Biomedical subjects

Alvin V Terry

Publications and source records attributed to Alvin V Terry.

24 records · Page 2Linked to original sources

PubMed2003

Relative levels of cytoprotection produced by analogs of choline and the role of alpha7-nicotinic acetylcholine receptors.

Several analogs of the acetylcholine precursor molecule choline have been widely studied as potential false cholinergic neurotransmitters with the therapeutic goal of using them to limit cholinergic neurotransmission. More recently, choline itself has been shown to act as a full, if low potency, agonist at the alpha7 subtype of the nicotinic acetylcholine receptor. This pharmacological property has been associated with the ability of nicotine and other related alpha7 receptor agonists to offer neuroprotection in a variety of experimental models. We confirm here that choline offers a significant degree of protection against the cytotoxicity induced by growth factor deprivation in differentiated PC-12 cells. Choline-induced cytoprotection ( approximately 1 mM) was about 3 orders of magnitude less potent than that for nicotine (EC(50) = 0.7 microM). Choline also exhibited only about 40% of the full cytoprotective effect of nicotine. Ethyl substitution for choline's N-methyl groups did not result in a significant improvement over choline as a cytoprotective agent. In contrast, pyrrolidinecholine exhibited much greater potency (EC(50) = 20 microM) and increased efficacy (about 55% of nicotine's effect) than choline. Like choline and nicotine, pyrrolidinecholine fully displaced [(125)I]alpha-bungarotoxin binding (K(i) = 33 microM) and chronic exposure to the analog increased cell surface binding sites. The cytoprotective effects of the analog were completely inhibited by coincubation with methyllycaconitine (MLA), a selective alpha7-nicotinic receptor antagonist. These findings are consistent with the possibility that the choline structure may serve as a template for the development of novel agents with both alpha7-nicotinic agonist activity and potential neuroprotective ability, as many of these compounds, including pyrrolidinecholine, are transported along with choline into the central nervous system.

Animals↗

PubMed2003

Spontaneously hypertensive rats: further evaluation of age-related memory performance and cholinergic marker expression.

OBJECTIVE: The spontaneously hypertensive rat (SHR), often used to study cardiovascular disease processes, may also be utilized to model certain central nervous system changes associated with memory disorders. Previous work in our laboratory indicated that central nicotinic acetylcholine receptors are markedly diminished and that memory-related task performance is impaired in this rodent phenotype. Due to the well-documented importance of the central cholinergic system to memory processes and its vulnerability to the effects of aging, it was of interest to measure other cholinergic markers and to further evaluate memory function in older SHRs. METHOD: Radial arm maze performance was used to assess working memory, quantitative receptor autoradiography with [3H]-pirenzipine, [3H]-AFDX-384 and [3H]-epibatidine (combined with cytisine) was used to determine the densities of muscarinic-M1 and -M2 and nicotinic cholinergic alpha3 receptors, respectively. Immunoblotting experiments were also used to determine the expression of the presynaptic cholinergic markers, choline acetyltransferase and the vesicular acetylcholine transporter. RESULTS: Radial arm maze performance was impaired in hypertensive (compared with normotensive Wistar and Wistar-Kyoto) rats, regardless of age. M1 binding was increased in frontal and prefrontal cortical areas in SHR (p < 0.05), whereas M2 densities were higher in the hypertensive phenotype in the caudate putamen. A lower expression of alpha3-containing nicotinic receptors was observed in the superior colliculus in SHRs. Age-related differences in the expression of the vesicular acetylcholine transporter were noted in the hippocampus. CONCLUSION: The SHR may be useful to model some aspects (particularly hypertension-related) of memory disorders, especially those in which cholinergic function is altered.

Aging↗

PubMed2002

Differential effects of haloperidol, risperidone, and clozapine exposure on cholinergic markers and spatial learning performance in rats.

Haloperidol (HAL), a potent typical antipsychotic, continues to be a frequently prescribed medication for behavioral disturbances associated particularly with schizophrenia despite well-documented adverse effects associated with its chronic use. Animal experiments have even indicated that HAL can damage cholinergic pathways and thus could be especially deleterious to those experiencing cognitive deficits. However, several recent clinical studies indicate that atypical antipsychotics may actually improve cognitive function in some patients, although this assertion requires further investigation. The purpose of this study was to compare the effects of prior chronic (45- or 90-day) oral exposure to HAL and the atypical antipsychotics risperidone (RISP) and clozapine (CLOZ) on cognitive performance and central cholinergic markers in rats. All analyses were done after 4 days of drug washout in order to minimize direct drug effects. Learning performance and choline acetyltransferase (ChAT) levels were assessed in a water maze task and with immunofluorescence staining, respectively. HAL significantly impaired learning performance after 90 but not after 45 days of treatment when compared to both vehicle controls and the atypical agents, while RISP slightly improved task performance. Both 45 and 90 days of previous HAL exposure reduced ChAT staining in several brain regions, including the cortex, caudate-putamen, and hippocampus. ChAT staining in the caudate-putamen and hippocampus was also decreased after 90 days of RISP exposure, raising the possibility of deleterious cognitive effects after exposure to this dosage for longer periods of time. The results suggest that antipsychotic drugs exert differential and temporally dependent effects on central cholinergic neurons and learning performance.

Animals↗

PubMed2002

Memory-related task performance by aged rhesus monkeys administered the muscarinic M(1)-preferring agonist, talsaclidine.

RATIONALE: Muscarinic-acetylcholine receptor agonists are yet to be used clinically for the treatment of Alzheimer's disease (AD) even though laboratory evidence continues to support the potential for such an approach. OBJECTIVES: The purpose of this study was to evaluate the M(1)-preferring agonist talsaclidine in aged monkeys for effects on working memory. METHODS: Three doses (0.6, 1.2, and 2.4 mg/kg, PO) of talsaclidine and two time intervals (45 min and 8 h) after drug administration were evaluated in seven aged rhesus macaques trained to perform a computer-assisted delayed matching-to-sample (DMTS) task. The relative effectiveness of talsaclidine was also compared with another M(1)-preferring agonist WAY-132983 that was previously studied in this laboratory. RESULTS: Talsaclidine improved DMTS accuracy only during sessions initiated 8 h after administration of one of the doses (i.e. 0.6 mg/kg). The drug's enhanced effectiveness at the 8-h time point relative to the 45-min time point was surprising in view of the fact that plasma concentrations were highest 45 min after administration. A higher dose of talsaclidine (4.7 mg/kg) resulted in side effects (lethargy and excessive drooling) in some animals. Individualized optimal doses of talsaclidine were associated with 7.4% and 10.6% improvement in overall (all trials averaged) DMTS accuracy during the 45 min and 8 h post-administration sessions, respectively. Under similar experimental conditions WAY-132983 increased DMTS accuracy by up to 15.6% above control levels. CONCLUSION: Both talsaclidine and WAY-132983 provide at least modest improvements in DMTS accuracy in aged monkeys at some doses; however, challenges remain regarding the achievement of an adequate level of efficacy and reliability while minimizing side effects with these compounds. The positive findings do, however, support further study of the potential use of direct muscarinic agonists in the treatment age-related disorders of memory function.

Aging↗

PubMed2002

Nicotine increases the expression of high affinity nerve growth factor receptors in both in vitro and in vivo.

Impairment in nerve growth factor (NGF)-mediated support to basal forebrain cholinergic neurons may represent an initial insult to certain neural cells in Alzheimer's disease (AD). High affinity NGF receptor (TrkA) levels are decreased in AD brains as compared to age-matched control brains. One of the approaches suggested for the treatment of AD exploits the ability of small molecular substances to enhance the expression of endogenous growth factors and/or their receptors. The purpose of this study was to determine whether treatment with nicotine in both in vitro and in vivo settings would increase the neural expression of TrkA receptors. Using a differentiated PC12 neuronal-like system, chronic nicotine treatment increased cell surface TrkA receptor expression. Nicotine's action was blocked by co-treatment with either the non-competitive nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine or with the alpha7 nAChR-selective antagonist methyllycaconitine. Surprisingly, certain low doses of mecamylamine alone also increased TrkA receptor levels. Rats prepared with chronic indwelling intravenous catheters were continuously infused with nicotine to deliver a total dose of 12 mg/kg over 24 hr. This treatment resulted in a significant 44% increase in TrkA receptor expression in the hippocampus. As in the cell experiments, mecamylamine also increased hippocampal TrkA receptor expression. In fact, the ratio of the maximal mecamylamine response to the maximal nicotine response that was measured in vitro, i.e., 0.43 was remarkably similar to that for the in vivo experiment, i.e., 0.47. Since in our previous studies the increase in TrkA expression produced by nicotine was shown to be related to its cytoprotective actions, these results suggest that nicotine's neuroprotective actions might also be mediated through the drug's interaction with central alpha7 nAChRs and subsequent increase in TrkA receptor expression.

Aconitine↗

PubMedDate not supplied

A computer-assisted cognitive test battery for aged monkeys.

A computer-assisted version of the delayed matching-to-sample (DMTS) task has been of enormous utility in our non-human primate model for assessment of memory-enhancing agents. To avoid ceiling effects as might be encountered by using fixed delay intervals in monkeys exhibiting varying performance efficiencies, delay intervals are adjusted to provide similar baseline levels of delay-dependent performance. Macaques well trained in the task exhibited a marked age-dependent sensitivity to the effects of the amnestic drug scopolamine. Aged animals also were more affected than their younger counterparts by the presentation of a distractor shortly after receiving the stimulus component of the DMTS task. One limitation of the DMTS task is that under baseline conditions certain aged subjects may perform the task as well or better than some younger animals. To help avoid this situation, we developed a titrating version of the DMTS which was administered similarly to the standard DMTS task. Animals begin the first trial with a 0 s delay interval. Delay intervals after a correct response are incremented by 1 s. Delay intervals after an incorrect match are decreased by 1 s. Rhesus and pigtail macaques who ranged in age from 5-27 years and who were maintained on the standard DMTS for at least one year performed 3-4 consecutive 96 trial sessions. The maximum delay intervals attained by the study group, exhibited a significant correlation with age (p < 0.02). Decrements in task accuracy, and in the number of trials completed/session showed a trend with age (p < 0.08). If the titrating version of the DMTS is sensitive to mnemonic drugs, the task may prove useful for drug comparisons with aging.

Aging↗