Behavioural activity of rats measured by a new method based on the piezo-electric principle

Spontaneous and drug-induced (haloperidol, apomorphine, and amphetamine) motor activity of rats was measured simultaneously via two distinct and independent methods: the classical optical scanning technique and a new procedure based on the piezo-electric principle. The latter procedure measured animal-induced mechanical vibrations of a flexible cage floor which were transduced into electric signals via piezo-electricity. The piezo method appeared to be relatively more sensitive in recording the small, stereotyped motor movements induced by apomorpine (0.63–10 mg/kg) and high doses of amphetamine (2.5–20 mg/kg). The optical scanning technique, on the other hand, was more sensitive in recording horizontal displacements across the cage such as induced by low doses of amphetamine (0.31–2.5 mg/kg). Both methods showed comparable sensitivity in recording the depression of behaviour induced by haloperidol (0.04–1.25 mg/kg) or low doses of apomorphine (0.04–0.16 mg/kg). The piezo method may complement the optical scanning procedure, and thereby enhance the information on the extent that test compounds modify animal behaviour.     

Loperamide

In castor oil challenged rats, low doses of loperamide inhibit diarrhea and normalize intestinal propulsion. Unlike other opioids, loperamide is devoid of central opiate-like effects, including blockade of intestinal propulsion, up to the highest subtoxic oral dose. Nevertheless, the antidiarrheal action of loperamide can be considered to be -opiate receptor mediated, only a fewin vitro effects at rather high concentrations being not naloxone-reversible. There is little evidence that interactions with intestinal opiate receptors directly change epithelial cell function. When secretory stimuli increase mucosal tension, however, loperamide may reverse the elevated hydrostatic tissue pressure that opposes normal absorption. This antisecretory effect at the mucosal level is accompanied by motor effects when loperamide reaches the myenteric -opiate receptors. At therapeutic doses for the treatment of acute diarrhea, it is likely that the mucosal effect prevails.     

Antiemetic specificity of dopamine antagonists

Twelve antagonists of apomorphine-induced emesis in dogs were studied in different tests to evaluate their antiemetic specificity. Ten of these antagonists were neuroleptics: benzquinamide, clebopride, bromopride, prochlorperazine, haloperidol, chlorpromazine, thiethylperazine, metoclopramide, droperidol, and pimozide blocked conditioned responding in dogs and apomorphine-induced stereotyped behavior in rats. The use of these compounds as anti-emetics entails a risk of neurological side effects. Metopimazine and domperidone were devoid of neuroleptic activity. Metopimazine, however, showed potent -adrenergic blocking activity, showed histamine H₁ antagonism, and induced palpebral ptosis. Therapeutic doses of metopimazine are, therefore, likely to produce sedation and side-effects related to autonomic blockade. Domperidone showed potent antiemetic activity and, up to high doses, no other central or peripheral effects. Therefore, domperidone is the only specific antiemetic known.     

Gastrointestinal effects and acute toxicity of suprofen.

The acute effects of orally administered, high doses of alpha-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen) were studied in various tests, related to gastrointestinal functions. A decrease of the diarrheal stools in the castor oil test in rats was the first effect noted; the ED50 in this test was 40 mg/kg. This dose is 540 times higher than the ED50 of suprofen in the acetic acid-induced writhing test in rats (ED50 = 0.074 mg/kg). Temporarily decreased food consumption in rats was first noted after administration of 80 mg/kg. This is more than 1000 times the ED50 in the rat anti-writhing test. The appearance of gastrointestinal lesions was also studied in rats and a direct quantitative comparison was made with indometacin, acetyl-salicylic acid and ketoprofen. The dose of suprofen that produced lesions in 50% of the rats was 200 mg/kg, viz. 2700 times the ED50 in the rat anti-writhing test. Similarly obtained safety margins are 9.0 for indometacin, 78 for acetyl-salicylic acid and 102 for ketoprofen. The mortality after a single oral administration of suprofen was studied in mice, rats, guinea-pigs and dogs. LD50-values, based on mortality 7 days after administration, were 590 mg/kg, 353 mg/kg, 280 mg/kg and more than 160 mg/kg, respectively. Comparative LD50's in mice and rats were 14 and 19 mg/kg for indometacin, 280 and 70 mg/kg for ketoprofen. Therefore the safety margin in rats, with respect to the ED50 in the acetic acid-induced writhing test, is 4770 for suprofen, 156 for ketoprofen and 17.3 for indometacin. In guinea-pigs the safety margin of suprofen is 1470 with respect to the ED50 in UV-erythema and in dogs more than 250 with respect to the ED50 in urate-induced arthritis. From these data we may conclude that suprofen is comparatively safer than the reference compounds studied and that its effects on the gastrointestinal tract appear at doses far above those required for effectiveness in tests related to pain, fever and inflammation.     

Discriminative stimulus properties of cocaine and d-amphetamine,and antagonism by haloperidol: A comparative study

This paper presents a comparative study of the discriminative stimulus properties of cocaine and d-amphetamine in the rat. Using a discrete-trial, food-reward, two-lever drug discrimination procedure, one group of rats (n = 7) were trained to discriminate 10 mg/kg cocaine from saline, whereas 1.25 mg/kg d-amphetamine served as a cue to a second group (n = 6). Following training, stimulus generalization gradients were determined for cocaine and d-amphetamine in both groups, and so were the antagonistic effects of haloperidol vs the training drug conditions. The results indicate that the acquisition of discrimination proceeded at a comparable rate in the two groups. In both groups, d-amphetamine was about 5 times more potent than cocaine, and individual threshold doses for the two drugs showed a significant correlation. Haloperidol appeared equally effective in antagonizing 1.25 mg/kg d-amphetamine and 10 mg/kg cocaine. These findings converge to suggest that to a large extent the cueing properties of d-amphetamine and cocaine are similar.     

Intracranial self-stimulation in rats as a function of various stimulus parameters

The effects of different subcutaneous doses (0.08, 0.16, 0.31, 0.63 and 1.25 mg/kg) of apomorphine on self-stimulation in rats, with monopolar nichrome electrodes, implanted in the medial forebrain bundle at the level of the lateral hypothalamus were studied. Six different selected stimulus parameter combinations inducing different predictable response rates were used. Apomorphine was found to produce a dose-related response stimulation and a dose-related response depression. The highest stimulation was obtained at 0.63 mg/kg, the highest depression at 1.25 mg/kg. The response stimulation with apomorphine was 1. inversely related to the control response rate, i.e. the higher the control response rate, the lower the response stimulation after apomorphine and vice versa, 2. directly related to the control response rate of the individual rats, i.e. the highest response stimulation was obtained with the most sensitive rat and vice versa. The response inhibition with apomorphine was not related to the control response rates but was more pronounced during the first 1/2 h of the session. It is postulated that

1. increased self-stimulation with apomorphine could be the result of an increased motor response output;
2. decreased self-stimulation with apomorphine could be due to non-adaptive behaviour as a result of non-physiological overexcitation with interruption of integrated behaviour;
3. a complex behavioural pattern like intracranial self-stimulation depends on different interacting systems, mediated by different transmitters.

     

Rapid desensitization and down-regulation of 5-HT2 receptors by DOM treatment

The regulation of the 5-HT2 receptor-mediated head twitch response and of 5-HT2 receptor binding in the frontal cortex was studied in rats treated repeatedly with the 5-HT2 agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) (2.5 mg/kg, s.c.). Four injections in 24 h produced a near maximal reduction in the behaviour (-70%) and in the Bmax for [3H]ketanserin binding (-41%). The KD values tended to increase slightly. 5-HT2 receptors reappeared, with half-lives of 5.5 to 3 days. In view of the reported anomalous 5-HT2 receptor regulation by antagonists and the regular regulation by agonists, we propose a refinement in the receptor regulation theory.     

The pharmacological profile of a specific,safe, effective and non-sedative anti-allergic,astemizole

In the compound 48/80 lethality test in rats, which is based on the specific activation of mast cells, astemizole was selected as a potent, long-acting and orally very effective inhibitor of anaphylactoid shock. In comparison to other histamine-H₁ antagonists astemizole was also a very effective inhibitor of allergic reactions in rats and dogs and remarkably free of non-specific interactions with other biological amines and normal body functions. In numerous tests no evidence of central activity was found and toxicity studies have shown astemizole to be a very safe drug despite of its long duration of action. A daily dose of 10 mg of astemizole was found clinically free of side-effects and more effective than conventional antihistamine treatment.