S.D. Iversen

The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor

The selective non-competitive NMDA receptor antagonist, MK-801, potently blocked convulsions induced in the mouse by N-methyl-DL-aspartic acid (NMDLA) with an i.v. ED50 dose of 0.2 mg/kg. Similar doses of MK-801 were also effective in blocking seizures induced by pentylenetetrazol (PTZ), electroshock and by sound in audiogenic seizure-prone animals. Other less selective non-competitive NMDA receptor antagonists including phencyclidine (PCP), thienylcyclohexylpiperidine (TCP), (+)-N-allylnormetazocine [+)-NANM, (+)-SKF 10,047) and ketamine also blocked NMDLA-induced seizures with a rank order of potency of MK-801 greater than PCP greater than TCP = (+)-NANM greater than ketamine. The competitive NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked NMDLA-induced seizures with an ED50 of 4.5 mg/kg, 22- and 560-fold more potently than the competitive antagonists, 2-DL-amino-7-phosphonoheptanoic acid (2-APH) and 2-DL-amino-5-phosphonovaleric acid (2-APV), respectively. MK-801 was the most potent of the non-competitive antagonists to induce a motor syndrome including head weaving, body rolling, increased locomotion and ataxia, characteristic of the behavioural response to PCP in the mouse. The syndrome was also present following injection of the competitive NMDA receptor antagonists, although they were generally less potent (probably a reflection of poor brain penetration) and less efficacious than the non-competitive antagonists. For all compounds except CPP, the anticonvulsant ED50 dose was close to the minimum effective dose to induce motor stimulation: CPP was 5- to 10-fold more potent as an anticonvulsant.(ABSTRACT TRUNCATED AT 250 WORDS)

The selective CCK-B receptor antagonist L-365,260 enhances morphine analgesia and prevents morphine tolerance in the rat

The effects of the selective CCK-A antagonist L-365,031 and the selective CCK-B antagonist L-365,260 on morphine analgesia and opiate tolerance and dependence in rats were examined. L-365,031 and L-365,260 had no effect on baseline pain thresholds in the radiant heat tail flick test but enhanced analgesia induced by a submaximal dose of morphine (4 mg/kg). Similarly, L-365,260 did not effect pain thresholds in the paw pressure test but enhanced morphine analgesia in this model. Rats injected twice daily for 6 days with incremental doses of morphine became tolerant to the analgesic effects of the drug. Twice daily injections of either 8 mg/kg L-365,031 or 0.2 mg/kg L-365,260 prevented the development of tolerance to morphine analgesia. In contrast, L-365,260 had no influence on the development of opiate dependence in these animals, as assessed by naloxone-precipitated withdrawal. The results of the present study, when considered together with previous data, indicate that the rank order of potency of non-peptide CCK antagonists for enhancing morphine analgesia is L-365,260 greater than MK-329 greater than L-365,031. This rank order correlates well with the potency of the antagonists in blocking CCK-B receptors in rodents and suggests that CCK/opiate interactions in this species are mediated by CCK-B receptors.

Delay-dependent short-term memory deficits in aged rats.

Separate groups of rats of three ages (6 month, 15 month or 24 month) were trained in a two-lever operant chamber on one of two versions of a paired-trial delayed response task involving either matching or non-matching of the choice response to a sample lever. The older rats were unimpaired in learning either version of the task during initial training with no (0 s) delay between the sample and choice responses. However, when variable 0–24 s delay intervals were introduced, the 24-month group was impaired on acquisition of the delayed non-matching task, and both the 15- and 24-month groups were impaired on acquisition of the delayed matching task compared to the 6-month group. Deficits in the older groups in asymptotic performance were attributable to an impairment at longer delay intervals whilst maintaining near perfect performance at the shorter delay intervals, suggesting a selective short-term memory impairment. The delay-dependent deficits of the older groups were not ameliorated by the muscarinic agonist arecoline or the cholinesterase inhibitor physostig-mine, and so failed to corroborate a cholinergic interpretation of the observed age-related impairment in short-term memory.

Topography of choline acetyltransferase Immunoreactive Neurons and fibers in the rat spinal cord

The topography of choline acetyltransferase immunoreactivity was studied in the rat spinal cord with a monoclonal antibody. Cholinergic fibers were most prominent in lamina III of the dorsal horn and originated from cholinergic neurons within the spinal cord. Lamina X, which was rich in cholinergic neurons and fibers, provided cholinergic interconnections between the dorsal, intermediate and ventral gray. Within the ventral gray, choline acetyltransferase immunoreactive boutons were found on motor neurons. This study suggests that the cholinergic innervation of the spinal cord arises from neurons intrinsic to the spinal cord. The cholinergic neurons within the spinal cord may provide several, overlapping levels of regulation of spinal cord neurons.

Evidence that the anxiolytic-like effects of chlordiazepoxide on the elevated plus maze are confounded by increases in locomotor activity

In exploratory animal models of anxiety, such as the elevated plus maze, the anxiogenic- and anxiolytic-like effects of drugs may be confounded by changes in locomotor activity. In the present experiments, the sensitivity of several measures of anxiety and locomotor activity in the elevated plus maze were assessed. Both chlordiazepoxide hydrochloride (CDP, 7.5 mg/kg) andd-amphetamine sulphate (AMP, 0.75, 1.5 mg/kg) increased the percent time on the open arms and doses of 7.5 mg/kg and 1.5 mg/kg CDP and AMP, respectively, increased the number of entries into the open arms. The increase in these measures might suggest that both compounds induced an anxiolytic-like effect. Although FG 7142 (30.0 mg/kg) did not decrease the number of entries to the open arms, it did decrease the time on the open arms, which might suggest that it had anxiogenic-like effects. Similarly, buspirone reduced both the number of entries into the open arms and the time spent on the open arms. However, all the compounds significantly affected locomotor activity. CDP (3.0 and 7.5 mg/kg) increased the total number of arm entries, the distance travelled on the open arms and the mean speed of the animals on the open, and in the closed arms. Moreover, the distance travelled by the animals in the closed arms was increased by 1.0 mg/kg CDP, a dose that had no measurable effects on the indices of anxiety. Similarly, although AMP failed to increase the total number of arm entries, it did increase the distance travelled in the closed arms (0.75 and 1.5 mg/kg), on the open arms (1.5 mg/kg) and the speed of the animals in the closed arms (1.5 mg/kg), a measure that is independent of the time spent in the closed arms. By contrast, both FG 7142 (30.0 mg/kg) and buspirone decreased the total number of arm entries (0.3–8.0 mg/kg), the speed of the animals in the closed arms and the distance travelled in the closed arms (1.0–4.0 mg/kg). These experiments suggest that: (i) the anxiogenic- and anxiolytic-like effects of drugs in the elevated plus-maze are confounded by changes in locomotor activity and that “total arm entries” is a relatively insensitive measure of drug-induced changes in locmotor activity; (ii) psychostimulant compounds, such as AMP, at doses that increase locomotor activity have an anxiolytic-like profile in the elevated plus maze and (iii) the measurement of speed of movement is a more sensitive index of changes in locmotor activity than the conventional measure of “total arm entries”.

Cholinergic grafts in the neocortex or hippocampus of aged rats: reduction of delay-dependent deficits in the delayed non-matching to position task.

Aged (24 month) rats have previously been shown to manifest delay-dependent deficits in the performance of an operant delayed non-matching to position task. In the present experiment, cholinergic-rich grafts implanted into either the neocortex or the hippocampus of aged rats are shown to reinnervate the host neocortex and hippocampus, respectively, and to provide a significant amelioration of the host animals short-term memory impairments. The results are discussed in light of the cholinergic hypothesis of geriatric memory dysfunction.

Impairment in T-maze reinforced alternation performance following nucleus basalis magnocellularis lesions in rats

Rats were trained on a reinforced alternation paradigm using an elevated T-maze. After pre-surgical training subjects received either ibotenic acid (4 micrograms/0.4 microliter) or vehicle (pH 7.4, 0.4 microliter) bilaterally into the region of the nucleus basalis magnocellularis--an important source of neocortical acetylcholine projections. Acetylcholinesterase staining of sectioned brains revealed a loss of neocortical, but not hippocampal staining in lesioned animals. On the T-maze task, lesioned rats showed significantly impaired choice performance relative to controls. They also demonstrated significant side biases, the degree of which was correlated with choice performance deficit.

Evidence that decreased feeding induced by systemic injection of cholecystokinin is mediated by CCK-A receptors

In the present study, we examined the effects of devazepide and L-365,260 on hypophagia induced by CCK in food-deprived rats

Behavioural and pharmacological characterization of the mouth movements induced by muscarinic agonists in the rat

Pilocarpine administered in doses of 1.25–10.0 mg/kg (IP) produced a variety of mouth movements in the rat. The most frequent of these movements was a chewing behaviour, which increased up to a mean frequency of over 40 per min at the highest doses. Tongue protrusion and gaping also showed dose-dependent increases. Yawning tended to increase in some doses, though these increases were not significant, and yawning was relatively infrequent. Pre-treatment with scopolamine reduced these responses, while pre-treatment with methyl scopolamine did not. Injections of oxotremorine or arecoline, but not carbachol, produced dose-related increases in mouth movements similar to those produced by pilocarpine. These results suggest that mouth movements in the rat are caused by stimulation of central muscarinic receptors. This may prove to be an important behavioural sign of central cholinomimetic activity.

One-trial tolerance to the effects of chlordiazepoxide on the elevated plus maze may be due to locomotor habituation, not repeated drug exposure.

The phenomenon of “one-trial tolerance” to the effects of chlordiazepoxide hydrochloride (CDP) in the elevated plus maze was re-examined. Unlike previous experiments, pre-exposure to the maze resulted in habituation and a consequential reduction in time spent on the open arms. The habituation effect was measured by recording the actual distance travelled by the rats in the maze and this was found to be significantly reduced by pre-exposure. Pre-exposure to the maze in the presence of CDP resulted in a reduced response to its “anxiolytic-like” effects (increasing time on the open arms compared to vehicle control rats). However, although the time spent on the open arms was reduced by pre-exposure, CDP significantly increased the time spent on the open arms by rats pre-exposed under a non-drugged state. These results suggest that rats do not become tolerant to the effects of CDP, but rather the reduced response to CDP after pre-exposure is due to habituation of exploratory behaviour.