Non-peptide angiotensin II receptor antagonist and angiotensin-converting 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.

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 Alzheimer's 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)

Protection against hypoxia-induced passive avoidance deficits: interactions between DuP 996 and ketanserin.

DuP 996 and ketanserin have previously been shown to protect against experimentally induced passive avoidance (PA) deficits. In the present experiment the potential interaction between DuP 996 and ketanserin on hypoxia-induced amnesia was evaluated. Exposure to hypoxia (6.5% oxygen) produced a reliable deficit in PA retention which was attenuated by posthypoxia treatment with DuP 996 (0.01-0.1 mg/kg SC). Similar effects were found with ketanserin at 1.0 and 3.0 mg/kg SC. Coadministration of ketanserin, at a dose that did not protect against hypoxia (0.3 mg/kg SC), and DuP 996 (at doses of 0.005, 0.1, 0.03, 0.1, 0.3 and 1.0 mg/kg SC) revealed a potentiation of both previously inactive doses of DuP 996 (e.g., 0.005, 0.3, and 1.0 mg/kg SC) and an increase in the protective effect of previously active doses of DuP 996 (0.01, 0.03, 0.1 mg/kg SC). These results suggest that combined administration of DuP 996, a neurotransmitter release enhancer, with ketanserin, a serotonin (5HT) antagonist, may provide a useful treatment for dementia.

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.

Differential effects of sigma and phencyclidine receptor ligands on learning.

Several phencyclidine (PCP) and sigma receptor ligands were examined for their effects on a single trial passive avoidance test in rats. Rats were administered the PCP receptor ligands (+)-5-methyl-10,11-dihydro-5Hdibenzo[a,d]cyclohepten-5,10-im ine maleate (MK-801), PCP, ketamine or the sigma receptor ligands (+)-N-allylnormetazocine ((+)-NANM), (+)-pentazocine, (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((+)-3-PPP) or 1,3-Di(2-[5-3H]tolyl)guanidine (DTG) subcutaneously prior to acquisition of the passive avoidance response, and tested 24 h later for retention. MK-801 (0.1-0.3 mg/kg), PCP (0.54-1.7 mg/kg), ketamine (10.0-17.2 mg/kg) and (+)-N-allylnormetazocine (5.4-10.0 mg/kg) produced significant memory deficits. (+)-Pentazocine (54 mg/kg) and (+)-3-PPP (30 mg/kg) also produced retention deficits, but at significantly higher doses. DTG (0.3-3.0 mg/kg s.c.) had no effect on retention. There was a positive correlation between production of retention deficits and the compounds' PCP receptor binding affinity. The results suggest that the sigma receptor is not involved in learning the passive avoidance response.

3-((+-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) 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 diazepam's 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.

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.

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.

Vinpocetine enhances retrieval of a step-through passive avoidance response in rats.

Vinpocetine, vincamine, apovincaminic acid, vinconate, aniracetam, Hydergine, and pemoline were evaluated for their ability to enhance retrieval of a step-through passive avoidance response in rats. The percentage of rats performing the avoidance response was found to decrease as a function of the number of days between training and retention testing (Day 1, 100%; Day 2, 65%; Day 3, 23%; Days 4 and 5, 0%). Vinpocetine administered 60 minutes prior to testing for retention significantly increased the number of rats performing the passive avoidance response. Retrieval enhancement was dose-related in an inverted U-shaped function with the effective doses at 18 and 30 mg/kg PO. In contrast, apovincaminic acid (1-400 mg/kg PO), vincamine (1-200 mg/kg PO), vinconate (1-200 mg/kg PO), aniracetam (1-300 mg/kg PO), Hydergine (0.1-10 mg/kg PO), and pemoline (1-30 mg/kg PO) were not effective. These data support the view that vinpocetine has cognition-activating abilities as defined in an animal model of memory retrieval.

Vinpocetine: nootropic effects on scopolamine-induced and hypoxia-induced retrieval deficits of a step-through passive avoidance response in rats.

Vinpocetine, vincamine, aniracetam, and Hydergine, compounds with purported cognition activating activity, were evaluated for their ability to prevent scopolamine-induced and hypoxia-induced impairment of passive avoidance retention (24 hr) in rats. Vinpocetine (peak effect dose [PED]= 200 mg/kg PO), aniracetam (PED = 100 mg/kg PO), vincamine (PED = 30 mg/kg PO), and Hydergine (PED = 1 mg/kg PO) prevented memory disruption by scopolamine. Vinpocetine (PED = 3 mg/kg PO) and aniracetam (PED = 30 mg/kg PO) were also effective in preventing disruption of passive avoidance retention impaired by 7% oxygen hypoxia. In contrast, Hydergine (0.05 to 3 mg/kg PO) and vincamine (0.3 to 100 mg/kg PO) were not effective against hypoxia-induced impairment. Hydergine at doses greater than 10 mg/kg PO markedly impaired motor function. In both tests the protection was dose-related for all test substances in an inverted U-shaped manner. Mecamylamine (1, 3, 10 mg/kg SC), (-)-nicotine (0.1 to 0.4 mg/kg SC), apovincaminic acid (1-400 mg/kg PO) and pemoline (1-100 mg/kg PO) did not protect against memory impairment induced by either procedure. These data support the view that vinpocetine, a compound chemically distinct from the pyrrolidinones, has a cognitive activating ability as defined in models of both scopolamine-induced and hypoxia-induced memory impairment in rats.

Brain sites involved in the mediation of the behavioral effects of intraventricularly administered (-)-nicotine.

Fifteen hooded rats were trained to lever press for food under a fixed ratio (FR) 32 schedule. When lever pressing stabilized all rats were implanted with two cannulae, one in the lateral ventricle (LV) and the second in one of the following brain structures: dorsal hippocampus (DH), locus ceruleus (LC), lateral hypothalamus (LH), reticular formation (RF), or the vestibular nucleus (VN). All rats when infused with 5.0 micrograms (-)-nicotine (LV) showed an increased latency to complete the first ratio. Infusions of (-)-nicotine (0.25 microgram) into specific brain sites showed that qualitatively and quantitatively similar effects on FR performance could be produced when nicotine was infused into the VN. When lidocaine (5.0 micrograms) was applied to the RF the latency to complete the first ratio following 5.0 micrograms (-)-nicotine infusion into the LV was decreased by 55%. Lidocaine infused into the VN completely blocked the effect of LV (-)-nicotine. Neither lidocaine nor (-)-nicotine had any effect on responding when applied to the other brain structures. The results suggest that a primary site of central action of (-)-nicotine is the VN and that inhibition of the RF will attenuate the behavioral effects of LV infusions of (-)-nicotine.

Intravenous self-administration of pentobarbital and ethanol in rats.

Rats provided with unlimited access to intravenous doses of ethanol (30, 60, 90, 180, and 360 mg/kg/infusion) failed to initiate and maintain lever pressing that resulted in ethanol delivery. When pentobarbital (0.5 mg/kg/infusion) was substituted for ethanol, lever pressing increased. There were three indications of the positive reinforcing effects of pentobarbital: (1) a greater number of lever presses occurred when pentobarbital was response-contingent than when saline was available; (2) a greater number of responses were made on the pentobarbital lever than on a control "activity" lever; and (3) systematic changes in lever pressing were a function of pentobarbital dose (0.125, 0.25, 0.5, 1.0, and 2.0 mg/kg/infusion). Sequential substitution of ethanol (30, 90, 360 mg/kg/infusion) for pentobarbital failed to maintain lever pressing. However, access to combinations of ethanol (1, 3, 10, 30, 60 mg/kg/infusion) and a nonreinforcing dose of pentobarbital (0.125 or 0.25 mg/kg/infusion) did maintain lever pressing. As the dose of ethanol increased, the daily number of infusions first increased then decreased. Following a history of self-administration of ethanol-pentobarbital combinations, a retest of ethanol alone (10 or 30 mg/kg/infusions) followed by pentobarbital alone (0.125 or 0.25 mg/kg/infusion) failed to maintain lever pressing.

Behavioral effects of intraventricularly administered (-)-nicotine on fixed ratio schedules of food presentation in rats.

The behavioral effects of intraventricularly (IVT) administered (-)-nicotine on food-maintained behavior were studied. Rats responded by pressing a lever under various fixed ratio (FR) schedules. Infusion of 5 microgram of (-)-nicotine suppressed responding under an FR 16 schedule for 11-13 min. The effect was inversely related to the ratio size (16, 32, 64 responses per food delivery), but it was directly related to the infused (-)-nicotine dose (0.312, 0.624, 1.25, 2.5, 5.0, 10.0 microgram) when ratio size was held constant. Responses rates following the (-)-nicotine-induced suppression were similar to those obtained prior to infusion. The behavioral effects of (-)-nicotine were blocked, in a dose-related manner, by the centrally acting nicotinic-cholinergic antagonist, mecamylamine (0.05-3.0 mg/kg) but not by ther peripherally acting antagonist, hexamethonium (0.5-3.0 mg/kg), suggesting that the behavioral effects of IVT infusions of (-)-nicotine are mediated by central nicotine-cholinergic receptors.

Orally delivered pentobarbital as a reinforcer for rhesus monkeys with concurrent access to water: effects of concentration, fixed-ratio size, and liquid positions.

The number of liquid deliveries and pattern of concurrent pentobarbital and water drinking were studied in three food deprived rhesus monkeys during daily 3-hr sessions. During the daily sessions, deliveries of approximately 0.6 ml of each liquid occurred under fixed-ratio (FR) schedules of lip contact responses. Between sessions water was freely available. Session drinking was studied as a function of pentobarbital concentration (1.0, 1.41, 2.0, and 4.0 mg/ml) and FR size (4, 8, 16 and 32 lip contacts per delivery). The number of drug deliveries decreased with increases in drug concentration. Drug intake ranged from 21 to 52 mg/kg of body wt./3-hr session. At all concentrations and FR values tested, the number of pentobarbital deliveries substantially exceeded the number of water deliveries. The positive reinforcing effect of the pentobarbital was indicated by a consistent choice of drug over water irrespective of the side position of pentobarbital and by higher rates of drug responding. Pentobarbital drinking occurred in a negatively accelerated pattern whereas water drinking did not have any consistent pattern. Marked intoxication followed bouts of drug drinking.

Impairment of acquisition of a DRL schedule following prolonged ethanol consumption.

Two groups of male hooded rats (N = 9) were given either ethanol or sucrose solutions as their only source of fluid for six months. Thirty days after the ethanol treatment, the rats were reduced to 85% of their free-feeding weights and allowed to obtain 45 mg of food pellets on an FR 1 schedule fof five consecutive days. Subsequently, the rats were tested on four DRL schedules (6. 12, 18, 24 sec). There was no difference between the two groups on FR 1 or DRL 6 sec schedules; however, when the DRL interval was lengthened to 12, 18, and 24 sec, the ethanol group required more sessions than the sucrose group to reach criterion performance. After increases in the DRL interval, the modal interresponse time of the ethanol group shifted more slowly than that of the sucrose group.

Alcohol self-administration in monkeys (Macaca radiata): the effects of prior alcohol exposure.

Responding by 4 monkeys was maintained under a fixed ratio 10 (FR 10) schedule for either food, intravenous sucrose or alcohol. The 20 hr sessions were divided so that food was available during hours 1, 6, 11, 16 and alcohol or sucrose during hours 2-5, 7-10, 12-15, and 17-20. All animals failed to maintain responding for isocaloric sucrose but continued to respond for food during those sessions. Responding under alcohol conditions was positively accelerated in 2 animals that were not previously exposed to alcohol, whereas prior exposure to alcohol produced maximal response rates during the first alcohol test session. The effects of alcohol in all monkeys were to suppress responding maintained by food and this suppression could not be produced with programmed infusions of isocaloric sucrose.