AMPA antagonists differ from NMDA antagonists in their effects on operant DRL and delayed matching to position tasks

The effects of NBQX (1.56–7.5 mg/kg, IP), a competitive antagonist at the AMPA type of glutamate receptor, were studied in two operant behavioural paradigms, differential reinforcement of low response rates (DRL), and delayed matching to position (DMTP), which have been shown to be sensitive to the antagonists of the NMDA type of glutamate receptor. Additionally, the non-competitive AMPA antagonist, GYKI 52466 (7.5–15 mg/kg, IP), was studied in the DRL procedure. As a positive control, the non-competitive NMDA antagonist, MK 801 (0.0125–0.1 mg/kg, IP) was studied in both procedures. During performance of the DRL schedule, MK 801 increased response rates in a dose dependent manner, and decreased the number of reinforcers obtained. The increase in response rates could be attributed to both a shift in the median inter-response time (IRT) to shorter intervals, and to a marked, dose dependent increase in the occurrence of bursts of responses (responses occurring within 3 s of a previous response). In contrast, NBQX and GYKI 52466 both decreased response rates in a dose dependent fashion, and did not shift the distribution of the IRTs, or increase the occurrence of burst responding. In the DMTP procedure, accuracy of matching decreased with increasing delay (up to 30 s, between presentation of sample and opportunity to respond). NBQX disrupted responding at a dose of 7.5 mg/kg, but lower doses were ineffective in influencing accuracy of performance of the discrimination. In contrast, MK 801 (0.1 and 0.2 mg/kg) reduced accuracy of matching at all delays, while tending to increase the speed of responding. These data demonstrate differences in the effects of AMPA and NMDA antagonists on performance of well trained operant behaviour.     

Effects of gamma-hydroxybutyrate (GHB) and its metabolic precursors on delayed-matching-to-position performance in rats

The purpose of the present study was to provide further information about the effects of gamma-hydroxybutyrate (GHB) on memory. Initially, the acute effects of gamma-butyrolactone (GBL, 75-200 mg/kg IP), 1,4-butanediol (1,4-BD, 100-300 mg/kg IP), and ethanol (1.0-3.0 g/kg, oral), as well as GHB (100-300 mg/kg IP), were examined in rats responding under a delayed-matching-to-position (DMTP) procedure with delays from 0 to 32 s. Acute administration of all four drugs reduced the number of trials completed and also reduced accuracy during delay trials, but not during trials without a delay. Some tolerance developed to the disruptive effects of GHB following exposure to 300 mg/kg/day for 29 consecutive days. These data indicate that GHB can disrupt working memory and speed of responding, and that tolerance can develop to these effects. Moreover, the acute effects of GHB under the DMTP procedure resemble those of its metabolic precursors, GBL and 1,4-BD, and of the prototypical CNS depressant drug, ethanol.     

Detecting drug effects on short-term memory function using a combined delayed matching and non-matching to position task

Operant delayed non-matching-to-position (DNMTP) and delayed matching-to-position (DMTP) have become standard techniques to investigate drug effects on short-term memory function in rats. However, these two tasks are normally conducted in isolation. Using two standard drugs, the 5HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and the muscarinic antagonist scopolamine, this study looked at a two-choice operant task that essentially involved a mixed DNMTP/DMTP paradigm. Thus, DNMTP trials were interspersed with DMTP trials in a random sequence for the duration of a session. 8-OH-DPAT (0.03 mg/kg) slightly but significantly improved response accuracy in a delay-dependent fashion during DMTP but not DNMTP trials. The highest dose of 8-OH-DPAT (0.1 mg/kg) impaired accuracy during DNMTP trials independent of delay and had no significant effect during DMTP trials. Scopolamine (0.1 mg/kg) produced delay-dependent deficits in accuracy during DMTP trials but delay-independent impairments during DNMTP trials. Because both 8-OH-DPAT and scopolamine produced delay-dependent effects with DMTP trials types and either had no effect (8-OH-DPAT) or produced delay-independent impairments (scopolamine) during DNMTP trials types, it is suggested that DMTP trials had a greater dependence on short-term working memory function than DNMTP trials that probably relied more on positional (mediating) strategies for solving the task. Therefore, we believe that this mixed DNMTP/DMTP task offers greater potential for more reliable and discerning interpretation of data regarding short-term memory function in rodents than either of the paradigms performed in isolation.     

Effects of ethanol and GABAB drugs on working memory in C57BL/6J and DBA/2J mice

RATIONALE: It has been suggested that GABA(B) receptors may be part of a neural substrate mediating some of the effects of ethanol. OBJECTIVE: The purpose of this experiment was to investigate, in mice, the effects of ethanol on working memory in a delayed matching-to position (DMTP) task, and additionally to determine if these effects were modulated by GABA(B) receptors. METHODS: Female C57BL/6J and DBA/2J mice were trained in the DMTP task, and after asymptotic levels of performance accuracy were achieved, injections (IP) of ethanol, baclofen, or phaclofen were administered. Baclofen or phaclofen were then co-administered with ethanol. Each test was repeated twice. RESULTS: Ethanol caused deficits in working memory at 2.0 g/kg and higher. The highest dose (2.5 g/kg) produced additional non-specific effects, indicative of sedation. Baclofen increased performance accuracy (2.5 mg/kg), while decreasing the total number of trials completed. When combined with ethanol (1.5 g/kg), baclofen increased memory deficits at the highest dose (7.5 mg/kg). Phaclofen increased performance accuracy at 10 and 30 mg/kg but had no effect on the total number of trials completed. When combined with ethanol (2.5 g/kg), phaclofen did not significantly alter ethanol-induced deficits in performance. CONCLUSIONS: Analyses of performance accuracy, total trials completed and variables indexing bias and motor impairment indicated that GABA(B) drugs modulate working memory in a behaviorally specific manner. Overall, these receptors may be part of a neural substrate that modulates some of the effects of ethanol.     

Effects of ethanol and GABA<Subscript>B</Subscript> drugs on working memory in C57BL/6J and DBA/2J mice

Rationale It has been suggested that GABA_B receptors may be part of a neural substrate mediating some of the effects of ethanol.Objective The purpose of this experiment was to investigate, in mice, the effects of ethanol on working memory in a delayed matching-to position (DMTP) task, and additionally to determine if these effects were modulated by GABA_B receptors.Methods Female C57BL/6J and DBA/2J mice were trained in the DMTP task, and after asymptotic levels of performance accuracy were achieved, injections (IP) of ethanol, baclofen, or phaclofen were administered. Baclofen or phaclofen were then co-administered with ethanol. Each test was repeated twice.Results Ethanol caused deficits in working memory at 2.0 g/kg and higher. The highest dose (2.5 g/kg) produced additional non-specific effects, indicative of sedation. Baclofen increased performance accuracy (2.5 mg/kg), while decreasing the total number of trials completed. When combined with ethanol (1.5 g/kg), baclofen increased memory deficits at the highest dose (7.5 mg/kg). Phaclofen increased performance accuracy at 10 and 30 mg/kg but had no effect on the total number of trials completed. When combined with ethanol (2.5 g/kg), phaclofen did not significantly alter ethanol-induced deficits in performance.Conclusions Analyses of performance accuracy, total trials completed and variables indexing bias and motor impairment indicated that GABA_B drugs modulate working memory in a behaviorally specific manner. Overall, these receptors may be part of a neural substrate that modulates some of the effects of ethanol.     

5-HT1A receptor agonists improve the performance of normal and scopolamine-impaired rats in an operant delayed matching to position task

A series of experiments examined the effects of 5-HT_1A ligands alone and in combination with the muscarinic antagonist scopolamine on short term working memory in the rat. The behavioural paradigm was a discrete trial, operant delayed matching to position task, with delays of 0, 5, 15 and 30 s. The 5-HT_1A ligands tested were the full agonist, 8-OH DPAT (0, 0.1, 0.3 and 1 mg/kg), the partial agonist, ipsapirone (0, 1, 3 and 10 mg/kg), and the purported antagonist, NAN 190 (0, 1, 2, and 4 mg/kg). 1-PP (0, 0.1, 0.3, 1 mg/kg), the major metabolite of ipsapirone, was also tested. The lowest dose of 8-OH DPAT significantly improved matching accuracy at the longest delay, whereas the highest dose impaired matching accuracy and increased the latency to respond. Ipsapirone also significantly improved the accuracy of performance at a dose of 3 mg/kg, but the doses of 1 and 10 mg/kg did not significantly affect performance. NAN-190, at the highest dose tested (4 mg/kg), impaired matching accuracy, whereas the two lower doses did not significantly affect performance. The highest dose also increased the latency to respond. 1-PP had no effect on performance. Scopolamine HBr (0.14 mg/kg) caused a delay dependent impairment in matching accuracy, and had no effect on missed trials or the latency to respond. Low doses of 8-OH DPAT (0.1 and 0.3 mg/kg) significantly attenuated the scopolamine induced accuracy impairment, whereas 1 mg/kg 8-OH DPAT potentiated the impairment. Ipsapirone (3 mg/kg) also significantly improved the performance of scopolamine impaired rats. NAN-190 increased the latency to respond and reduced the number of nose pokes made during the delays in scopolamine-treated rats, and tended to potentiate the scopolamine-induced accuracy impairment. 1-PP did not affect the performance of scopolamine treated rats. Taken together, these results suggest that modulation of 5-HT_1A receptors influences short term spatial working memory in the rat.     

The NMDA antagonist EAA 494 does not impair working memory in an operant DNMTP task in rats

There is contrasting evidence for an impairment of spatial working memory in operant delayed matching/or nonmatching to position (DMTP/DNMTP) tasks, as both delay-dependent and -independent disruption of choice accuracy has been found following N-methyl-D-aspartate (NMDA) receptor blockade. Using a within-subjects experimental design, the effect of the competitive NMDA receptor antagonist, EAA 494 (D-CPP-ene) (1, 1.5, 2 mg/kg IP 30 min prior), on working memory was investigated in male Lister Hooded rats pretrained to the DNMTP task (0-16-s delay in intervals). Metal barriers were inserted between the food magazine and levers to inhibit the use of mediating strategies, such as orientation towards the correct lever during the delay interval, because this behavior may contribute to the delay-dependent disruption noted in previous studies. It was found that EAA 494 did not modify working memory either in the presence or absence of barriers. However, a dose-dependent impairment of task performance was recorded, notably in the presence of barriers. These results indicate that competitive blockade of NMDA receptors with EAA 494 does not result in impaired working memory in rats and parallel the lack of effect of the compound upon working memory in humans. Activation of NMDA receptors does not appear to be essential for the performance of spatial tasks requiring working memory.     

Dithiobiuret toxicity in the rat: Evidence for latency and cumulative dose thresholds

Treatment of rats with 2,4-dithiobiuret (DTB) causes a delayed onset skeletal muscle weakness which was detected by a rotarod test. Daily doses of 0.125 mg/kg failed to cause muscle weakness after 52 days of treatment (cumulative dose = 6.5 mg/kg). However, daily doses of DTB ranging from 0.25 to 16 mg/kg caused muscle weakness, and the onset of this weakness was determined by either a latency threshold of 3–4 days or a cumulative dose threshold of 4–5 mg/kg. At daily doses greater than 1 mg/kg, the latency threshold determined the onset of toxicity; at daily doses of 0.25–1 mg/kg the cumulative dose threshold was the determining factor. The basis for these thresholds is not known. When DTB treatment was stopped after the first day of toxicity, rats treated with 0.25–1 mg/kg/day regained normal rotarod performance within 2–5 days. However, rats treated with 2 mg/kg/day or more, died between 0 and 2 days of stopping treatment. Distribution and elimination studies revealed that urine was the main route of elimination of DTB-derived ¹⁴C and that feces was a minor route. Inasmuch as only 70–75% of a daily dose was eliminated in the first 24 hr, when administered at the rate of 0.25, 0.5, and 1 mg/kg/day, DTB-derived ¹⁴C accumulated in rats maintained on these dosing regimens. On the second day of rotarod test failure, the body burden of DTB equivalents in the three dosage groups ranged from 0.7 to 1 mg/kg. The highest concentration of DTB-derived ¹⁴C was found in the thyroid gland. However, accumulation of DTB in the thyroid and its potential antithyroid action are probably not responsible for toxicity. The most important finding was the demonstration that latency and cumulative dose thresholds determine the onset of DTB intoxication. The cause of these thresholds, if determined, may ultimately lead to an understanding of the mechanism of the toxicity of DTB.     

Effects of the potassium channel blockers, apamin and 4-aminopyridine, on scopolamine-induced deficits in the delayed matching to position task in rats: a comparison with the cholinesterase inhibitor E2020

 The effects of the muscarinic antagonists, scopolamine HBr and MeBr, a cholinesterase inhibitor, E2020, and K⁺ channel blockers, 4-aminopyridine (4-AP) and apamin, on the performance of rats in a delayed matching to position (DMTP) task were examined. The percentage of correct choices (choice accuracy), number of trials completed and intertrial intervals were measured. Discriminability and response bias were also calculated, using signal detection analysis. Scopolamine HBr (0.1 mg/kg), but not scopolamine MeBr (0.1 mg/kg), significantly and consistently reduced the choice accuracy and discriminability, but neither affected the other measurements. E2020 (0.03–1.0 mg/kg) had no effect on the baseline performance in the DMTP task, but at 1.0 mg/kg, it significantly attenuated the deficits in choice accuracy induced by scopolamine. 4-AP (0.001–0.1 mg/kg) had no effect on either baseline performance or deficits induced by scopolamine. Apamin (0.1–0.4 mg/kg) had no effect on choice accuracy and discriminability. Apamin also failed to attenuate the scopolamine-induced deficits. When administered in combination with scopolamine, apamin at 0.4 mg/kg significantly decreased the number of trials completed and increased the intertrial interval relative to that of the control group. Taken together, these results demonstrate that K⁺ channel blockers (4-AP and apamin), unlike a cholinesterase inhibitor (E2020), fail to reverse the scopolamine-induced deficits in the DMTP task. Received: 27 March 1997/Final version: 19 June 1997     

The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates PCP-induced cognitive deficits in rats

Rationale Recent studies have shown that metabotropic glutamate receptor 5 (mGluR5) can modulate N-methyl-d-aspartate (NMDA) receptor function in vivo. For example, the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP) can potentiate PCP (phencyclidine)-evoked hyperactivity and PCP-induced disruptions in pre-pulse inhibition (PPI) in rats.Objective To extend these previous behavioral findings and determine whether the mGluR5 antagonist MPEP can modulate the disruptions in learning and memory induced by PCP in rats.Methods The effects of MPEP, alone and in combination with PCP, were evaluated in rats trained to perform a repeated acquisition procedure (learning) or a delayed non-matching to position (DNMTP) radial maze task (spatial memory).Results In the repeated acquisition task, MPEP (0–10 mg/kg, IP) dose-dependently decreased response rates but had no effect on response accuracy. In contrast, PCP (0.625–1.25 mg/kg, SC) reduced response rate and response accuracy in a dose-dependent manner. Although MPEP (10 mg/kg, IP) had no effect when administered alone, the mGluR5 antagonist potentiated the disruptions in learning induced by a low dose of PCP (0.625 mg/kg, SC). In the DNMTP maze task, MPEP (0–10 mg/kg, IP) had no effect on spatial memory, whereas PCP (1.25–2.5 mg/kg, SC) produced a dose-dependent disruption. MPEP (10 mg/kg, IP) potentiated the impairments in memory induced by PCP (1.25 mg/kg, SC).Conclusion The mGluR5 antagonist, MPEP, potentiated the disruptions in learning and memory induced by PCP. These behavioral data extend previous behavioral findings and further suggest that mGluR5 can modulate NMDA receptor function in vivo.     

The Effects of 2,4-Dithiobiuret on Sensory and Motor Function

The Effects of 2,4-Dithiobiuret on Sensory and Motor Function.CROFTON, K. M., DEAN, K. F., HAMRICK, R. C, and BOYES, W. K.(1991). Fundam. Appl. Toxicol. 16, 469–481. 2,4-Dithiobiuret(DTB) exposure causes a delayed onset muscle weakness in ratsthat has been attributed to depressed neuromuscular transmission.The present study compares the effects of DTB on both sensoryand motor function in rats. Adult male Long-Evans hooded ratswere exposed to saline, 0.25, 0.5, or 1.0 mg/kg/day DTB, ip,for 5 consecutive days (Days 1–5). Body weights were monitoredthroughout the experiment. Motor activity was measured for 1hr in figure-eight mazes on Days 0, 6, 13, and 27. Forelimband hindlimb grip strength were assessed on Days 6, 13, and27. Auditory thresholds were determined for 5- and 40-kHz tonesusing reflex modification of the startle response on Days 0,7, 14, and 28. Visual function was examined on Day 6 in animalsexposed at 0.5 mg/kg/day using flash- and pattern-elicited visualevoked potentials (FEPs and PEPs, respectively). Thermal sensitivitywas measured using the hot plate procedure. All motor endpointswere decreased in a dosage- and time-dependent manner; the higherthe dosage the longer the effects lasted. There were no effectson any measure of sensory function with the exception of peakN2 of the FEP. Both the amplitude and latency of FEP N2 werealtered by DTB exposure. Decreases in body weight were maximalon Day 9 at 1.0 mg/kg/day (20% from control), but recoveredby Day 22. Motor activity was suppressed on Day 6 only, whereasgrip strength measures were decreased on both Days 6 and 13.Auditory thresholds were not significantly altered; however,baseline startle amplitude was decreased at the highest dosageon Days 7 and 14, but recovered by Day 28. Hot plate latencieswere not altered by DTB treatment. These data demonstrate thatDTB produces a reversible impairment of motor function, withoutaltering auditory, thermal, or pattern visual function. FEPN2, which is thought to arise from activity generated in thesuperficial layers of visual cortex, was diminished by DTB treatment,indicating that DTB can alter the function of the CNS, althougheffects on the motor system are more pronounced.     

Automatic recording of mediating behavior in delayed matching- and nonmatching-to-position procedures in rats

Rationale

Delayed matching-to-position and nonmatching-to-position procedures are widely used to model working memory in rodents. Mediating behavior??which enhances performance but is not explicitly required by the task??is generally considered an obstacle to the measurement of memory, but often occurs despite attempts to prevent it. The ubiquitous nature of mediating behavior suggests it might be analogous to rehearsal, an important component of learning and memory in humans.

Objectives

The aim was to study an easily recordable, rehearsal-like mediating response in rats under baseline conditions and after treatment with amnestic drugs [scopolamine (0.1?C0.3?mg/kg) and delta-9-tetrahydrocannabinol (THC; 1?C5.6?mg/kg)].

Methods

Lighted nosepoke holes were used to present position cues and record delayed matching or nonmatching responses. Performance of a distractor task was required to prevent simply waiting at the correct choice, but the nosepoke holes were left accessible during the delay.

Results

Each rat trained with the nonmatching task exhibited one of two mediating ??strategies?? that increased the odds of a correct choice: responding in the to-be-correct hole during the delay or responding in the opposite hole during the delay. Rats trained with the matching task all showed the former strategy. Treatment with scopolamine disrupted performance of the mediating response. Scopolamine and THC both decreased the effectiveness of the mediating response, increasing errors even on trials when the ??appropriate?? mediating behavior did occur.

Conclusions

The procedures and data analysis approach used here provide an objective, automated means of measuring mediating behavior, which might be useful as an animal model of memory rehearsal.     

Chlorpyrifos: lack of cognitive effects in adult Long-Evans rats

Female Long-Evans rats were gavaged 5 days a week for 4 weeks with chlorpyrifos in oil at dosages of 0, 1, 3, and 10 mg/kg/day. Clinical observations were conducted, and memory was tested with a delayed matching-to-position task (DMTP). Before exposure started, the rats were divided into four groups of ten of comparable overall performance. Then, they were tested during four weeks of dosing and for another four weeks thereafter. The observer was not provided information about each rat's dose group identification. Miosis was a prominent sign observed in the 3 and 10 mg/kg/day groups. Rectal temperature was reduced in the 10 mg/kg/day group. Noncognitive performance measures in the DMTP test (e.g., actual total delay, void trials) were affected and consistent with decreased motor activity. There was a statistically significant difference in the intercept at the zero delay (i.e., a measure of encoding/motivation/attention), which was attributed to deviations from controls in the high-dosage group during dosing weeks 2 and 3 (in opposite directions). This difference was not considered treatment related. The slope of the retention gradient (i.e., a measure of forgetting rate) did not show any statistically significant difference between groups at dosages that inhibited brain cholinesterase by up to approximately 85%. In conclusion, chlorpyrifos decreased motor activity but had no effects on short-term memory (i.e., information retention capability) and on encoding/motivation/attention.     

The effect of the mGlu5 receptor antagonist MPEP in rodent tests of anxiety and cognition: a comparison

Rationale Antagonists at the metabotropic glutamate 5 (mGlu5) receptor produce robust anxiolytic effects in a number of rat tests. However, there is evidence that mGlu5 receptor antagonists may also impair working memory and spatial learning following intracerebroventricular administration.Objectives The aim of this study is to compare the effect of the potent and selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-piperidine (MPEP), administered systemically on rodent tests of cognition and anxiety.Methods MPEP was assessed in the following rodent tests, 60 min following oral administration: Geller–Seifter conflict, conditioned emotional response (CER), Vogel conflict, delayed match to position (DMTP) and Morris water maze. Diazepam was also tested as a comparator.Results MPEP had a significant anxiolytic effect, comparable in magnitude to diazepam, at 10–30 mg/kg in the two conflict and CER tasks. There was no effect of MPEP up to 30 mg/kg on working memory in the DMTP task, but at 100 mg/kg, there was a significant reduction in choice accuracy at the longest delay interval (24 s). MPEP (3–30 mg/kg) did not significantly impair spatial learning in the Morris water maze, although during the last probe trial, 30-mg/kg-treated rats were significantly less accurate than controls. In contrast, diazepam significantly impaired performance in both the DMTP and Morris water maze tests. Assessment of plasma and brain concentration of MPEP 75 min following oral administration showed a dose linearity from 3 to 30 mg/kg and good brain penetration, i.e. a brain/plasma ratio of 3.1.Conclusions Oral administration of the selective mGlu5 receptor antagonist MPEP induces a robust anxiolytic-like effect in rat conflict tests comparable to that seen with diazepam, but in contrast to diazepam, MPEP does not impair working memory or spatial learning at anxiolytic doses.     

Additive deficits in the choice accuracy of rats in the delayed non-matching to position task after cholinolytics and serotonergic lesions are non-mnemonic in nature

The role of serotonin (5-HT) and its interaction with the muscarinic or nicotinic receptor-mediated mechanisms in the modulation of working memory and motor activity was investigated by assessing the effects of 5-HT lesion and cholinergic receptor blockade on the performance of rats in a working memory (delayed non-matching to position, DNMTP) task. A global serotonergic lesion was induced by the intracerebroventricular adminstration of 5,7-dihydroxytryptamine (5,7-DHT). Post-mortem neurochemical analysis revealed that serotonin and 5-hydroxyindoleacetic acid (5-HIAA) levels were reduced in frontal and parieto-occipital cortices and in hippocampi of 5,7-DHT lesioned rats. 5-HIAA levels were also reduced in striatum. 5,7-DHT lesion slightly impaired choice accuracy of rats in the DNMTP task and also transiently reduced motor activity in rats. Even the lower dose of scopolamine (0.075 mg/kg), a muscarinic receptor antagonist, impaired the choice accuracy already at the shortest delay (i.e. not indicative of a working memory impairment per se), and caused a marked disruption of motor activity (lengthened response latencies, increased probability of omissions and decreased trials completed). Furthermore, the quaternary analogue, N-methylscopolamine (0.150 mg/kg), affected the motor activity of rats to the same extent as scopolamine. Mecamylamine (1.0; 3.0 mg/kg) also interfered with motor activity and it slightly decreased the choice accuracy, which was not dependent on the delay. Although mecamylamine disrupted the performance of rats in the DNMTP task, the disruption was not as severe as that seen with scopolamine. Moreover, both scopolamine and mecamylamine augmented the slight impairment on the choice accuracy of 5,7-DHT lesioned rats, but this was non-mnemonic in character. We conclude that there is no evidence for any major interaction between the serotonergic system and muscarinic or nicotinic cholinergic mechanisms in working memory per se, but muscarinic and nicotinic receptor antagonists may act additively with the 5,7-DHT lesion to disrupt the choice accuracy of rats. Received: 22 November 1995 / Final version: 25 November 1996     

Impaired performance on delayed matching in monkeys by heptabarbitone, pentobarbitone sodium and quinalbarbitone sodium

The effect of three barbiturates, heptabarbitone (20 and 30 mg/kg), pentobarbitone sodium (10 and 15 mg/kg) and quinalbarbitone sodium (10 and 15 mg/kg), have been studied in monkeys on a delayed matching task. No differential effects could be shown between the three drugs, nor could the effect of the drugs be related to the delay between stimuli. Both doses of each drug produced very highly significant increases in total response time 2 hr after administration but only the higher dose of each barbiturate had an effect at the 6 hr interval.Changes in accuracy of matching were not observed after the lower dose of each drug, but at the higher doses there was a reduction in accuracy of matching significant at the 5 % level.It was considered that barbiturates have a depressive effect on motor responsiveness, but that the decreased performance in accuracy of matching was not due to the impaired motor activity. The present studies do not provide any evidence of an effect of barbiturates on short term memory.     

Log dose/response curve flattening in rats after daily injection of opiates

Rats injected (IP) daily with 0, 20, and 200 mg/kg morphine-SO₄ for 25–49 days experienced log dose/response (LDR) curve flattening (decrease in slope and/or maximum response) for analgesia (tail immersion test) produced by etorphine-HCl injected IP or intracerebroventricularly (ICV), and for latency to maximum rectal temperature increase produced by IP etorphine. Rats treated similarly with 0, 50, and 500 g/kg etorphine-HCl for 32 days exhibited LDR-curve flattening for analgesia produced by etorphine and morphine (IP). In addition, a profound body weight loss produced by high-dose morphine treatment (200 mg/kg) was found not to be involved in flattening, since similar body weight decreases produced by food restriction in 0 and 20 mg/kg rats did not have this effect. Flattening, however, may be due to a rapidly acquired and rapidly lost within-session (acute) tolerance. When flattening was not seen at short intervals after IP or ICV test etorphine doses, flattening was seen when rats were retested at longer test intervals. Forty-eight hours after cessation of chronic etorphine treatment, flattening of the etorphine analgesia LDR curve was lost, but parallel shift was unaffected. Similarly, 200 mg/kg morphine-treated rats lost morphine tolerance more rapidly than 20 mg/kg-treated rats during the first 12 days after the last treatment injection. Subsequently, however, levels of the analgesia and the amounts of tolerance loss were comparable in both chronically treated groups. The data support the notion that chronic tolerance reflects an enhancement or prolongation of acute tolerance.     

BIMT 17: a putative antidepressant with a fast onset of action?

 BIMT 17, the only compound reported to be a full 5-HT_1A agonist and a 5-HT_2A antagonist at the frontal cortex, was assessed in three animal paradigms sensitive to antidepressants in rats: olfactory bulbectomy (OB), differential-reinforcement-of-low rate 72-s (DRL 72-s) and learned helplessness (LH). In the OB rats, BIMT 17, given once daily for 14 consecutive days at an IP dose of 10 mg/kg, but not of 20 mg/kg, reduced the increase in ambulation of OB rats, 24 h after the last administration. In the DRL 72-s test, BIMT 17 had a different profile than imipramine. A single IP injection of 5, 10, 15 or 20 mg/kg BIMT 17, in contrast to the same doses of imipramine, did not affect response and reinforcement rate in DRL 72-s 1 h after the administration. On the other hand, BIMT 17 slightly shifted the peak of the interresponse time (IRT) distribution towards shorter IRT duration, while imipramine shifted the peak of the IRT distribution towards longer IRT duration. In the LH test, acute oral doses (36, 48 or 60 mg/kg) of BIMT 17, given 30 min before testing, reduced the number of escape failures in LH without altering the intertrial crossings. This effect was also induced by a repeated, but not single, administration with 8 or 16 mg/kg imipramine. The plasma levels following IP 10 or oral 48 mg/kg BIMT 17 were in the same range. These results indicate that BIMT 17 does not behave like imipramine in all the tests, and suggest that BIMT 17 acts through different mechanisms of action than imipramine. Only clinical trials will tell whether these mechanisms will be relevant, but if so, BIMT 17 might induce a faster onset of therapeutic activity. Received: 10 March 1997 / Final version: 9 July 1997     

Dissociation between cognitive and motor/motivational deficits in the delayed matching to position test: effects of scopolamine, 8-OH-DPAT and EAA antagonists

The effects of the muscarinic antagonists scopolamine HBr and MeBr, the 5-HT_1A agonst 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and theN-methyl-d-aspartate (NMDA) antagonists MK-801 and CGS-19755 on performance of rats in a delayed matching-to-position task were examined. Pretreatment with scopolamine HBr (0.05 and 0.1 mg/kg), resulted in a delay-dependent decrease in the percentage of correct responses and discriminability (logd), but had no effect on either the latency to complete trials, or the rate of trial completion during the fixed duration session. Scopolamine MeBr (0.1 mg/kg) did not impair percent correct or increase the response latency but did decrease the rate of trial completion. 8-OH-DPAT (up to 0.3 mg/kg), had no effect on percent correct, but did induce a small decrease in discriminability. The impairment in discriminability occurred only at a dose that substantially reduced the rate of trial completion. Both MK-801 (0.05 mg/kg) and CGS 19755 (10 mg/kg) induced a delay-independent impairment in percent correct, discriminability and a reduction in the rate of trial completion without affecting latency. A lower dose of CGS 19755 (5.0 mg/kg) induced a slight impairment in discriminability without significantly affecting the other measures. Taken together, these results demonstrate some dissocation between drug-induced cognitive and motor/motivational deficits in the DMTP test. However, the data question the specificity of putative cognitive impairments reported in many previous studies with the 5-HT_1A agonist 8-OH-DPAT.     

Effects of benzodiazepine receptor ligands on the performance of an operant delayed matching to position task in rats: opposite effects of FG 7142 and lorazepam

The effects of a series of benzodiazepine (BZ) receptor ligands, ranging from a full agonist through to partial inverse agonists, were examined on short term working memory in the rat. The behavioural paradigm used was a discrete trial, operant delayed matching to position task, as originally described by Dunnett (1985), with delays of 0, 5, 15 and 30 s. The benzodiazepine receptor (BZR) full agonist lorazepam (0.25, 0.375 and 0.5 mg/kg) dose and delay dependently impaired matching accuracy. Lorazepam also increased the latency to respond and decreased the number of nose pokes made into the food tray during the delays. In contrast, the BZR partial agonist ZK 95 962 (1, 3, 10 mg/kg) did not affect matching accuracy, but did increase the speed of responding. The BZR antagonist ZK 93 426 (1.25, 5, 25 mg/kg) had no effects in this paradigm. The BZR weak partial inverse agonists Ro 15-4513 (0.1, 1 and 10 mg/kg) and ZK 90 886 (1, 3 and 10 mg/kg) did not affect accuracy of performance. However, both of these drugs increased the latency to respond and decreased nose poke responses. These motoric effects were particularly strong following 10 mg/kg Ro 15-4513. This shows that the effects of drugs on the accuracy of responding and on the speed of responding can be dissociated. The BZR partial inverse agonist FG 7142 had effects on matching accuracy that were dependent upon dose. The lowest dose of FG 7142 (1 mg/kg) significantly improved accuracy, whereas the highest dose (10 mg/kg) impaired accuracy. This impairment induced by FG 7142 (10 mg/kg) was accompanied by an increase in the latency to respond and a decrease in the number of nose pokes. Taken together, these results show that the accuracy of delayed matching performance can be modulated in opposite ways by the BZR full agonist lorazepam and a low dose of the BZR partial inverse agonist, FG 7142.