Biomedical subjects

M A Prendergast

Publications and source records attributed to M A Prendergast.

At least 19 recordsLinked to original sources

PubMed2005

Corticosterone and dexamethasone potentiate cytotoxicity associated with oxygen-glucose deprivation in organotypic cerebellar slice cultures.

Many patients display elevated levels of serum cortisol following acute ischemic stroke. Given that glucocorticoids may potentiate some forms of insult, these studies examined the effects of corticosterone or dexamethasone exposure on cytotoxicity following oxygen-glucose deprivation in the cerebellum, a brain region susceptible to stroke. In organotypic cerebellar slice cultures prepared from neonatal rat pups, 90-min of oxygen-glucose deprivation at 15 days in vitro resulted in significant cytotoxicity at 24-, 48-, and 72-h post-oxygen-glucose deprivation, as measured by uptake of propidium iodide. Exposure of cultures following oxygen-glucose deprivation to the antioxidant trolox (500 microM), but not to the glucocorticoid receptor antagonist RU486 (10 microM), completely blocked oxygen-glucose deprivation-induced cytotoxicity. Corticosterone (1 microM) or dexamethasone (10 microM) exposure alone did not significantly increase propidium iodide uptake above levels observed in control cultures. However, corticosterone or dexamethasone exposure after oxygen-glucose deprivation potentiated oxygen-glucose deprivation-mediated propidium iodide uptake at each time point. Trolox, as well as RU486, co-exposure of cultures to corticosterone or dexamethasone after oxygen-glucose deprivation abolished all cytotoxicity. In conclusion, these data demonstrated that glucocorticoid exposure modulated oxygen-glucose deprivation-mediated propidium iodide uptake, which likely involved glucocorticoid receptor activation and pro-oxidant effects.

Animals↗

PubMed2005

Thiamine deficiency in the pathogenesis of chronic ethanol-associated cerebellar damage in vitro.

Nutritional deficiencies associated with long-term ethanol consumption may cause neuronal damage in ethanol-dependent individuals. Thiamine deficiency, in particular, is thought to contribute to ethanol-associated cerebellar degeneration, although damage may occur in adequately nourished alcoholics. Thus, the present study examined the effects of thiamine depletion and ethanol exposure on cytotoxicity in rat cerebellum. Organotypic cerebellar slice cultures were treated starting at 25 days in vitro with 100 mM ethanol for 11 days or 10 days followed by a 24-h withdrawal period. This exposure paradigm has previously been shown in hippocampal slice cultures to result in spontaneous cytotoxicity upon ethanol withdrawal. Additional cerebellar cultures were exposed to the thiamine depleting agent pyrithiamine (10-500 microM) for 10 or 11 days, some in the presence of ethanol exposure or withdrawal. Other cultures were co-exposed to thiamine (1-100 microM), 500 microM pyrithiamine, and ethanol for 10 or 11 days. The results demonstrated that neither 11-day ethanol treatment nor withdrawal from 10-day exposure significantly increased cerebellar cytotoxicity, as measured by propidium iodide fluorescence. The 11-day treatment with 100 or 500 microM pyrithiamine significantly increased propidium iodide fluorescence approximately 21% above levels observed in control tissue. Cultures treated with both ethanol (11 days or 10 days plus withdrawal) and 500 microM pyrithiamine displayed a marked increase in cytotoxicity approximately 60-90% above levels observed in control cultures. Pyrithiamine and ethanol-induced cytotoxicity was prevented in cultures co-exposed to thiamine (10-100 microM) for the duration of pyrithiamine treatment. Findings from this report suggest that the cerebellum may be more sensitive to the toxic effects of thiamine deficiency, as compared with alcohol withdrawal, associated with alcohol dependence.

Animals↗

PubMed2004

Hippocampal CA1 region neurodegeneration produced by ethanol withdrawal requires activation of intrinsic polysynaptic hippocampal pathways and function of N-methyl-D-aspartate receptors.

Long-term intake of ethanol produces adaptive alterations in multiple transmitter systems in the hippocampal formation that likely contribute to ethanol withdrawal-induced seizure and excitotoxicity. The present studies were designed to examine the role of N-methyl-d-aspartate receptor activation and cytosolic Ca(2+) accumulation in the neurotoxic effects of ethanol withdrawal. Further, these studies investigated the role of hippocampal network excitation in promoting both Ca(2+) accumulation and neurotoxicity during ethanol withdrawal. Chronic, continuous (11 day) exposure to ethanol (91 mM starting concentration) did not produce neurotoxicity in any region of organotypic hippocampal explants, as measured by uptake of the non-vital fluorescent marker propidium iodide. Withdrawal from chronic (10 day) ethanol exposure was associated with rapid (30 min) and significant increases in intracellular Ca(2+), assessed by visualization of Calcium-Orange fluorescence, in each region of hippocampal explants. However, neurotoxicity was observed 24 h after initiation of withdrawal and was only seen in the cornu ammonis 1 (CA1) region. Exposure to MK-801 (20 microM) at the start of ethanol withdrawal markedly attenuated Ca(2+) entry in all regions, as well as, CA1 region neurodegeneration. Further, treatment of explants with tetrodotoxin (500 nM) as well as surgical transection of mossy fiber or Schaffer collateral projections immediately prior to ethanol withdrawal blocked both regional increases in Ca(2+) accumulation and CA1 neurotoxicity. These data suggest that neurodegeneration observed during ethanol withdrawal is dependent upon polysynaptic propagation of action potentials ("network excitation") and whole-hippocampal excitation of glutamatergic systems.

Animals↗

PubMed2004

(-)-nicotine ameliorates corticosterone's potentiation of N-methyl-d-aspartate receptor-mediated cornu ammonis 1 toxicity.

Hypercortisolemia, long-term exposure of the brain to high concentrations of stress hormones (i.e. cortisol), may occur in patients suffering from depression, alcoholism, and other disorders. This has been suggested to produce neuropathological effects, in part, via increased function or sensitivity of N-methyl-d-aspartate (NMDA)-type glutamate receptors. Given that cigarette smoking is highly prevalent in some of these patient groups and nicotine has been shown to reduce toxic consequences of NMDA receptor function, it may be suggested that nicotine intake may attenuate the neurotoxic effects of hypercortisolemia. To investigate this possibility, organotypic hippocampal slice cultures derived from rat were pre-treated with corticosterone (0.001-1 microM) alone or in combination with selective glucocorticoid receptor antagonists for 72-h prior to a brief (1-h) NMDA exposure (5 microM). Pre-treatment with corticosterone (0.001-1 microM) alone did not cause hippocampal damage, while NMDA exposure produced significant cellular damage in the cornu ammonis (CA)1 subregion. No significant damage was observed in the dentate gyrus or CA3 regions following NMDA exposure. Pre-treatment of cultures with corticosterone (0.1-1 microM) markedly exacerbated NMDA-induced CA1 and dentate gyrus region damage. This effect in the CA1 region was prevented by co-administration of the glucocorticoid receptor antagonist RU486 (>or=1 microM), but not spironolactone (1-10 microM), a mineralocorticoid receptor antagonist. In a second series of studies, both acute and pre-exposure of cultures to (-)-nicotine (1-10 microM) significantly reduced NMDA toxicity in the CA1 region. Co-administration of cultures to (-)-nicotine (1-10 microM) with 100 nM corticosterone prevented corticosterone's exacerbation of subsequent CA1 insult. This protective effect of (-)-nicotine was not altered by co-exposure of cultures to 10 microM dihydro-beta-erythroidine but was blocked by co-exposure to 100 nM methyllycaconitine, suggesting the involvement of nicotinic acetylcholine receptors possessing the alpha7* subunit. The present studies suggest a role for hypercortisolemia in sensitizing the hippocampal NMDA receptor system to pathological activation and indicate that prolonged nicotine exposure attenuates this sensitization. Thus, it is possible that one consequence of heavy smoking in those suffering from hypercortisolemia may be a reduction of neuronal injury and sparing of cellular function.

Aconitine↗

PubMed2003

Repeated exposures to subthreshold doses of chlorpyrifos in rats: hippocampal damage, impaired axonal transport, and deficits in spatial learning.

Organophosphorus (OP) compounds are detectable in the environment for years after use and endanger many populations. Although the effects of acutely toxic doses of many OP compounds are well described, much less is known about repeated low-level exposures. The purpose of these studies was to further evaluate potential toxicological effects of the extensively used OP pesticide chlorpyrifos (CPF) in rats. CPF, across a range of subthreshold doses (i.e., for acute toxicity), reduced rearing and sniffing activity and the magnitude of weight gain over 14 days of repeated exposure. Performance in a spatial learning task was impaired after 14 days of exposure to CPF (18.0 and 25.0 mg/kg) when testing was initiated 24 h after the last injection but not after a 14-day washout. However, inhibition of both fast anterograde and retrograde axonal transport was observed for up to 20 days after exposure to 25.0 mg/kg CPF. Studies using hippocampal cultures indicated that 8 days of continuous exposure to the parent compound, CPF (> or =100 micro M), resulted in cell toxicity and death. Furthermore, a dose (2.5 mg/kg) of CPF that had no effects on weight gain or memory performance when administered 5 days per week over 38 days impaired forelimb grip strength in the later days of testing. Collectively, these results indicate that repeated exposures to subthreshold doses of CPF may lead to growth retardation, behavioral abnormalities, and muscle weakness. Some of these symptoms may be attributed to effects of the OP on axonal transport.

Animals↗

PubMed2001

Chronic nicotine exposure reduces N-methyl-D-aspartate receptor-mediated damage in the hippocampus without altering calcium accumulation or extrusion: evidence of calbindin-D28K overexpression.

Neuronal accumulation of excess Ca2+ has been implicated in cellular death following several forms of physical and chemotoxic insult. Recent studies have suggested that exposure to agonists at brain nicotinic acetylcholine receptors reduces cytotoxic consequences of increased intracellular Ca2+ following some insults. In the present study, the ability of chronic exposure to (-)-nicotine to reduce cytotoxicity and attenuate increases in intracellular Ca2+ caused by exposure to N-methyl-D-aspartate were examined in organotypic cultures of rat hippocampus. Cultures were exposed to nicotine (0.1-10.0 microM) for five days prior to excitotoxic insult with N-methyl-D-aspartate. Exposure to N-methyl-D-aspartate produced concentration-dependent increases in both accumulation of 45Ca and in early and delayed cell death in the CA1, CA3 and dentate gyrus regions of cultures. The CA1 region of the hippocampus displayed the greatest sensitivity to cytotoxic effects of N-methyl-D-aspartate exposure; however, this regional difference was not associated with increased accumulation of 45Ca. Prior exposure to nicotine markedly attenuated N-methyl-D-aspartate-induced early and delayed cell death in each hippocampal region at concentrations as low as 0.1microM. However, nicotine did not alter the initial N-methyl-D-aspartate-stimulated influx of 45Ca or enhance extrusion of accumulated 45Ca measured at several time-points after insult. Five days of exposure to nicotine markedly increased immunoreactivity of the Ca2+ binding protein calbindin-D28K in each region of hippocampal cultures, effects reduced by mecamylamine co-exposure. These findings suggest that the potent protective effects of chronic nicotine exposure against neuronal overexcitation are not likely attributable to attenuations of Ca2+ accumulation, but are likely related to increased buffering of accumulated Ca2+.

Animals↗

PubMed2000

Protractive effects of chronic treatment with an acutely sub-toxic regimen of diisopropylflurophosphate on the expression of cholinergic receptor densities in rats.

Individuals chronically exposed to low levels of organophosphate insecticides may present with subtle impairments in cognition. In addition, low level diisopropylflurophosphate (DFP) exposure (0.25 mg/kg per day for 2 weeks) in rats resulted in protracted working memory impairment [29]. The current studies attempt to show a temporal relationship between the DFP-induced impairment in performance of a spatial memory task and the protracted decrease in the expression of cholinergic receptors and acetylcholinesterase in specific brain regions. Cholinergic receptors labeled with the ligands [(3)H]epibatidine and [(3)H]AFDX-384 were affected to a much greater extent and for a longer period of time than were both acetylcholinesterase activities and cholinergic receptors labeled with [(3)H]QNB. Pre-testing administration of nicotine was shown to completely reverse this DFP-induced impairment in memory-related task performance. Additionally, prophylaxis with pyridostigmine bromide (PB) caused DFP-treated animals to exhibit near normal levels of memory-related task performance. These results are consistent with the development of a protracted phase of learning impairment to sub-acute DFP exposure, which may involve the loss of hippocampal nicotinic receptors, and may be prevented or reversed by PB or nicotine, respectively.

Acetylcholinesterase↗

PubMed2000

Chronic, but not acute, nicotine exposure attenuates ethanol withdrawal-induced hippocampal damage in vitro.

BACKGROUND: Long-term ethanol use and long-term tobacco use frequently occur together, which suggests concurrent dependence on ethanol and nicotine. Consequences of this form of polydrug dependence are not well understood, however. Previous evidence suggests detrimental effects of long-term ethanol and beneficial effects of nicotine exposure on neuronal viability. Thus, the present study was designed to use an organotypic hippocampal slice culture model to examine the ability of chronic and acute nicotine exposure to reduce neurotoxicity associated with withdrawal from long-term ethanol exposure. METHODS AND RESULTS: Twenty-four hours of withdrawal after continuous 10 day ethanol exposure (50 or 100 mM in culture medium) resulted in cytotoxicity in hippocampal slice explants obtained from neonatal rat, most notably in pyramidal cell layers of the CA1 region. Exposure of slices to the N-methyl-D-aspartate receptor blocker MK-801 during ethanol withdrawal significantly reduced this toxicity. Exposure of slices to nicotine (0.1-10.0 microM) during the 24 hr withdrawal period did not reduce hippocampal damage. However, treatment of slices with nicotine (0.1-10.0 microM) during 10 days of ethanol exposure was associated with significant reductions in subsequent withdrawal-induced cytotoxicity, an effect reduced by mecamylamine coexposure with nicotine and ethanol. CONCLUSIONS: These findings indicate the development of marked hippocampal neurotoxicity during withdrawal from long-term ethanol exposure that is mediated, in part, by overactivation of N-methyl-D-aspartate receptors. Furthermore, these data suggest that one consequence of concurrent dependence on ethanol and nicotine may be reduced neurological damage associated with ethanol withdrawal.

Animals↗

PubMed2000

In vitro effects of ethanol withdrawal and spermidine on viability of hippocampus from male and female rat.

BACKGROUND: Long-term ethanol dependence results in neuronal adaptation that likely contributes to ethanol withdrawal-induced central nervous system excitability and, potentially, neurotoxicity. This has been suggested to result, in part, from increased release of or response to endogenous polyamines. Furthermore, it has been reported that neurological difficulties related to ethanol dependence and withdrawal may be more severe in female than in male alcoholics. Thus, we designed this study to examine effects of the polyamine spermidine on neurotoxicity associated with withdrawal from long-term ethanol exposure by using organotypic hippocampal slice cultures derived from male and female rats. METHODS AND RESULTS: Twenty-four hours of withdrawal after continuous 10 day ethanol exposure (100 mM in culture medium) resulted in cytotoxicity in hippocampal slice explants obtained from both sexes. This was most evident in pyramidal cell layers of the CA1 region, and no sex differences were observed in the severity of damage. Exposure of explants from both sexes to the NMDA blocker MK-801 during ethanol withdrawal significantly reduced this toxicity. In control cultures, exposure to spermidine (100 microM) alone produced significant and similar cytotoxicity in hippocampal explants of male and female rats. Exposure to spermidine (100 microM) during ethanol withdrawal significantly increased cytotoxicity in all regions of explants. In the CA3 region, spermidine-potentiation of ethanol withdrawal damage was significantly greater in explants from female rats compared with those from male rats. CONCLUSIONS: These data demonstrate the presence of significant hippocampal neurotoxicity during withdrawal from long-term ethanol exposure that is mediated, in part, by overactivation of NMDA receptors. Furthermore, these findings suggest that the central nervous system of females may be more susceptible than that of males to polyamine-mediated neuronal damage during withdrawal from long-term ethanol exposure.

Alcohol Withdrawal Delirium↗

PubMed1998

(-)-Nicotine increases mRNA encoding G3PDH and the vesicular acetylcholine transporter in vivo.

The effects of acute in vivo (-)-nicotine exposure on neuronal expression of mRNA encoding the vesicular acetylcholine transport (VAChT) and the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (G3PDH) were examined. The reverse transcription polymerase chain reaction was used to amplify cDNA derived from brain tissue of adult male rats injected acutely with (-)-nicotine and semi-quantification of cDNA products conducted using anion exchange chromatography. In cerebral cortex, levels of cDNA derived from the VAChT mRNA were increased by > 65% above control levels 1 h after (-)-nicotine (0.8 mg/kg, s.c.) exposure. In hippocampal samples, levels of this cDNA were increased by 15% above control levels. cDNA derived from G3PDH mRNA was increased by 86% and 280% above control levels in the cerebral cortex and hippocampus, respectively. Thus, increased expression and function of proteins associated with these mRNA species are likely consequences of acute (-)-nicotine exposure.

Acetylcholine↗

PubMed1998

Enhanced delayed matching performance in younger and older macaques administered the 5-HT4 receptor agonist, RS 17017.

Recent evidence indicates that the 5-HT4 subtype of serotonin receptor may modulate central cholinergic activity in regions of the mammalian CNS important to memory such as the frontal cortex, hippocampus and amygdala. These receptors could represent targets for drugs designed for the symptomatic therapy of Alzheimer's disease (AD) and other disorders of memory. In the present study, the binding activity of RS 17017 (previously described as a selective 5-HT4 agonist) was assessed across a number of neurotransmitter receptors and binding sites, pharmacokinetic data were obtained, and the compound was evaluated in macaques for mnemonic effects via a computer-assisted delayed matching-to-sample task (DMTS). Binding data confirmed the 5-HT4 selectivity of the compound, while pharmacokinetic results revealed low oral bioavailability, but a large volume of distribution of the compound. Significant and reproducible improvements in DMTS accuracy were observed after oral administration of the compound across a dose-effect series in both younger and older monkeys. The results suggest that RS 17017 offers a potential for memory enhancement in disorders involving cognitive decline, and are consistent with a role for central 5-HT4 receptors in memory. Improvements in DMTS performance in aged monkeys may have particular implications for neurodegenerative conditions such as AD, whereas positive results in the younger monkeys indicate that RS 17017 (or similar compounds) may have additional potential in the therapeutics of memory disorders not necessarily associated with advanced age.

Aging↗

PubMed1998

Central nicotinic receptor agonists ABT-418, ABT-089, and (-)-nicotine reduce distractibility in adult monkeys.

Increased distractibility is associated with both Alzheimer's disease and attention deficit disorder. The present study examined the effects of (-)-nicotine and the novel central nicotinic receptor (nAChR) agonists ABT-418 [(S)-3-methyl-2-pyrrolidinyl)isoxazole] and ABT-089 [2-methyl-3-(2-(S)-pyrrolindinylmethoxy)pyridine dihydrochloride] on the delayed recall accuracy of adult monkeys exposed to distracting stimuli. Unpredictable exposure to a random visual array produced marked decrements in recall accuracy on trials with the shortest delay intervals, reducing the accuracy on these trials by 23.4%. Intramuscular (i.m.) administration of (-)-nicotine, in doses of 5.4-43.3 nmol/kg, attenuated the effect of the distractor, but did not completely prevent it. Both ABT-418 (2.0-16.2 nmol/kg, i.m.) and ABT-089 (16.4-32.8 nmol/kg, i.m.) prevented distractibility, producing increases of 7.5-25.0% in accuracy on trials disrupted by distractor exposure. Further, both compounds also improved accuracy on trials during which distractors were not presented, an effect which was not observed after (-)-nicotine administration. Nicotinic-mediated side effects were not observed following administration of any compound. Thus, nAChR stimulation reduces distractibility in adult monkeys and may, therefore, represent a target for the pharmacologic treatment of disorders associated with susceptibility to distraction. ABT-418 and ABT-089 appear to be particularly useful in this regard, a likely result of their selective agonist activity at nAChRs expressed in the brain.

Animals↗

PubMed1998

Age-related differences in distractibility and response to methylphenidate in monkeys.

Increased susceptibility to distraction is a symptom of normal aging and several clinical syndromes, including Alzheimer's disease and attention deficit disorders. In the present study, aged and young adult macaques were well-trained to perform an automated delayed matching-to-sample (DMTS) task which assesses both attention and short-term memory. On 19% of all trials, a task-relevant distracting stimulus was presented during either the initial 1 or 3 s of delay intervals (early onset) or the final 1 or 3 s of delay intervals (late onset). In aged monkeys, both early and late onset distractors lasting 1 or 3 s impaired delayed recall on trials with the shortest delay intervals, but did not affect accuracy on trials with long delay intervals. In contrast, young adult monkeys were impaired only by the presence of an early onset distractor lasting 3 s. Impairment was selective for only those trials with the shortest delay intervals. Late onset distractors were relatively ineffective in producing distractibility in young adult animals. Methylphenidate (MPH; 0.005-1.0 mg/kg) failed to reduce distractibility in aged monkeys, producing locomotor abnormalities and hypophagia at doses ranging from 0.25 to 1.0 mg/kg. In young adult monkeys, however, distractibility was significantly attenuated by administration of the 0.125 mg/kg dose. Habituation to the distracting stimulus (under saline conditions) was assessed throughout the study and was not evident at any time point of testing. These data indicate that attention and recall after brief delays are impaired following exposure to a task-relevant distracting stimulus in both aged and young adult monkeys, but that aged monkeys are more susceptible to distraction and do not receive significant benefit from MPH administration.

Aging↗

PubMed1997

Structure-activity studies on 2-methyl-3-(2(S)-pyrrolidinylmethoxy) pyridine (ABT-089): an orally bioavailable 3-pyridyl ether nicotinic acetylcholine receptor ligand with cognition-enhancing properties.

2-Methyl-3-(2(S)-pyrrolidinylmethoxy)pyridine, ABT-089 (S-4), a member of the 3-pyridyl ether class of nicotinic acetylcholine receptor (nAChR) ligands, shows positive effects in rodent and primate models of cognitive enhancement and a rodent model of anxiolytic activity and possesses a reduced propensity to activate peripheral ganglionic type receptors. The profiles of S-4, its N-methyl analogue, and the corresponding enantiomers across several measures of cholinergic channel function in vitro and in vivo are presented, together with in vitro metabolism and in vivo bioavailability data. On the basis of its biological activities and favorable oral bioavailability, S-4 is an attractive candidate for further evaluation as a treatment for cognitive disorders.

Administration, Oral↗

PubMed1997

Chronic, low-level exposure to diisopropylfluorophosphate causes protracted impairment of spatial navigation learning.

Chronic, low-level exposure to cholinesterase inhibitor organophosphate (OP) insecticides or chemical warfare agents produces abnormalities in CNS acetylcholine (ACh) function, and in humans, may be associated with impaired cognitive function as well after withdrawal from such exposure. The purpose of the present study was to identify the severity of impairment in spatial learning of rats following protracted withdrawal from chronic, low-level exposure to the OP agent diisopropylfluorophosphate (DFP). Assessment of spatial learning began either 3 or 17 days after completion of a 14-day DFP treatment regimen (50, 250, or 500 micrograms/kg). During the 14-day treatment regimen, spontaneous activity and olfactory behaviors were suppressed, effects which subsided with repeated exposure to the 250 micrograms/kg dose regimen. In contrast, both behaviors were stimulated by exposure to the 50 micrograms/kg dose regimen, as was body weight gain. Performance of the spatial test of working memory was impaired for up to 21 days after withdrawal from treatment with a 250 micrograms/kg dose of DFP. AChE activity in the frontal cortex and hippocampus was suppressed to 42.58% and 50.35% of control levels, respectively, 3 days after completion of the DFP (250 micrograms/kg) treatment regimen. By 7 days after withdrawal from treatment, AChE activity in the cortex and hippocampus had recovered to 81.87% and 64.61% of control levels, respectively. These levels represent increases in activity of 39.29% and 14.26% in these regions, as compared to AChE activity in 3 days after DFP withdrawal. By 21 days after withdrawal from treatment, AChE in both brain regions had recovered to levels similar to those of controls. Chronic, low-level OP exposure, therefore, produces protracted impairment of working memory after drug withdrawal that is not associated with continued suppression of AChE activity. This impairment may, however, be associated with a decreased rate of AChE recovery in the hippocampus, relative to the cortex. This decreased rate of enzyme recovery may contribute to hippocampal toxicity underlying protracted impairment of working memory.

Animals↗

PubMed1997

Improvement in accuracy of delayed recall in aged and non-aged, mature monkeys after intramuscular or transdermal administration of the CNS nicotinic receptor agonist ABT-418.

ABT-418 was evaluated for its ability to enhance accuracy on a delayed matching-to-sample (DMTS) task by aged monkeys following intramuscular administration, and in non-aged mature monkeys following transdermal application. Aged monkeys were impaired in their performance of the DMTS task such that the longest delay intervals performed at above-chance levels extended only to 20 s. In contrast, for non-aged, mature animals, delay intervals extended to 140 s. In aged monkeys, the response to ABT-418 was highly individualized with animals responding to one or more doses in the range of 2-259 nmol/kg. A systematic dose-dependent enhancement of DMTS accuracy was not observed. When the individualized "best dose" was administered on a separate occasion, overall DMTS accuracy was increased by 12.6%. By 24 h after administration, accuracy was at control levels. In young monkeys, a significant dose-dependent enhancement of DMTS performance (an overall increase of 11.25% above baseline accuracy) was observed 5 h after application of a transdermal patch designed to maintain steady-state plasma levels of ABT-418 of 40-60 ng/ml over a 24-h period. Again there was some individual responsiveness to one of the three doses. When data included only the individualized best doses of ABT-418 for each animal, a similar enhancement of accuracy was observed for both the 5-h and 24-h test intervals. In neither the aged nor the young cohorts was enhancement of performance associated with altered response latencies or with any overt side effects of ABT-418. Thus, these data are consistent with the ability of ABT-418 to improve DMTS performance in both young and aged monkeys. In aged monkeys, this response was observed only after administration of individualized optimal doses for different monkeys. In young monkeys, a more systematic enhancement of DMTS accuracy was observed. Further, transdermal delivery of ABT-418 in non-aged monkeys demonstrated prolonged performance enhancement compared with IM injection to at least 24 h after patch administration.

Administration, Cutaneous↗

PubMed1997

Nitric oxide synthase inhibition impairs delayed recall in mature monkeys.

The gaseous neuromodulator nitric oxide (NO) is formed in brain regions known to mediate learning and memory processes. In rodent models, pharmacologic inhibition of NO synthesis impairs such processes. In the present study, N omega-nitro-L-arginine methyl ester (L-Name), an inhibitor of the constitutive form of the NO synthetic enzyme, was administered to seven non-aged, mature monkeys (Macaca Fascicularis, Macaca Mulatta, and Macaca Nemestrima) trained to perform a delayed matching-to-sample task (DMTS). L-Name (1.5, 25, and 50 mg/kg) produced marked decrements in task performance, as well as a reduction in the number of trials completed at the highest dose. This impairment of DMTS accuracy by the 50 mg/kg doses of L-Name appears to be associated with an aversive state marked by gastrointestinal disturbance and lethargy. The detrimental effects of the 25 mg/kg dose of L-Name on DMTS accuracy were completely blocked by concurrent administration of a mole-equivalent dose of the NO amino acid precursor L-arginine. As a whole, these data suggest that L-Name impairs processes involved in delayed recall in monkeys and that this impairment is associated with attenuated synthesis of NO. However, at higher doses (> or = 25 mg/kg) this impairment is associated with aversive effects of L-Name, possibly at both central and peripheral sites.

Animals↗

PubMed1997

ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride]: II. A novel cholinergic channel modulator with effects on cognitive performance in rats and monkeys.

ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride], a novel ligand at neuronal nicotinic acetylcholine receptors with reduced adverse effects and improved oral bioavailability relative to (-)-nicotine, was tested in a variety of cognitive tests in rats and monkeys. Administered acutely, ABT-089 only marginally improved the spatial discrimination water maze performance of septal-lesioned rats. However, more robust improvement (45% error reduction on the last training day) was observed when ABT-089 was administered continuously via subcutaneous osmotic pumps (minimum effective dose: 1.3 micromol/kg/day). Continuous infusion of (-)-nicotine produced comparable improvement in the spatial discrimination water maze performance of septal-lesioned rats, but a 40-fold higher dose of (-)-nicotine was required (62 micromol/kg/day). Continuous infusion of ABT-089 to aged rats enhanced spatial learning in a standard Morris water maze, as indexed by spatial bias exhibited during a probe trial conducted after 4 days of training, but not when they were subsequently trained in a two-platform spatial discrimination water maze. The compound induced a small impairment in young rats on the standard water maze, but not on the two-platform task. A probe trial conducted after additional training in the standard water maze revealed no age or drug effects. ABT-089 did not affect performance of either the aged or young rats during inhibitory (passive) avoidance training. Also, continuous infusion of ABT-089 did not affect responses to acoustic startle or prepulse inhibition of acoustic startle in young, aged or septal-lesioned rats and did not affect locomotor activity in either sham-lesioned or septal-lesioned rats. In monkeys, acute administration of ABT-089 modestly improved the delayed matching-to-sample performance of mature, adult monkeys and more robustly improved performance in aged monkeys. Improved performance in the aged monkeys was restricted to the longest delay intervals and was not accompanied by changes in response latencies.

Animals↗