic- and anxiolytic-like effects of drugs may be confounded by changes in locomotor activity. In the present experiments, the sensitivity of several measures of anxiety and locomotor activity in the elevated plus maze were assessed. Both chlordiazepoxide hydrochloride (CDP, 7.5 mg/kg) and d-amphetamine sulphate (AMP, 0.75, 1.5 mg/kg) increased the percent time on the open arms and doses of 7.5 mg/kg and 1.5 mg/kg CDP and AMP, respectively, increased the number of entries into the open arms. The increase in these measures might suggest that both compounds induced an anxiolytic-like effect. Although FG 7142 (30.0 mg/kg) did not decrease the number of entries to the open arms, it did decrease the time on the open arms, which might suggest that it had anxiogenic-like effects. Similarly, buspirone reduced both the number of entries into the open arms and the time spent on the open arms. However, all the compounds significantly affected locomotor activity. CDP (3.0 and 7.5 mg/kg) increased the total number of arm entries, the distance travelled on the open arms and the mean speed of the animals on the open, and in the closed arms. Moreover, the distance travelled by the animals in the closed arms was increased by 1.0 mg/kg CDP, a dose that had no measurable effects on the indices of anxiety.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed1994

A comparison of the effects of the novel muscarinic receptor agonists L-689,660 and AF102B in tests of reference and working memory.

Four experiments compared the CNS effects of a novel M1/M3 receptor agonist L-689,660 with those of the M1/M3 muscarinic receptor agonist AF102B. In the mouse tail-flick test of antinociception (TF) the minimum effective doses to increase tail-flick latency (MED) of L-689,660 and AF102B were 0.03 mg/kg and 10.0 mg/kg, respectively. In a rat conditioned-suppression-of-drinking (CSD) test of reference memory, doses of 0.3 and 1.0 mg/kg L-689,660 and a dose of 5.0 mg/kg AF102B reversed a scopolamine-induced deficit in performance (0.6 mg/kg). Although there was a tendency for L-689,660 to reverse the scopolamine-induced (0.4 mg/kg) performance deficit in a rat delayed-matching-to-position (DMTP) test, the difference failed to reach statistical significance. In contrast, a 5.0 mg/kg dose of AF102B potentiated the scopolamine-induced deficit in choice accuracy and the number of trials completed on this task. In a response sensitivity (RS) test, chain-pulling rates were significantly decreased by L-689,660 (MED = 0.03 mg/kg) and by AF102B (MED = 5.0 mg/kg). These results suggest that L-689,660 and AF102B may ameliorate or reverse a scopolamine-induced deficit, but only at doses that also reduce chain-pulling rates on operant schedules of reinforcement.

Animals↗
PubMed1994

One-trial tolerance to the effects of chlordiazepoxide on the elevated plus maze may be due to locomotor habituation, not repeated drug exposure.

The phenomenon of "one-trial tolerance" to the effects of chlordiazepoxide hydrochloride (CDP) in the elevated plus maze was re-examined. Unlike previous experiments, pre-exposure to the maze resulted in habituation and a consequential reduction in time spent on the open arms. The habituation effect was measured by recording the actual distance travelled by the rats in the maze and this was found to be significantly reduced by pre-exposure. Pre-exposure to the maze in the presence of CDP resulted in a reduced response to its "anxiolytic-like" effects (increasing time on the open arms compared to vehicle control rats). However, although the time spent on the open arms was reduced by pre-exposure, CDP significantly increased the time spent on the open arms by rats pre-exposed under a non-drugged state. These results suggest that rats do not become tolerant to the effects of CDP, but rather the reduced response to CDP after pre-exposure is due to habituation of exploratory behaviour.

Animals↗
PubMed1994

Temporal changes in the messenger RNA levels of cellular immediate early genes and neurotransmitter/receptor genes in the rat neostriatum and substantia nigra after acute treatment with eticlopride, a dopamine D2 receptor antagonist.

The cellular immediate early genes are involved in the transcriptional events associated with the dopaminergic regulation of neurotransmitter expression within neurons of the neostriatum. To characterize these events in detail, quantitative in situ hybridization histochemistry was used to assess the temporal effects of acute dopamine receptor blockade with eticlopride, a dopamine D2 receptor antagonist, on the messenger RNA expression of the immediate early genes and neurotransmitters/receptors in the caudate-putamen and ventral tegmental area/substantia nigra pars compacta of the rat. Groups of rats were injected with a single dose of either isotonic saline or eticlopride (0.5 mg/kg i.p.) and killed at various time intervals ranging from 5 min to 24 h and frozen brain sections processed by in situ hybridization histochemistry. Using computerized image analysis, the changes in messenger RNA expression for c-fos, c-jun, jun B, jun D, nerve growth factor I-A and nerve growth factor I-B and for neurotensin, glutamate decarboxylase, proenkephalin, the dopamine D1 receptor and the short and long isoforms of the D2 receptor were examined in the caudate-putamen. In the ventral tegmental area and substantia nigra pars compacta, the messenger RNA expression of the above early response genes and that for neurotensin, tyrosine hydroxylase, cholecystokinin and the D2 receptor isoforms were also examined. In the neostriatum, eticlopride caused a rapid increase in c-fos messenger RNA with significantly increased levels at 10 min (P < 0.01). The levels peaked at 30 min and thereafter declined to control levels. A similar profile was observed for jun B messenger RNA, although levels were still significantly (P < 0.01) elevated at 1 h and declined to basal levels thereafter. No significant changes were observed for c-jun, jun D, nerve growth factor I-A and nerve growth factor I-B messenger RNAs. In the dorsolateral neostriatum, there was an increase in proneurotensin messenger RNA 10 min after eticlopride, this increase becoming significant (P < 0.01) at 60 min. Levels were maximal at 2-6 h and decreased after 12 h to basal levels. There were small increases in proenkephalin messenger RNA, but these were not significant (P < 0.05) until 6 h after the injection. Eticlopride did not have any significant effects on the messenger RNA levels for glutamate decarboxylase, the D1 receptor and the short and long isoforms of the D2 receptor.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Biological properties of the benzodiazepine amidine derivative L-740,093, a cholecystokinin-B/gastrin receptor antagonist with high affinity in vitro and high potency in vivo.

A novel series of 5-amino-1,4-benzodiazepin-2-one derivatives (amidines), which contain a cationic solubilizing group and which are antagonists for the cholecystokinin (CCK)-B receptor, have been identified. Optimization of this series led to the identification of an azabicyclononane amidine, L-740,093 [N-[(3R)-5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-1-methyl-2- oxo- 1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea], that bound with high affinity of CCK-B receptors from guinea pig cerebral cortex (IC50 of 0.1 nM) and had a CCK-B/CCK-A receptor selectivity of 16,000. In comparison, L-365,260 had 85-fold lower affinity (8.5 nM) and was only 87-fold selective for CCK-B over CCK-A receptors. L-740,093 bound with high affinity to guinea pig gastrin receptors in vitro (IC50 of 0.04 nM). Electrophysiological studies on slices of rat ventromedial hypothalamic nucleus showed that L-740,093 produced rightward shifts of the concentration-response curve for the CCK-B receptor agonist pentagastrin (Kb of 0.06 nM). L-740,093 blocked pentagastrin-induced gastric acid secretion in anesthetized rats with a 50% inhibitory dose of 0.01 mg/kg, intraperitoneally, showing 100-fold greater activity, compared with L-365,260 (50% inhibitory dose of 1 mg/kg, intraperitoneally). An ex vivo binding assay in mice was used to investigate the interaction of L-740,093 with central CCK binding sites. After intravenous administration, L-740,093 inhibited ex vivo binding dose dependently, with a 50% effective dose of 0.2 mg/kg. These studies demonstrate that L-740,093 is the most potent and selective CCK-B antagonist yet described and that it has excellent central nervous system penetration.

Animals↗
PubMed1993

The effects of novel cholinesterase inhibitors and selective muscarinic receptor agonists in tests of reference and working memory.

In recent years muscarinic receptor agonists and cholinesterase inhibitors have been developed for the treatment of Alzheimer's disease. We have evaluated examples from both classes of compounds in rodent tests of reference and working memory, as well as tests that are sensitive to the side-effects of these compounds. Thus, three selective muscarinic receptor partial agonists L-689,660, (M1/M3), AF102B (M1/M3) and L-687,306 (M1) and two cholinesterase inhibitors, E2020 and eptastigmine, were compared in a mouse tail-flick (TF) test, a rat response sensitivity (RS) test, in rat tests of reference memory, passive avoidance (PA) or conditioned suppression of drinking (CSD), and working memory (delayed-matching-to-position, DMTP). In the TF test, all of the compounds tested, with the exception of L-687,306, (1.0-30.0 mg/kg) dose-dependently induced antinociception of which L-689,660 was the most potent (minimum effective dose (MED) = 0.03 mg/kg). In the RS test, all of the compounds, but again with the exception of L-687,306, (1.0-30.0 mg/kg), dose-dependently reduced response rates, of which L-689,660 was again the most potent (MED = 0.1 mg/kg). In the reference memory test, all the compounds reversed the effects of a scopolamine-induced deficit with L-687,306 being the most potent (MED = 0.01 mg/kg). By contrast, in the DMTP test, although both the cholinesterase inhibitors and L-687,306 reversed the effects of scopolamine-induced deficit, L-689,660 and AF102B were without effects. These results suggest that cholinesterase inhibitors and low efficacy M1 selective muscarinic receptor agonists can reverse the effects of a scopolamine-induced deficit in animal tests of reference and working memory at doses that do not induce the side-effects usually associated with cholinomimetics.

Animals↗
PubMed1993

Cognitive impairment in schizophrenia: how experimental models using nonhuman primates may assist improved drug therapy for negative symptoms.

Antipsychotic drugs provide effective relief from hallucinations but do not improve, and may even induce, other symptoms of schizophrenia. Tardive dyskinesia, which is often associated with intellectual impairment, is generally attributed to chronic therapy with antipsychotic drugs. However, the possible contribution of medication to cognitive impairment is not easily dissociated from the underlying progression of the disease. Recently evidence has accumulated from studies performed in patients and experimental monkeys that augmentation of catecholamine function may improve performance on certain cognitive tasks. Further investigation of the role of catecholamines in cognition is warranted in order to assist development of antipsychotic drugs with fewer undesirable effects and entirely new approaches to therapy for cognitive impairment in schizophrenia.

Animals↗
PubMed1993

Anxiolytic-like and antinociceptive effects of MK-801 accompanied by sedation and ataxia in primates.

Anxiolytic-like and antinociceptive activities of the noncompetitive NMDA receptor antagonist MK-801 (dizocilpine) were compared with sedative and ataxic side effects in primates. Administration of MK-801 (0.1 mg/kg) caused taming in cynomolgus monkeys and increased tail withdrawal latencies in squirrel monkeys; both effects were accompanied by sedation and ataxia. These findings are discussed in relation to the possible therapeutic uses of NMDA antagonists and differences in the behavioural effects of such compounds in primate and rodent species.

Analgesics↗
PubMed1993

Failure of intravenous pentagastrin challenge to induce panic-like effects in rhesus monkeys.

We examined the ability of intravenous (i.v.) challenge with pentagastrin to induce behavioural and cardiovascular effects consistent with panic attack in conscious rhesus monkeys. For behavioural evaluation, 4 naive male rhesus monkeys familiar with minimal manual restraint necessary for drug administration received a rapid i.v. bolus of pentagastrin (4, 8 or 16 micrograms/kg) or water on four separate occasions according to a randomised cross-over design. Behaviour was rated by a blind observer continuously during, and for the first 5 min immediately following i.v. injections while the monkey sat on the handler's lap, and then for a further 25 min in an individual observation cage. In separate experiments, the ability of pentagastrin to alter cardiovascular parameters which may accompany panic or anxiety (elevated heart rate and blood pressure) was explored. For cardiovascular studies, 8 male or female rhesus monkeys with femoral artery catheters were chair restrained and received a bolus injection of pentagastrin (4, 8 or 16 micrograms/kg) or saline into the saphenous vein at 30 min intervals. Blood pressure and heart rate were monitored continuously using a Statham Gould pressure transducer. Pentagastrin induced no consistent behavioural or cardiovascular changes. Similar pilot studies using CCK4 also failed to reveal such effects. We conclude that CCK-induced panic-like effects may not be demonstrable following challenge with pentagastrin under laboratory conditions in rhesus monkeys.

Analysis of Variance↗
PubMed1993

Antinociceptive activity of NK1 receptor antagonists: non-specific effects of racemic RP67580.

1. Release of substance P in the dorsal horn is considered a primary event in the perception of pain. The profile of racemic RP67580, a non-peptide antagonist at the NK1 (substance P) receptor, was examined in a range of antinociception tests on rodents. 2. At doses up to 30 mg kg-1, s.c. racemic RP67580 exhibited antinociceptive activity in writhing and formalin paw tests in mice and gerbils. Acetic acid induced writhing and the licking response to formalin were reduced to 40-50% of the level observed in vehicle-treated animals (P < 0.05). However, this agent was not active in mouse tail flick, rat paw pressure or rat and guinea-pig formalin paw tests. 3. Like racemic RP67580, the calcium channel blockers nifedipine (30 mg kg-1, i.p.) and verapamil (10 or 20 mg kg-1, s.c.) inhibited the response to formalin by approximately 60% in gerbils (P < 0.05 compared with vehicle-treated animals). 4. Evidence for calcium channel antagonist activity of RP67580 was obtained in vitro. Racemic RP67580 inhibited calcium entry into depolarized strips of guinea-pig ileum longitudinal muscle myenteric plexus (apparent KB = 587 +/- 115 nM), inhibited [3H]-diltiazem binding to rabbit skeletal membranes (IC50 = 298 nM) and depressed high threshold calcium currents in neurones cultured from rat cortex (10% inhibition at 10 microM). 5. These findings indicate that the acute antinociceptive effects of RP67580 may not be attributable to a specific interaction with NK1 receptors and may be mediated via calcium channel blockade.

Analgesics↗
PubMed1992

Dystonia induced by combined treatment with L-dopa and MK-801 in parkinsonian monkeys.

We examined whether the N-methyl-D-aspartate antagonist MK-801 (dizocilpine) would reverse parkinsonism or potentiate the effects of L-dopa in primates treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In contrast to its effect in rodent models, treatment with MK-801 (0.1 mg/kg) caused bradykinesia and ataxia in parkinsonian primates, but no locomotor stimulation. Coadministration of MK-801 (0.1 mg/kg) with L-dopa (20 mg/kg) induced marked dystonia accompanied by bradykinesia and ataxia. Dystonia was not induced by either treatment given alone. These findings indicate that MK-801 should not be advocated as an adjunct to dopamine agonist therapy in Parkinson's disease.

Animals↗
PubMed1992

Blockade of conditioned taste aversion by scopolamine and N-methyl scopolamine: associative conditioning, not amnesia.

The anticholinergic, scopolamine, consistently disrupts one-trial passive avoidance conditioning but the effects of such drugs on one-trial conditioned taste aversion (CTA) are variable and contradictory. In the present study, treatment of rats with scopolamine impaired the suppression of sucrose intake by post-ingestion administration of lithium chloride (LiCl) in a two-bottle choice test. A similar effect was obtained by using N-methyl scopolamine which penetrates the brain only to a limited degree on acute administration. The blockade of CTA could be prevented in three ways: (i) by exposing the rats to sucrose only on the training day, (ii) by pre-exposing the rats to both sucrose and scopolamine, and (iii) by using a less palatable sucrose/ascorbate mixture. The results demonstrate that the effect of scopolamine on taste aversion is not mediated by the central nervous system, and can be modified by altering the novelty and relative salience of the taste conditioned stimulus. These experiments suggest that conditioned associations between taste and LiCl, and scopolamine and LiCl may underlie the blockade of CTA by scopolamine.

Amnesia↗