A randomized, double-blind, placebo-controlled trial of deprenyl and thiotic acid in HIV-associated cognitive impairment.
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Antioxidants↗
Biomedical subjects
R Roesler
Publications and source records attributed to R Roesler.
Differential effects of post-training muscimol and AP5 infusions into different regions of the cingulate cortex on retention for inhibitory avoidance in rats.
Adult male Wistar rats were bilaterally implanted with indwelling cannulae in four different coordinates of the cingulate cortex: (1) the anterior cingulate (AC), (2) the rostral region of the posterior cingulate (RC), (3) the upper portion of the caudal region of the posterior cingulate (UC), and (4) the lower portion of the caudal region of the posterior cingulate (LC). After recovery, animals were trained in a step-down inhibitory avoidance task (3.0-s, 0.4-mA foot shock). Either immediately, or 90 or 180 min after training, animals received a 0.5-microl infusion of vehicle (phosphate buffer, pH 7.4), of muscimol (0.5 microg), or of AP5 (5.0 microg). Retention testing was carried out 24 h after training. Muscimol was amnestic when given into any of the three coordinates of the posterior cingulate cortex 90 min after training, and when given into LC immediately post-training. In addition, AP5 was amnestic when given into UC 90 min post-training, but not when given into any other region and/or at any other time. None of the treatments had any effect when given into AC. The results suggest that memory processing of the inhibitory avoidance task is regulated by the posterior but not by the anterior cingulate cortex, through muscimol-sensitive synapses, relatively late after training. AP5-sensitive synapses appear to play a very limited role in these processes, restricted to UC.
2-Amino-5-phosphonovalerate↗
Memory-enhancing treatments do not reverse the impairment of inhibitory avoidance retention induced by NMDA receptor blockade.
The aim of the present research was to verify whether the impairment of retention induced by the N-methyl-d-aspartate (NMDA) receptor blocker (+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cycloheptene-5,10 imine (MK-801) can be reversed by memory-enhancing treatments. Adult female Wistar rats were trained and tested in a step-down inhibitory avoidance task (0.3-mA foot shock, 24-h training-test interval). Animals were given an ip injection of saline (SAL) or MK-801 (0.0625 mg/kg) 30 minutes before training, and an ip injection of SAL, epinephrine (EPI) (25 microg/kg), the opioid receptor antagonist naloxone (NAL) (0.4 mg/kg), the glucocorticoid receptor agonist dexamethasone (DEX) (0.3 mg/kg), or glucose (GLU) (320 mg/kg) immediately after training. There was an impairment of inhibitory avoidance retention in the MK-801-SAL, MK-801-EPI, MK-801-NAL, MK-801-DEX, and MK-801-GLU groups. There was an enhancement of retention in the SAL-EPI, SAL-NAL, SAL-DEX, and SAL-GLU groups. A control experiment showed that the amnestic effects of MK-801 could not be attributed to decreased reactivity to the foot shock. The results suggest that memory-enhancing treatments directed at modulatory mechanisms do not reverse the memory impairment induced by NMDA receptor blockade.
Animals↗
Effects of suramin on hippocampal apyrase activity and inhibitory avoidance learning of rats.
The action of suramin on apyrase activity in hippocampal synaptosomes and its effects on retention of inhibitory avoidance learning were evaluated. Suramin, a P2-purinoceptor antagonist, significantly inhibited in a noncompetitive manner the ATP and ADP hydrolysis promoted by apyrase in hippocampal synaptosomes of adult rats. The Ki values obtained were 72.8 and 109 microM for ATP and ADP hydrolysis, respectively. Intrahippocampal infusion of suramin (0.01, 0.1, 1, and 10 microg) immediately posttraining, in a dose-dependent effect, significantly reduced the response latency during the retention test applied 24 h after the rats received step-down inhibitory avoidance training. The amnesic effects promoted by suramin probably occur by its antagonist action on hippocampal P2-purinoceptors and NMDA receptors. In view of the fact that ATP-metabolizing enzymes and P2-purinoceptors have similar binding domains, these results suggest that suramin can either alter ATP degradation and/or block purinergic neurotransmission.
Adenosine Triphosphate↗
Effects of post-training infusions of a mitogen-activated protein kinase kinase inhibitor into the hippocampus or entorhinal cortex on short- and long-term retention of inhibitory avoidance.
We recently demonstrated the time-dependent impairment of long-term retention of a step-down inhibitory avoidance task in rats induced by post-training infusion of the specific MAPKK (mitogen-activated protein kinase kinase) inhibitor PD 098059 into the hippocampus (HIP), amygdala (AMY), entorhinal cortex (EC) and posterior parietal cortex (PPC). Here we investigate the role of the MAPK cascade in the HIP and the EC on both short- and long-term retention of inhibitory avoidance in rats, using three different doses of the MAPKK inhibitor PD 098059. Adult male Wistar rats were trained and tested in inhibitory avoidance and given an infusion of PD 098059 (0.5, 5.0 or 50.0 microM) at 0, 30, 90, 120, 180, 270 or 360 min after training. A retention test session was carried out at 90, 180 or 270 min after training (short-term memory, STM) and/ or 24 h after training (long-term memory, LTM). When infused into the HIP at 0 min, but not at 30, 90, 120 or 180 min after training, PD 098059 impaired STM. Intrahippocampal PD 098059 impaired LTM when infused at 180 min, but not at 0, 30, 90, 120 or 270 min after training. When infused into the EC, PD 098059 enhanced STM when given at 0 min after training and had no effect when given at 30, 90, 120 or 180 min after training. In this structure, PD 098059 impaired LTM when given at 180 or 270 min, but not at 30, 90, 120 or 360 min after training. All effects were dose-dependent. These findings indicate that the MAPK cascade in the HIP and EC is differentially involved in short- and long-term retention of inhibitory avoidance in rats.
Animals↗
Increased sensitivity to seizures in mice lacking cellular prion protein.
PURPOSE: The physiologic role of the cellular prion protein (PrPc) is unknown. Mice devoid of PrPc develop normally and show only minor deficits. However, electrophysiologic and histologic alterations found in these mice suggest a possible role for PrPc in seizure threshold and/or epilepsy. METHODS: We tested the sensitivity of PrPc knockout mice to seizures induced by single convulsant or repeated subconvulsant (kindling) doses of pentylenetetrazol (PTZ), and to status epilepticus (SE) induced by kainic acid or pilocarpine. RESULTS: In PTZ kindling, seizure severity progressed faster in the PrPc knockout group, in which 92.8% reached stage 5 or death after 4 days of stimulation, as opposed to 38.4% in wild-type animals. After 10 injections, mortality was 85.7% among knockouts and 15.3% among controls. After a single PTZ injection (60 mg/kg), overall mortality due to seizures was 91% in knockout mice, but only 33% among wild-type animals. Pilocarpine-induced SE (320 mg/kg) caused an 86.7% mortality in knockouts, as opposed to 40% in wild-type animals. Finally, after kainic acid injections (10 mg/kg), 70% of the knockouts developed at least one severe seizure, and 50% showed repetitive seizures, whereas no wild-type animal exhibited observable seizures. CONCLUSIONS: Animals lacking cellular prion protein expression are more susceptible to seizures induced by various convulsant agents. This is perhaps the most striking alteration yet found in PrPc-null mice, who at first analysis appeared to be completely normal. A possible role for PrPc in chronic and idiopathic (familial), secondary, or cryptogenic epilepsies in humans remains to be investigated.
Animals↗
Increased training prevents the impairing effect of intra-amygdala infusion of the non-NMDA receptor antagonist CNQX on inhibitory avoidance expression.
Intra-amygdala infusion of the non-N-methyl-D-aspartate (NMDA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) prior to testing impairs inhibitory avoidance retention test performance. Increased training attenuates the impairing effects of amygdala lesions and intra-amygdala infusions of CNQX. The objective of the present study was to determine the effects of additional training on the impairing effects of intra-amygdala CNQX on expression of the inhibitory avoidance task. Adult female Wistar rats bilaterally implanted with cannulae into the border between the central and the basolateral nuclei of the amygdala were submitted to a single session or to three training sessions (0.2 mA, 24-h interval between sessions) in a step-down inhibitory avoidance task. A retention test session was held 48 h after the last training. Ten minutes prior to the retention test session, the animals received a 0.5-microliter infusion of CNQX (0.5 microgram) or its vehicle (25% dimethylsulfoxide in saline). The CNQX infusion impaired, but did not block, retention test performance in animals submitted to a single training session. Additional training prevented the impairing effect of CNQX. The results suggest that amygdaloid non-NMDA receptors may not be critical for memory expression in animals given increased training.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
Intrahippocampal infusion of the NMDA receptor antagonist AP5 impairs retention of an inhibitory avoidance task: protection from impairment by pretraining or preexposure to the task apparatus.
The purpose of the present research was to further evaluate the role of hippocampal N-methyl-D-aspartate (NMDA) receptors in inhibitory avoidance task consolidation. Adult male Wistar rats were trained and tested in a step-down inhibitory avoidance task (0.4 mA footshock, 24 h training-test interval). Immediately after training, animals received a 0.5-microl intrahippocampal infusion of the NMDA receptor antagonist aminophosphonopentanoic acid (AP5) (5.0 microg) or vehicle (phosphate buffer in saline, pH 7.4). The infusion of AP5 impaired retention test performance. Both pretraining with a low footshock intensity (0.2 mA) or preexposure to the inhibitory avoidance box 24 h before training prevented the amnestic effect of AP5. The results suggest that hippocampal NMDA receptors are critical for neither the enhancement of retention induced by an additional training session nor the inhibitory avoidance retention in animals that have previously learned about the task environment by preexposure to the apparatus.
2-Amino-5-phosphonovalerate↗
L-type voltage-dependent calcium channel blocker nifedipine enhances memory retention when infused into the hippocampus.
Wistar rats with cannulae bilaterally implanted in the CA1 region of the dorsal hippocampus were trained in a step-down inhibitory avoidance task. Through these cannulae they received an infusion of 28 or 280 ng per side of the L-type voltage-dependent calcium channel antagonist nifedipine, or of its vehicle (20% dimethyl sulfoxide in saline). The two doses of the drug were studied by administration 0 or 30 min after training; in addition, the higher dose was studied by infusion 10 min before training. A retention test was carried out 24 h after the training session. The highest dose of nifedipine administered 0 min post-training enhanced test session performance of the animals compared to the control group; the effect of the lower dose was not statistically significant. There was no effect of the drug given 30 min post-training or 10 min pretraining. Despite the inability to discriminate direct neural from indirect vascular effects, these results are consistent with previous reports on nootropic actions of the dihydropyridine class of calcium channel blockers. The data are at variance with the amnestic effect of intrahippocampal nifedipine described by Lee and Lin (1991, Life Sciences, 48, 1333-1340), which may be attibuted to the different range of doses studied here. This might resemble the inverted U-shaped dose-response curve observed with another dihydropyridine, nimodipine, by other authors.
Animals↗
Drugs acting at the glycine site on the NMDA receptor as cognitive enhancers in patients with Alzheimer's disease.
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Alzheimer Disease↗
Involvement of hippocampal NMDA receptors in retention of shuttle avoidance conditioning in rats.
The purpose of this research was to evaluate the role of hippocampal N-methyl-D-aspartate (NMDA) receptors in acquisition and consolidation of memory during shuttle avoidance conditioning in rats. Adult male Wistar rats were surgically implanted with cannulae aimed at the CA1 area of the dorsal hippocampus. After recovery from surgery, animals were trained and tested in a shuttle avoidance apparatus (30 trials, 0.5-mA footshock, 24-h training-test interval). Immediately before or immediately after training, animals received a bilateral intrahippocampal 0.5-microliter infusion containing 5.0 microgram of the NMDA competitive receptor antagonist aminophosphonopentanoic acid (AP5) or vehicle (phosphate-buffered saline, pH 7.4). Infusion duration was 2 min per side. Pre-training infusion of AP5 impaired retention test performance (mean +/- SEM number of conditioned responses (CRs) during retention test session was 16.47 +/- 1.78 in the vehicle group and 9.93 +/- 1.59 in the AP5 group; P < 0.05). Post-training infusion of AP5 did not affect retention (mean +/- SEM number of conditioned responses during retention test session was 18.46 +/- 1.94 in the vehicle group and 20.42 +/- 2.38 in the AP5 group; P > 0.10). This impairment could not be attributed to an effect on acquisition, motor activity or footshock sensitivity since AP5 affected neither training session performance measured by the number of CRs nor the number of intertrial crossings during the training session. These data suggest that NMDA receptors in the hippocampus are critical for retention of shuttle avoidance conditioning, in agreement with previous evidence showing a role of NMDA receptors in fear memory.
2-Amino-5-phosphonovalerate↗
NMDA receptor and retinal laser injury.
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Animals↗
The N-methyl-D-aspartate receptor blocker MK-801 prevents the facilitatory effects of naloxone and epinephrine on retention of inhibitory avoidance task in rats.
The aim of this study was to evaluate the interaction between N-methyl-D-aspartate (NMDA) receptors and the adrenergic and opioid systems in the modulation of inhibitory avoidance retention. Rats were trained and tested in the step-down inhibitory avoidance task (0.3 mA footshock). The training-test interval was 24 h. The animals received an i.p. injection of saline or MK-801 (0.0625 mg/kg) 30 min before training, and saline, epinephrine (25 micrograms/kg), or naloxone (0.4 mg/kg) i.p. immediately after training. In the saline-pretreated rats, epinephrine and naloxone enhanced memory retention. Pretraining MK-801 prevented the facilitatory effects of those treatments. The present findings suggest that the facilitation of learning by post-training epinephrine and naloxone is prevented by the pretraining NMDA receptor blockade.
Adrenergic Agonists↗
Involvement of mechanisms dependent on NMDA receptors, nitric oxide and protein kinase A in the hippocampus but not in the caudate nucleus in memory.
The effects of the NMDA receptor antagonist AP5, the nitric oxide synthase (NO) inhibitor NO-arg or the protein kinase A (PKA) inhibitor KT5720 on memory were evaluated. Rats bilaterally implanted in the CA1 region of the dorsal hippocampus were trained and tested in a step-down inhibitory avoidance task, and rats unilaterally implanted in the left posteroventral region of the caudate nucleus were trained and tested in a cued water maze task. Previous findings from this and other laboratories had found that lesions or pharmacological treatments of these sites significantly altered memory of these two tasks. Immediately after training, animals received intrahippocampal or intracaudate 0.5 microliter microinfusions of saline, AP5, NO-arg or KT5720. All three drugs impaired retention of inhibitory avoidance, but did not affect retention of the cued water maze. The findings suggest that NMDA receptor-, NO- and PKA-mediated processes in the dorsal hippocampus, but not in the caudate nucleus, are involved in memory.
2-Amino-5-phosphonovalerate↗
Age-related effects of diazepam on retention of inhibitory avoidance and shuttle avoidance tasks in rats.
We investigated the effect of diazepam on memory of 30 days-old and 60-70 days-old female Wistar rats, using two behavioral tasks: step-down inhibitory avoidance (IA) and shuttle avoidance (SA). Diazepam (0.2, 1.0 or 5.0 mg/kg) or its vehicle were given i.p., 60 min prior to the training session. Training-test interval was 24 h. Diazepam impaired the retention of IA in 30 days-old rats at the three doses used, while retention of SA was not impaired by any dose. In the 60-70 days-old animals, diazepam at the dose of 0.2 mg/kg was facilitatory in IA and had no effect on SA, while doses of 1.0 mg/kg and 5.0 mg/kg impaired retention of both tasks. We suggest that these age-dependent effects of diazepam on memory of IA and SA could be related to developmental changes in brain GABAA receptors.
Age Factors↗
Two time windows of anisomycin-induced amnesia for inhibitory avoidance training in rats: protection from amnesia by pretraining but not pre-exposure to the task apparatus.
We have studied the effect of training conditions on hippocampal protein synthesis-dependent processes in consolidation of the inhibitory avoidance task. Adult male Wistar rats were trained and tested in a step-down inhibitory avoidance task (0.4 mA foot shock, 24 hr training-test interval). Fifteen minutes before or 0, 3, or 6 hr after training, animals received a 0.8-microl intrahippocampal infusion of the protein-synthesis inhibitor anisomycin (80 microg) or vehicle (PBS, pH 7.4). The infusion of anisomycin impaired retention test performance in animals injected 15 min before and 3 hr after the training session, but not at 0 or 6 h post-training. Pretraining with a low foot shock intensity (0.2 mA) 24 hr before training, prevented the amnestic effect of anisomycin injected at 15 min before or 3 hr after training. However, simple pre-exposure to the inhibitory avoidance apparatus did not alter the amestic effects of anisomycin. The results suggest that hippocampal protein synthesis is critical in two periods, around the time of, and 3 hr after training. A prior weak training session, however, which does not itself alter step-down latencies, is sufficient to prevent the amnestic effect of anisomycin, suggesting that even if not behaviorally detectable, weak training must be sufficient to produce some lasting cellular expression of the experience.
Age Factors↗