Biomedical subjects

R W Stackman

Publications and source records attributed to R W Stackman.

23 records · Page 2Linked to original sources

PubMed1993

AF64A (ethylcholine mustard aziridinium) impairs acquisition and performance of a spatial, but not a cued water maze task: relation to cholinergic hypofunction.

The cholinergic neurotoxin AF64A (ethylcholine mustard aziridinium) produced alterations in a spatial but not a nonspatial cognitive task following ICV injection. AF64A impaired acquisition and performance in the standard Morris water maze task, evidenced by significantly longer latencies to find the submerged platform. However, the AF64A group exhibited shorter latencies and more direct paths to the target at the end of training, which suggests acquisition of efficient search strategies and a sparing of procedural memory. However, the AF64A group spent significantly less time in the target quadrant during the probe trial than the CSF group. This suggests a failure to learn the specific location of the target and impaired declarative memory processes. In contrast, AF64A did not affect performance of a cued MWM task that did not involve spatial memory processing, demonstrating the absence of motoric, sensory, or motivational impairments. The AF64A-induced behavioral deficits were associated with a) a significant decrease in high affinity choline transport (HAChT), b) reduced concentrations of 5-HT and 5-HIAA, and c) an increased ratio of 5-HIAA/5HT, in the HPC. There were no changes in choline uptake in the gustatory cortex, the amygdala, or the striatum. Percent time in the target quadrant during the probe trial was significantly correlated with HAChT in the HPC. There were no correlations between any of the behavioral measures and HAChT in the striatum, gustatory cortex, or the amygdala, or between serotonergic or noradrenergic parameters in the HPC. These data suggest that AF64A produces cognitive deficits in spatial tasks that are correlated with the cholinergic hypofunction induced by the compound.

Acetylcholine↗

PubMed1993

Intraseptal injection of GABA and benzodiazepine receptor ligands alters high-affinity choline transport in the hippocampus.

Injection of GABA and benzodiazepine (BDZ) agonists and antagonists into the medial septum produced bidirectional alterations in hippocampal high-affinity choline transport (HAChT). Male Sprague-Dawley rats were injected in the medial septum with either drug vehicle, a BDZ agonist, antagonist, or inverse agonist, or with a GABA-A or GABA-B agonist or antagonist and sacrificed 1 h later for assessment of HAChT in hippocampal synaptosomes. The GABA-A agonist muscimol, the GABA-B agonist baclofen, and the BDZ agonist chlordiazepoxide (CDP) produced dose-related decreases in HAChT 1 h following injection into the septum. The muscimol-induced decrease in HAChT was prevented by prior intraseptal injection of the GABA-A antagonist, bicuculline. Intraseptal injection of GABA-A (bicuculline) or GABA-B (2-hydroxysaclofen) antagonists did not alter HAChT, whereas the BDZ antagonist flumazenil (RO15,1788) and the BDZ inverse agonist methyl-beta-carboline-3-carboxylate (beta-CCM) increased this measure up to 30% in a dose-dependent manner. These results demonstrate that cholinergic neurons in the medial septum can be modulated in a bidirectional way through the pharmacological manipulation of GABA-A, GABA-B, and BDZ receptors. The potential functional and therapeutic consequences of these interactions are discussed.

Acetylcholinesterase↗

PubMed1992

Chlordiazepoxide-induced working memory impairments: site specificity and reversal by flumazenil (RO15-1788).

The following studies examined the dose and time dependence, site specificity, and reversibility of chlordiazepoxide (CDP)-induced working memory impairments in adult male Sprague-Dawley rats. The rats were tested in a delayed non-match-to-sample radial-arm maze task in which a 1-h delay was imposed between the first four (predelay) and all subsequent (postdelay) arm choices. Intraperitoneal (ip) injection of 2.5 or 5.0 but not 1.25 mg/kg CDP immediately following the predelay session impaired performance in the task. CDP increased the number of errors and decreased the number of correct choices during the postdelay session. The observed working memory impairments also appeared to be site specific since injection of CDP into the medial septum, but not into the anterior amygdala nuclei, immediately following the predelay session also impaired working memory in a dose-related manner. Furthermore, there was a time window for CDP-induced working memory impairments since intraseptal injection of the drug immediately but not 15 min following the predelay session disrupted memory. This observation suggests that the performance deficits reflect disrupted working memory and not proactive effects on performance or the induction of state-dependent learning. In the final experiment, rats were injected ip with either saline or an amnestic dose of CDP (5.0 mg/kg) following the predelay session and then were immediately infused with 10 nmol flumazenil (RO15-1788), a benzodiazepine receptor antagonist or vehicle, into either the medial septum or anterior nuclei of the amygdala. Intraseptal injection of flumazenil prevented the working memory impairments produced by ip injection of CDP. In contrast, intra-amygdala injection of flumazenil did not attenuate, enhance, or modify the CDP-induced working memory impairment. These observations suggest that CDP disrupts working memory by interacting with benzodiazepine receptors in the medial septum.

Amygdala↗

PubMed1989

Hemicholinium-3 prevents the working memory impairments and the cholinergic hypofunction induced by ethylcholine aziridinium ion (AF64A).

The present study examined whether intraventricular administration of the potent high affinity choline transport (HAChT) inhibitor hemicholinium-3 (HC-3) would attenuate the memory impairments and the neurochemical deficits induced by i.c.v. ethylcholine aziridinium ion (AF64A). Male Sprague-Dawley rats were trained to perform a delayed-non-match to sample radial arm maze (RAM) task in which a 1-h delay was imposed between the fourth and fifth arm selections. Following 30 acquisition trials, animals were bilaterally injected with AF64A (3 nmol/side) or AF64A preceded by HC-3 (20 micrograms/side) into the lateral ventricles and allowed 7 days to recover before behavioral testing resumed. Control animals received either artificial cerebrospinal fluid or HC-3. AF64A-treated rats were significantly impaired in their performance of the RAM task as evidenced by fewer correct choices following the delay and more total errors to complete the task. This behavioral deficit was associated with a significant (32%) decrease in HAChT in the hippocampus. In contrast, animals pretreated with HC-3 exhibited no significant decreases in HAChT or decrements in RAM performance. These findings indicate that the memory deficits resulting from intraventricular administration of AF64A are a consequence of the compound's cholinotoxic properties and in particular its interaction with the HAChT carrier. Furthermore they demonstrate that a select alteration of septohippocampal cholinergic activity is sufficient to disrupt working memory processes.

Animals↗

PubMed1989

Intraseptal administration of muscimol produces dose-dependent memory impairments in the rat.

The present study examined the effects of intraseptal administration of the GABAergic agonist muscimol on performance of a radial-arm maze (RAM) task. Male Long-Evans rats were trained to perform a RAM task in which a 1-h delay was imposed between the sample and the test session. In this task rats have access to four out of eight maze arms during a predelay session. Following a 1-h delay, rats are returned to the maze and allowed to freely choose among all eight arms. Arms not blocked during the predelay session are baited, and entry into an arm chosen during the predelay session or a repeated entry into a postdelay chosen arm constitutes an error. Following acquisition, animals were implanted with a single cannula aimed at the medial septum. A within-subjects design was utilized to examine the effects of intraseptal administration of muscimol (0.0, 0.75, 1.5 or 3.0 nmol) on performance in this task. All drugs or artificial cerebrospinal fluid were administered immediately following the predelay session. Muscimol, a GABA-A agonist, produced a dose-dependent impairment in maze performance as evidenced by fewer correct choices in the first four postdelay choices and an increase in the number of errors. Intraseptal administration of muscimol did not significantly alter latency per choice on the RAM task nor did it affect locomotor activity levels. Muscimol-induced impairments were also observed when a 4-h delay was imposed between the fourth and the fifth maze selection, suggesting that the behavioral deficit represents an inability to store or retain spatial working memories rather than a general performance deficit. These data indicated that pharmacological manipulation of GABA-A receptors within the medial septum modifies working memory processes. The potential interaction of GABAergic and cholinergic mechanisms in the modulation of working memory processes is discussed.

Animals↗