Hippocampal histamine receptors and conflictive exploration in the rat: studies using the elevated asymmetric plus-maze

The possible role of histamine receptors in the hippocampal formation on the exploratory motivation and emotionality of the rat was studied. An elevated asymmetric plus-maze composed of 4 different arms (no walls, single high wall, high and low walls and two high walls) arranged at 90 degrees angles was used. The exploration score, considered to be an index of exploratory motivation, and the permanency score, considered to be an index of emotionality (anxiety), were determined. Histamine was administered locally into the ventral hippocampus at three different doses (9,45 and 90 nmol). Another group of rats was also microinjected with 45 nmol of pyrilamine (a histamine H1 receptor antagonist) or ranitidine (a histamine H2 receptor antagonist) in addition to 9 nmol of histamine in order to identify the possible type of histamine receptor involved. Histamine administration significantly inhibited the exploration score and increased the permanency score at the doses of 9 and 45 nmol in two of four arms. These effects were completely blocked by the administration of eitheer histamine receptor antagonist. The present results suggest that in the hippocampal formation histamine inhibits exploratory motivation and decreases emotionality by activating both types of histamine receptors. Also, the elvated asymmetric plus-maze appears to be a suitable technique to quantify exploration and possibly "anxiety".

Effect of histaminergic drugs on integumental melanophores of adult Bufo melanostictus.

Histamine and 2-methyl histamine caused dose-dependent aggregation of melanophores in toad B. melanostictus. The effects were effectively antagonised by mepyramine, a specific H1 histamine receptor antagonist, and metiamide a specific H2 receptor antagonist. On the other, hand 4-methyl histamine, a specific H2 receptor agonist dispersed the melanophores. The results suggest that adult Bufo melanophores have H1 histamine receptors which mediate melanophore aggregation, however, dispersion of melanophores may be controlled by undifferentiated histamine receptors of H2 type.

"In vivo" and "in vitro" antitumoral action of Larrea divaricata cav

We previously reported that aqueous extract of Larrea divaricata Cav had an antiproliferative activity upon tumoral lymphoid cells (BW 5147), without affecting normal immunity. To determine the probable mechanism of the inhibitory action of the extract upon cell growth, the participation of intracellular signals involved in the inhibition of cell proliferation, namely the activation of adenylate cyclase system was studied. The production of cyclic 3', 5 adenosine monophosphate (cAMP) in presence and absence of extract was analized. The extract increased the cAMP levels, but neither the cAMP production nor the inhibitory effect of the extract on proliferation were blocked by a beta adrenergic receptor antagonist (propranolol) or by histaminergic receptor antagonistis (cimetidine and mepyramine). So, we concluted that the antiproliferative activity of the extract of BW 5147 cells would be mediated by an increase in cAMP intracellular levels no related to the activation of the membrane receptors here studied. In parallel, the extract was administered to a pregnant rat with a spontaneous mammarian carcinoma and "in vivo"antitumoral activity was found.

Hippocampus and learning. Possible role of histamine receptors

The effect of local adminstration of histamine and its receptor antagonists into the hippocampus on the learning process of an active avoidance response was studied. The task that the animals had to learn consisted in avoiding an electric shock on their feet after a conditioning ultrasonic 40 kHz tone was on. Latency time was defined as the time in serc rats took to avoid or escape the eletric shock: per cent CAR was defined as the cummulative positive responses during learning session. All rats were implanted into the ventral hippocampus with guide cannulae. On the day of the experiment, rats were microinjected through the guide cannulae with 1 mug of saline solution containing 67.5 nmol of ranitidine or pyrilamine alone or in combination with 45 nmol histamine. All groups were subjected to two sessions of learning. Results show that treatment with histamine was effective to block the adquisition of the response, since animals showed a learning curve significantly inferior to that of the controls. Ranitidine treatment was not able to block the histamine effect. Pyrilamine treatment, instead, was effective to block the inhibitory action of histamine on learning. Results suggest that histamine in hippocampus may be exerting a modulatory control on retrieval processes of memory.

Antihistaminic activity of quinethindole: a 2-substituted pyrazinopyridoindole derivative.

Quinethindole, a 2-substituted pyrazinopyridoindole, showed specific antihistaminic (H1) activity in various in vivo and in vitro test models. It also inhibited antigen-induced contraction of ileum of sensitized guinea pig. The antihistaminic activity was of competitive nature.

Effects of antihistamines on wound healing.

Role of antihistamines (H1 and H2 blockers) in wound healing by utilizing incision and dead space wound models in albino rats was investigated. H1 blockers (mepyramine and promethazine) were found to decrease breaking strength of 10 day old dermal incision wounds and collagen content (as hydroxyproline) and breaking strength of granulation tissue harvested over tubular implant. On the other hand H2 blockers (Cimetidine and ranitidine) did not alter the above parameters. The findings that H1 blockers suppress healing implicate H1 receptors in alleged prohealing effect of histamine, and suggest clinical evaluation of these agents for suppression of overhealing states like keloid, adhesions and strictures.

Role of endogenous opioids and histamine in morphine induced emesis.

The role of opioid and histaminergic system in morphine induced emesis was investigated in dogs. Morphine (25 micrograms, icv) consistently evoked emesis with an average latency of 195 +/- 29 sec which was fully accounted for by an action on the chemoreceptor trigger zone (CTZ) as its ablation rendered animals refractory to vomiting. Intraventricular pretreatment with opioid antagonist naloxone, histamine H1 antagonist mepyramine and H2 antagonists metiamide and cimetidine afforded protection to icv morphine emesis. The CSF histamine concentration was significantly raised 5 min after icv morphine administration. The results suggest that both endogenous opioid and histamine are involved in morphine emesis. Naloxone in high doses (1600 micrograms, icv) elicited emesis which was not blocked by CTZ ablation confirming our earlier report.

Demonstration of histamine receptors on the surface of Entamoeba histolytica.

Histamine receptors on the surface of E. histolytica could be demonstrated by histochemical method using three isolates of the protozoa grown and maintained in modified Boeck and Drbohlav's medium. Prior treatment of E. histolytica with cimetidine a H2 blocker, blocked the histamine uptake. Similar treatment with mepyramine maleate, a H1 blocker, did not prevent histamine uptake by the protozoa. It is postulated that E. histolytica has H2 receptors on its surface.

Involvement of histamine receptors in mediation of histamine induced thermoregulatory response in rats.

At there ambient air temperature range, the rectal temperature changes following infusion of histamine either into lateral ventricle (L.V.) or IVth ventricle (IVth V) were studied. At an ambient temperature range of 19-22 degrees C, hypothermia occurred following histamine infusion either into L.V. or IVth V. Hypothermia elicited from infusion of histamine into L.V. was prevented with pretreatment of H1-receptor blocker (mepyramine), but in case of IVth V, it was prevented with H2-receptor blocker(cimetidine). These H1 and H2-receptor antagonists were ineffective in preventing hypothermia following histamine infusion into either L.V. or IVth V, when the ambient air temperature was maintained low (11-13 degrees C).

Evidence for histamine and 5-hydroxytryptamine like effects of MK-212 on guinea pig ileum, taenia coli and rat fundus strip.

MK-212 (1 x 10(-7)M -- 1 x 10(-5)M) produced dose-dependent contractions of guinea pig ileum, taenia coil and rat fundus strip. The responses to MK-212 in all three preparations were blocked competitively by cyproheptadine (1 x 10(-8)M) a 5-HT receptor antagonist. Mepyramine (1 x 10(-8)M)-H1 receptor antagonist also inhibited competitively the responses of guinea pig ileum and taenia coli to MK-212. However, it failed to block significantly the responses of rat fundus strip to MK-212. Metiamide (1 x 10(-6)M), propranolol (1 x 10(-6)M) or atropine (1 x 10(-6)M) did not produce any significant effects on MK-212 induced contractile responses of guinea pig ileum, taenia coli and rat fundus strip. Our findings suggest that MK-212 produces both 5-HT as well as histamine like effects on the guinea-pig ileum, taenia coli and rat fundus strip.

Effect of mepyramine on the histaminase release induced by heparin injection and anaphylaxis in guinea pigs.

Injection of heparin as well as antigenic challenge in sensitized guinea pigs are known to produce a release of histaminase into the plasma. In the present study, tissue histaminase estimation was done by Spencer's method (17) and plasma estimation by Kapellar Adler's (7) method. Mepyramine pretreatment considerably decreased the histaminase release by both heparin and anaphylaxis. Mepyramine did not antagonise the anticoagulant action of heparin in vitro.