Victor J. DeNoble

Cysteamine-induced depletion of somatostatin produces differential cognitive deficits in rats

The effects of a variety of doses of systemically administered cysteamine (a somatostatin depletor) were studied on step-through passive avoidance retention, as well as acquisition and performance of a delayed spatial alternation task and a signaled extinction discrimination task in rats. Retention of single trial passive avoidance was significantly reduced by a pretraining (60-min) dose of cysteamine at 50, 100, 150 and 200 mg/kg s.c. This effect was shown to be sensitive to behavioral manipulation; in a second experiment, a retention deficit was found only at the two highest doses tested (150 and 200 mg/kg s.c.) after a second exposure to the footshock. In the operant conditioning studies, biweekly injections (Monday and Wednesday) of cysteamine administered one hour before testing produced no statistically significant changes in acquisition or performance of either the delayed spatial alternation or the signaled discrimination task. The results of these series of experiments suggest that active somatostatin release or chronic somatostatin depletion may selectively affect performance maintained by different behavioral procedures.

Non-peptide angiotensin II receptor antagonist and angiotensin-convering enzyme inhibitor: effect on a renin-induced deficit of a passive avoidance response in rats

Non-peptide receptor ligands with differential affinity for the angiotensin II-1 (AII-1) receptor (EXP3312, EXP3880) or the AII-2 receptor (PD123177) and an angiotensin converting enzyme (ACE) inhibitor captopril were evaluated for the ability to protect against a renin-induced performance deficit in a passive avoidance (PA) task in rats. The ability to retain a PA response was shown to decrease as the dose of intracerebroventricularly (i.c.v.) administered renin increased with maximal retention deficits occurring at 1.0 micrograms/5 microliters i.c.v. EXP3312 (1-100 micrograms/5 microliters i.c.v.) and EXP3880 (1-100 micrograms/5 microliters i.c.v.) produced dose-dependent increases in retention latencies when co-administered with renin. The peak effect dose (PED) for EXP3312 and EXP3880 was 3 and 30 micrograms i.c.v., respectively. In contrast, PD123177 was not effective in preventing the renin-induced decrease in retention across a broad range of doses (0.1-100 micrograms/5 microliters i.c.v.). Captopril (1-100 micrograms/5 microliters i.c.v.) also prevented the renin-induced performance deficit with a PED of 30 micrograms/5 microliters i.c.v. These results suggest that renin given i.c.v. produces a deficit in performance of a PA response in rats and that this effect can be attenuated by an ACE inhibitor, AII-1 receptor ligands, but not AII-2 receptor blocker.

Manipulation of serotonin protects against an hypoxia-induced deficit of a passive avoidance response in rats

The 5-HT antagonists ketanserin, mianserin, methysergide, and cyproheptadine and the 5-HT uptake inhibitors fluoxetine and zimeldine were evaluated for their ability to protect against an hypoxia-induced performance deficit in a passive avoidance (PA) task. The ability to retain a PA response was found to decrease as the oxygen concentration decreased with the largest retention deficit occurring at 6.5% O2. The 5-HT2 selective antagonists ketanserin (0.01-10.0 mg/kg SC) and mianserin (0.05-10.0 mg/kg SC) administered one minute after PA training produced dose-dependent increases in retention latencies following exposure to a 6.5% oxygen environment. Peak effective doses (PED) for ketanserin and mianserin were 3.0 mg/kg SC and 0.05 mg/kg SC, respectively. In contrast, methysergide (0.05-30.0 mg/kg SC) and cyproheptadine (0.05-7.0 mg/kg SC), antagonists that show less affinity for the 5-HT2 receptor subtype, were not effective in preventing the hypoxia-induced amnesia. Inhibition of 5-HT reuptake by fluoxetine (0.01-1.0 mg/kg SC) produced dose-dependent increases in retention latencies with a PED of 0.05 mg/kg SC while zimeldine (0.1-10.0 mg/kg SC), another 5-HT reuptake inhibitor, had no effect on the amnesia. The results of this study suggest that modification of 5-HT after exposure to hypoxia can ameliorate a performance deficit in an animal model of learning and memory.

Comparison of DuP 996, with physostigmine, THA and 3,4-DAP on hypoxia-induced amnesia in rats

DuP 996, 3,3-bis(4-pyrindinylmethyl)-1-phenylindolin-2-one, physostigmine (PH), tetrahydroaminoacridine (THA) and 3,4-diaminopyridine (3,4-DAP) were compared for their ability to protect against hypoxia-induced performance deficits in a passive avoidance (PA) task. The ability to retain PA response was found to decrease as the oxygen concentration decreased with the largest retention deficit occurring at 6.5% oxygen. DuP 996 (0.01-0.1 mg/kg SC), 3,4-DAP (0.1-10.0 mg/kg SC), THA (0.3-5.0 mg/kg SC) and PH (0.001-0.1 mg/kg SC) administered one minute after PA training produced dose-dependent increases in retention latencies following exposure to 6.5% oxygen. In comparing each compound for side effects, DuP 996 induced tremor and mortality at 10 and 40 mg/kg SC, respectively, and PH at 0.3 and 0.8 mg/kg SC, respectively. With PH the 0.3 mg/kg SC dose also produced hypersalivation and a decrease in lift strength. THA produced tremor and mortality at 6.0 and 40 mg/kg SC, respectively, and 3,4-DAP at 50 and 200 mg/kg SC, respectively. 3,4-DAP also produced chromodacryorrhea and hypersalivation at 50 mg/kg SC. Dividing the dose necessary to produce mortality by the highest effective dose active in the hypoxia test yielded a safety ratio for DuP 996 of 400, for 3,4-DAP 20, for PH 8, and for THA 8, showing a greater safety margin for DuP 996 than the other cholinergic agents. These results suggest that DuP 996 may be of use in the treatment of diseases associated with cognitive impairment and may have a greater safety margin than other cholinergic agents.

3-((±)-2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CCP) and phencyclidine produce a deficit of passive avoidance retention in rats

3-((+-)-2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), phencyclidine (PCP) and diazepam were evaluated for their ability to produce a deficit for a single trial step-through passive avoidance response in rats. Pretraining administration with CPP at doses ranging from 2.0 to 10.0 mg/kg s.c. significantly decreased retention latencies 24 h after passive avoidance training. Similar effects were found with PCP at doses ranging from 0.5 to 1.7 mg/kg s.c. and diazepam at doses between 5.0-18.0 mg/kg s.c. Pretraining administration with the benzodiazepine antagonist, RO15-1788 at doses between 0.1-15 mg/kg s.c., did not alter retention latencies. Co-administration of RO15-1788 (0.01-15.0 mg/kg s.c.) with CPP (6.0 mg/kg s.c.) or PCP (1.0 mg/kg s.c.) failed to block decreases in latencies. However, when RO15-1788 was co-administered with diazepam (9.0 mg/kg s.c.) a dose-related antagonism of diazepams effects were found. These results suggest that the behavioral actions of CPP and PCP on passive avoidance retention are not mediated via the benzodiazepine receptor complex.

Systemically administered N-methyl-D-aspartate interferes with acquisition of a passive avoidance response in rats

The effect of several doses of systemically administered N-methyl-D-aspartate (NMDA) was studied on step-through passive avoidance (PA) retention in rats. Retention of single trial PA was significantly reduced by preacquisition (30 minutes) doses of NMDA (3, 10, 30, and 50 mg/kg SC). Preacquisition amnesia was found when NMDA (30 mg/kg SC) was administered between two and 60 minutes. At shorter and longer pretreatment times (0.5 and 180 minutes) NMDA (30 mg/kg SC) did not disrupt retention testing. Across the same dose range and pretreatment times, NMDA failed to interfere with PA retention when given after acquisition or before retention testing. The results suggest that systemic NMDA administration can interfere with the acquisition of a PA response but does not alter consolidation of information or retrieval.

Visual recognition memory in squirrel monkeys : effects of serotonin antagonists on baseline and hypoxia-induced performance deficits

Cognitive deficits resulting from neuropathological brain changes such as Alzheimers Disease or normal aging are most likely due to alterations in multiple neurotransmitter systems. While the majority of preclinical studies have focused on the effects of acetylcholine (ACh), it has been shown that activation of the serotonergic (5-HT) pathways in the central nervous system interferes with passive avoidance retention in rats. In contrast, decreased 5-HT activity has been shown to improve learning and memory in rats using similar procedures. In the present experiment, 5-HT antagonists were evaluated for their effects on performance in a delayed match to sample task (DMTS) in two groups of squirrel monkeys: one in which the baseline level of performance was low (less than 65% correct, N = 5; group 1) and another in which DMTS performance was high (greater than 80% correct, N = 3; group 2) but impaired by exposure to hypoxia. Initial parametric tests exposing group 2 to various levels of oxygen deprivation were conducted to determine optimal conditions for performance deficits. Each monkey in both normoxia (group 1) and hypoxia (group 2) served as his own control and received an individualized range of doses for each test compound. For both groups, ketanserin and mianserin, the 5-HT2-selective antagonists, produced dose-dependent increases in DMTS performance at 0.3-1.5 mg/kg PO and 0.05-1.5 mg/kg PO, respectively. Pirenperone, another 5-HT2-selective antagonist, was active in improving performance in group 1 at 0.001 to 0.2 mg/kg PO but was not effective against hypoxia-induced performance deficits.(ABSTRACT TRUNCATED AT 250 WORDS)