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S D Iversen

Publications and source records attributed to S D Iversen.

At least 55 records · Page 3Linked to original sources
PubMed1992

Comparison of the effects of selective and nonselective muscarinic agonists on cognition and thermoregulation in primates.

Peripheral toxicity may explain the disappointing therapeutic effects of nonselective muscarinic agonists in Alzheimer's disease. Partial agonists might exhibit an improved therapeutic index. We compare the central and peripheral cholinergic effects of RS86 with the M1/M3 partial agonists AF 102B and L-689,660 ((-)-3-[2-6 chloropyrazin)yl]-1-azabicyclo[2.2.2]octane) in primates. Administration of RS86 (1.5-2.25 mg/kg i.m.) or L-689,660 (0.1-0.3 mg/kg i.m.), but not AF 102B (up to 6 mg/kg i.m.), caused partial reversal of the disruptive effects of scopolamine on cognition. However, performance remained significantly poorer than in untreated control animals. Adverse effects prevented examination of higher doses. Centrally-mediated hypothermia was induced by RS86 (0.05 mg/kg p.o.) and L-689,660 (0.01 mg/kg p.o.) but only by a high dose of AF 102B (7 mg/kg p.o.). The putative therapeutic advantages of partial M1/M3 agonists over RS86 are discussed.

Animals↗
PubMed1992

Reversal of cognitive impairment by heptyl physostigmine, a long-lasting cholinesterase inhibitor, in primates.

Cholinergic replacement therapy for Alzheimer's disease using existing cholinesterase inhibitors is compromised by short duration, meagre benefits restricted to subgroups of patients, and peripheral toxicity. Heptyl physostigmine is a lipophilic carbamate derivative of physostigmine. In rhesus monkeys, heptyl physostigmine (0.2-0.9 mg/kg i.m.) fully reversed a scopolamine-induced cognitive impairment. Following oral administration in squirrel monkeys, heptyl physostigmine (8 mg/kg) induced long-lasting hypothermia (greater than or equal to 4 h), a centrally-mediated cholinergic effect. Erythrocyte acetylcholinesterase activity was inhibited by 86% at the time of peak hypothermia (180 min). Clinical trials with heptyl physostigmine will enable a more rigorous evaluation of cholinomimetic therapy for dementia.

Acetylcholinesterase↗
PubMed1992

Failure of d-cycloserine to reverse cognitive disruption induced by scopolamine or phencyclidine in primates.

The partial glycine agonist d-cycloserine may be of therapeutic use as a cognitive enhancer. We examined the ability of d-cycloserine (3-14 mg/kg i.m.) to reverse cognitive impairments induced by scopolamine (0.03 mg/kg) or PCP (0.25 mg/kg). There was no evidence for a dose-related improvement in visuospatial memory using retention intervals of 2,10 or 20 sec. A possible explanation for these findings is that central glycine function cannot be adequately increased using systemic administration of d-cycloserine in this dose range.

Animals↗
PubMed1992

Weak antiparkinsonian activity of the D1 agonist C-APB (SKF 82958) and lack of synergism with a D2 agonist in primates.

The role of D1 receptors in motor control is poorly understood. In parkinsonian squirrel monkeys, the full D1 agonist C-APB (SKF 82958; 0.1-0.4 mg/kg s.c.) caused weak stimulation of locomotor activity. However, the motor stimulant effects of the D2 agonist (+)-PHNO (0.001 mg/kg s.c.) were not potentiated by C-APB (0.3 mg/kg). Differences between these observations and expectations from experiments using rodents are discussed.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Evidence against a specific effect of cholinergic drugs on spatial memory in primates.

A scopolamine-like delay-dependent impairment in spatial delayed response performance in rhesus monkeys was induced by irrelevant interpolated activity or by using extended retention intervals. Physostigmine readily reversed the effects of scopolamine but had no effect on performance in young monkeys performing an irrelevant distractor task or in monkeys tested using extended retention intervals. Reducing stimulus control did not impair performance and did not alter the dose-response curve for induction of a deficit by scopolamine. Reducing the stimulus presentation time impaired performance across all retention intervals in a way which did not resemble the effect of scopolamine and which disappeared with practice. Our findings do not support the proposal that physostigmine interacts specifically with short-term spatial memory in primates.

Animals↗
PubMed1991

Psychomotor activity and cognitive disruption attributable to NMDA, but not sigma, interactions in primates.

We have compared the ability of phencyclidine (PCP)-like or sigma ligands to induce psychomotor effects in primates. In squirrel monkeys, administration of MK-801 (0.001-0.1 mg/kg), PCP (0.03-0.3 mg/kg), (+)-SKF10047 (0.001-3.0 mg/kg) or (-)-SKF10047 (0.1-10 mg/kg) induced ataxia, head weaving and bradykinesia. In contrast, treatment with the selective sigma ligand (+)-pentazocine using doses up to 20 mg/kg failed to induce any overt behaviours. The order of potency for induction of these behaviours was: MK-801 greater than PCP greater than (+)-SKF10047 greater than (-)-SKF10047 much greater than (+)-pentazocine. In rhesus monkeys treatment with MK-801 (0.01-0.04 mg/kg), PCP (0.05-0.2 mg/kg), (+)-SKF10047 (0.75-3.0 mg/kg) or (+)-pentazocine (1-10 mg/kg), disrupted performance of a spatial delayed response task. The potency to induce cognitive disruption was positively correlated with affinity for [3H]MK-801, but not [3H](+)-SKF10047, binding sites in vitro. These findings indicate that the psychomotor and cognitive effects of PCP-like and sigma ligands in primates are mediated through interactions at NMDA, not sigma, receptors.

Animals↗
PubMed1991

Hypolocomotion induced by peripheral or central injection of CCK in the mouse is blocked by the CCKA receptor antagonist devazepide but not by the CCKB receptor antagonist L-365,260.

The pharmacological mechanisms underlying the hypolocomotion induced by intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) injections of cholecystokinin octapeptide sulphated (CCK) in the mouse were examined using selective CCKA and CCKB receptor antagonists. Locomotor activity was measured in photocell cages. CCK (10 micrograms/kg i.p.) significantly reduced activity in mice tested in the afternoon but not in the morning, indicating a circadian variation in the effect of the peptide. The hypolocomotion induced by i.p. injection of 10 micrograms/kg CCK and i.c.v. injection of 3.5 micrograms CCK was reversed by the selective CCKA antagonist devazepide, but not by the selective CCKB antagonist L-365,260. This suggests that CCK-induced hypolocomotion is mediated by CCKA receptors. Larger doses of CCK were required to induce hypolomotion when injected i.c.v. (3.5 micrograms per mouse) than when given i.p. (10 micrograms/kg i.e. 0.2 microgram per mouse). Furthermore the latency to onset of the hypolocomotion after i.c.v. injection of CCK was longer than after i.p. injection of CCK. These data suggest that the sedative action of i.c.v. CCK may be due to leakage of the peptide from the brain and subsequent activation of peripheral CCKA receptors. However a role for CCKA receptors in the CNS in mediating hypolocomotion induced by i.c.v. injection of CCK cannot be ruled out on the basis of the present data.

Animals↗
PubMed1991

Striatal A2 receptor regulates apomorphine-induced turning in rats with unilateral dopamine denervation.

The effect of the purine agonist N-ethylcarboxamido-adenosine (NECA) on apomorphine-induced rotation was investigated in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway. Intrastriatal administration of NECA on the denervated side caused a dose-dependent inhibition of contralateral rotation. This inhibition was prevented by prior intrastriatal injection of theophylline. The adenosine A1 receptor antagonist 8-cyclopentyltheophylline was ineffective at concentrations which block this receptor, but effective in preventing the action of NECA at concentrations which block the adenosine A2 receptor. In the absence of apomorphine, NECA had no effect on behaviour. It is concluded that A2 receptor activation counteracts apomorphine effects in the striatum. Since the A2 receptor may be localized to striatal cholinergic neurones, the possible role of these neurones in purine-induced behaviours is discussed.

Adenosine↗
PubMed1991

Evidence for an involvement of D1 and D2 dopamine receptors in mediating nicotine-induced hyperactivity in rats.

Previous studies have suggested that repeated exposure of rats to the drug or to the experimental environment is necessary to observe nicotine-induced locomotor stimulation. In the present study the role of habituation to the experimental environment on the stimulant effect of nicotine in rats was examined. In addition, the role of dopamine receptors in mediating nicotine-induced locomotor stimulation was investigated by examining the effects of selective D1 and D2 dopamine receptor antagonists on activity induced by nicotine. Locomotor activity was assessed in male Sprague-Dawley rats tested in photocell cages. Nicotine (1.0 mg/kg) caused a significant increase in locomotor activity in rats that were habituated to the test environment, but had only a weak and delayed stimulant action in rats that were unfamiliar with the test environment. The stimulant action of nicotine was blocked by the central nicotinic antagonist mecamylamine but not by the peripheral nicotinic blocker hexamethonium, indicating that the response is probably mediated by central nicotinic receptors. Nicotine-induced hyperactivity was blocked by the selective D1 antagonist SCH 23390, the selective D2 antagonist raclopride and the D1/D2 antagonist fluphenazine. Pretreatment with the D2 agonist PHNO enhanced nicotine-induced hyperactivity, whereas the D1 agonist SKF 38393 had no effect. The results indicate that acute nicotine injection induces a pronounced hyperactivity in rats habituated to the test environment. The effect appears to be mediated by central nicotine receptors, possibly located on dopaminergic neurons, and also requires the activation of both D1 and D2 dopamine receptors.

Animals↗
PubMed1991

Induction of cognitive impairment by scopolamine and noncholinergic agents in rhesus monkeys.

In primates, treatment with scopolamine impairs performance of a spatial delayed response task in a way which mimics deficits seen spontaneously in aged primates and demented patients. Despite their efficacy in reversing scopolamine induced disruption, the effects of cholinergic agonists on cognition in aged primates and dements are unimpressive, suggesting that other neurotransmitter systems are also involved in this type of deficit. We have induced a scopolamine-like impairment of spatial delayed response performance in rhesus monkeys using phencyclidine (0.1-0.2 mg/kg i.m.), lorazepam (0.4-0.6 mg/kg s.c.) or tetrahydrocannabinol (1-4 mg/kg p.o.), but not amphetamine (0.1-0.4 mg/kg i.m.), yohimbine (0.1-1.0 mg/kg i.m.) or morphine (2-4 mg/kg i.m.). Our findings suggest that disruption of specific neurotransmitter systems other than acetylcholine may contribute importantly to cognitive decline in aging and dementia.

Amphetamine↗
PubMed1991

The behavioral effects of heptyl physostigmine, a new cholinesterase inhibitor, in tests of long-term and working memory in rodents.

We assessed the effects of heptyl physostigmine, a new cholinesterase inhibitor, in a mouse tail-flick (TF) test, a mouse and rat passive avoidance test, a rat conditioned suppression-of-drinking (CSD) test, a rat Random Interval (RI) response rate test and a rat delayed matching-to-position (DMTP) test. In the TF test, a dose of 8.0 mg/kg of heptyl induced a significant antinociceptive effect that was in excess of 75% of the maximum possible effect 300 minutes after administration. In the mouse passive avoidance test, a dose of 3.0 mg/kg of heptyl fully reversed, and a dose of 1.0 mg/kg partially reversed, a scopolamine-induced (0.2 mg/kg) deficit. In the rat passive avoidance test, a dose of 8.0 mg/kg fully reversed a scopolamine-induced (0.2 mg/kg) deficit, while a dose of 4.0 mg/kg of heptyl was without effect. In the same experiment, a dose of 0.6 mg/kg of physostigmine partially reversed the scopolamine-induced deficit. In the CSD test, a dose of 8.0 mg/kg of heptyl fully reversed, and doses of 1.0 and 4.0 mg/kg of heptyl partially reversed, the deficit induced by scopolamine (0.4 mg/kg). In the RI response rate test, doses of 8.0 mg/kg and 0.6 mg/kg of physostigmine fully suppressed lever pressing for food rewards. Doses of 4.0 mg/kg of heptyl and below had no effect on lever-pressing rates. In the working memory test (DMTP), 4.0 mg/kg heptyl partially reversed the scopolamine-induced deficit (0.2 mg/kg) in the number of correct choices made, but did not affect the scopolamine-induced deficit in the number of trials completed.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1991

Use of a grooming and foraging substrate to reduce cage stereotypies in macaques.

We examined the effects of a synthetic fleece pad on cage stereotypies in individually housed cynomolgus monkeys. Animals which received the fleece alone engaged in grooming which was associated with an increase in time spent resting. Monkeys given fleece pads sprinkled with morsels of food did not groom the fleece, but rather foraged for long periods (up to 27 min/h). Stereotyped behaviours were reduced by up to 73% by use of the fleece pad both alone and with foraging crumbles.

Animals↗
PubMed1990

Blockade of CCK-B receptors by L-365,260 induces analgesia in the squirrel monkey.

The potential antinociceptive effects of the selective cholecystokinin-B (CCK-B) antagonist L-365,260 were examined in the squirrel monkey tail withdrawal test. Pain threshold was measured in 6 male monkeys by recording the latency to remove the tail from a warm (55 degrees C) water bath. L-365,260 at doses of 100 ng/kg to 100 micrograms/kg significantly elevated tail withdrawal latencies throughout a 2 h test period. These data provide the first evidence that blockade of CCK-B receptors induces analgesia in primates.

Analgesia↗
PubMed1990

Pharmacological characterization of the behavioural syndrome induced by the NK-3 tachykinin agonist senktide in rodents: evidence for mediation by endogenous 5-HT.

The effects of various manipulations of brain 5-HT mechanisms on the behavioural responses induced by the selective NK-3 tachykinin agonist senktide in rodents were assessed. Senktide elicited wet dog shakes in the rat which were attenuated by the 5-HT1C/2 antagonist mianserin and the selective 5-HT2 antagonist altanserin. Senktide-induced forepaw treading was stereospecifically attenuated by the 5-HT1A + B antagonist (-)-alprenolol. Senktide also elicited chewing mouth movements and yawning, which were unaffected by mianserin, altanserin, (+)- or (-)-alprenolol, or the selective 5-HT3 antagonist ICS 205-930, but attenuated by the muscarinic antagonist scopolamine. Penile grooming elicited by senktide was attenuated by mianserin, but was unaffected by the other antagonists. Senktide-induced wet dog shakes were enhanced by the 5-HT reuptake inhibitors citalopram and fluoxetine, suppressed by the monoamine oxidase (MAO)-B inhibitor pargyline, but unaffected by the MAO-A inhibitor clorgyline. Forepaw treading was potentiated by citalopram and clorgyline, but not significantly altered by fluoxetine or pargyline. Depletion of 5-HT by p-chlorophenylalanine (PCPA) in the rat attenuated senktide-induced wet dog shakes and forepaw treading. Neither PCPA nor 5,7-dihydroxytryptamine affected senktide-induced behaviours in the mouse, but the degree of brain 5-HT depletion caused by these treatments in mice was relatively small. These findings indicate that stimulation of NK-3 tachykinin receptors by senktide results in a complex behavioural syndrome which is mediated by multiple 5-HT receptors, and dependent upon intact stores of endogenous 5-HT. Independent stimulation of brain cholinergic mechanisms by senktide is also confirmed.

Animals↗
PubMed1990

The selective CCK-B receptor antagonist L-365,260 enhances morphine analgesia and prevents morphine tolerance in the rat.

The effects of the selective CCK-A antagonist L-365,031 and the selective CCK-B antagonist L-365,260 on morphine analgesia and opiate tolerance and dependence in rats were examined. L-365,031 and L-365,260 had no effect on baseline pain thresholds in the radiant heat tail flick test but enhanced analgesia induced by a submaximal dose of morphine (4 mg/kg). Similarly, L-365,260 did not effect pain thresholds in the paw pressure test but enhanced morphine analgesia in this model. Rats injected twice daily for 6 days with incremental doses of morphine became tolerant to the analgesic effects of the drug. Twice daily injections of either 8 mg/kg L-365,031 or 0.2 mg/kg L-365,260 prevented the development of tolerance to morphine analgesia. In contrast, L-365,260 had no influence on the development of opiate dependence in these animals, as assessed by naloxone-precipitated withdrawal. The results of the present study, when considered together with previous data, indicate that the rank order of potency of non-peptide CCK antagonists for enhancing morphine analgesia is L-365,260 greater than MK-329 greater than L-365,031. This rank order correlates well with the potency of the antagonists in blocking CCK-B receptors in rodents and suggests that CCK/opiate interactions in this species are mediated by CCK-B receptors.

Analgesia↗
PubMed1990

Spontaneous orofacial dyskinesias in a captive cynomolgus monkey: implications for tardive dyskinesia.

We describe a syndrome of spontaneous orofacial dyskinesias and cage stereotypies in a singly housed adult cynomolgus monkey never previously exposed to neuroleptic drugs. Abnormal movements were readily suppressed by acute treatment with haloperidol (0.03-0.24 mg/kg i.m.) or SCH23390 (0.05-0.2 mg/kg i.m.) but not by physostigmine (0.005-0.04 mg/kg i.m.) or scopolamine (0.0025-0.04 mg/kg i.m.). The symptomatology and response to pharmacological manipulations was indistinguishable from that previously attributed to chronic neuroleptic treatment in primates. Our findings indicate that neuroleptic-induced tardive dyskinesias in most primate studies have not been clearly demonstrated.

Animals↗
PubMed1990

Drug-induced purposeless chewing: animal model of dyskinesia or nausea?

Drug-induced purposeless chewing movements in rodents are often considered to represent movement disorders or dyskinesias. We have compared the ability of drugs to induce chewing and retching or emesis in squirrel monkeys; such studies are not possible in rodents, which do not vomit. Acute administration of oxotremorine (3.3-33 micrograms/kg IM), SKF38393 (1-30 mg/kg SC) or ipecacuanha (0.5-0.75 mg/kg PO) caused dose-related increases in purposeless chewing which was frequently associated with retching and emesis. Treatment with haloperidol (0.015-0.06 mg/kg IM) did not induce chewing. Rather, haloperidol decreased spontaneous chewing at doses of 0.03 and 0.06 mg/kg. Our findings indicate that at least some drug-induced oral behaviours in rodents may reflect nausea rather than dyskinesia.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗