Administration Of Selective Antagonist Research Articles

The Effects of Systemic Administration of Selective Antagonists of Dopamine D1 and D2/D3 Receptors on Food-Related and Defensive (escape responses) Conditioned Paw-Placing Responses in Cats

Experiments were performed on cats to study the effects of systemic administration of antagonists of dopaminergic transmission on food-related and defensive (an escape response) operant conditioned reflexes acquired on the basis of the innate response of placing the forepaw on a support. Selective blockade of D1 receptors with SCH23390 (0.005-0.1 mg/kg) completely and selective blockade of D2/D3 receptors with raclopride (0.1-0.25 mg/kg) partially suppressed both reflexes. At these doses, both blockers had stronger actions on the defensive conditioned escape reflex than the food-related reflex: SCH23390 had significantly stronger inhibitory effects on both reflexes than raclopride.

Effects of Neuropeptides on the Sumatriptan-Disturbed Circulation in the Optic Nerve Head of Rabbits

The purpose of this work was to study ‘in vivo’ the vascular responses of retinal vessels of New Zealand white rabbits to substance P (SP), neurokinin A (NKA), neurokinin B (NKB), senktide, capsaicin (CAPS), and calcitonin gene related peptide (CGRP) before and after selective antagonist administration. We examined the effects of these neuropeptides on the normal circulation in the optic nerve head of the rabbit. Drugs were injected via pars plana through a micropipette system. Ten minutes before perivascular injection of 10 nmol/l sumatriptan (to contract the vessel), a selective antagonist or its solvent was administered. Then, cumulative injection of the agonist was performed. The other eye was used as control. Direct measurement of retinal arteriole diameters was performed using digital angiography. The quantification of the relaxing effect is expressed as percentage related to the precontracted vascular diameter. Microinjection of SP (NK1 receptor agonist) up to 10 nmol/l induced a dose-dependent arteriolar dilating effect [E_max (mean ± SEM) 21.3 ± 2.3%]. After the perivascular preinjection of 1 nmol/l L-668,169 or 1 nmol/l L-733,060 (NK1 receptor antagonists), the SP dose-response curve was shifted to the right. The same results were obtained with NKA (NK2 receptor agonist) which induced the most potent effect of all neuropeptides (E_max 53.3±2.5%). The NK2 receptor antagonists L-659,877 and GR 159897 (1 nmol/l) strongly inhibited this arteriolar vasodilation. As for CGRP, doses up to 10 nmol/l induced a marked vasodilation (E_max 41.1±0.4%) which decreased after microinjection of the selective antagonist CGRP8-37. The NK3 receptor agonists (senktide and NKB) showed a minor vasodilating effect (E_max 5.1±1.2 and 8.0±0.9%, respectively). On the contrary, CAPS showed a marked dose-dependent vasodilating effect (E_max 43.2±2.9%), antagonized by the tachykinin receptor antagonists and CGRP8-37. These results suggest, for the first time, the presence of NK1, NK2, and CGRP receptors on the retinal arteriolar wall of the rabbit.

Central α-adrenergic receptors and corticotropin releasing factor mediate hemodynamic responses to acute cold stress

Behavioral stress is likely to contribute to the development of hypertension in susceptible individuals. We reported that hemodynamic response patterns to acute startle vary and that those patterns predict the predisposition of rats to sustained stress-induced elevations in arterial pressure. Since considerable evidence suggests that central catecholamines and corticotropin releasing factor (CRF) contribute to the regulation of arterial pressure and the development of hypertension, we investigated the role of central α-adrenergic receptors and CRF in mediating different hemodynamic response patterns to acute cold water stress in conscious rats. Rats were instrumented for arterial pressure, heart rate and cardiac output determination and for intracerebroventricular (icv) administration of selective antagonists. After acclimation to a water tight cage, ice water (1 cm deep) was rapidly added then drained 1 min later. Although the early startle response to cold water stress elicited a pressor response in all rats, the hemodynamic response pattern varied between rats. Vascular responders ( n=19) had an initial considerable increase in systemic vascular resistance and a decrease in cardiac output. In contrast, mixed responders ( n=11) had a smaller increase in vascular resistance and an increase in cardiac output. Pretreatment with phentolamine (30 μg/5 μl, icv, n=8), prazosin (10 μg/5 μl, icv, n=12) or α-helical CRF 9–41 (10 μg/5 μl, icv, n=9) prevented the decrease in cardiac output elicited by acute cold water stress in vascular responders without affecting mixed responders. Yohimbine (3 μg/5 μl, icv, n=8) pretreatment did not alter hemodynamic responses. Therefore, we conclude that central α 1-adrenoceptors and CRF mediate the specific hemodynamic response patterns to acute startle and may be responsible for the predisposition to develop hypertension in vascular responders.

Concurrent blockade of hippocampal metabotropic glutamate and N-methyl-D-aspartate receptors disrupts working memory in the rat.

In order to clarify the roles of hippocampal metabotropic glutamate and N-methyl-D-aspartate receptors in working and reference memory performance of rats, the effects of intrahippocampal administration of selective antagonists for both receptors on these behaviours were examined with a three-panel runway task. In the working memory task, the potent and competitive N-methyl-D-aspartate receptor antagonist, (+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points), when injected bilaterally at 10 and 32 ng/side into the dorsal hippocampus. Intrahippocampal injection of CPP at a dose of 3.2 ng/side had no effect on the number of working memory errors. The metabotropic glutamate receptor antagonist, (+)-alpha-methyl-4-carboxyphenylglycine (+)-(MCPG), injected into the hippocampus at doses up to 3.2 micrograms/side, did not significantly affect the number of working memory errors. Combined administration of (+)-MCPG (3.2 micrograms/side) and CPP (3.2 ng/side) into the hippocampus, neither of which had an individual effect on errors, significantly increased the number of working memory errors. However, intrahippocampal administration of the relatively inactive isomer, (-)-MCPG, at 3.2 micrograms/side did not affect working memory errors, whether given independently or concurrently with the behaviourally ineffective dose of CPP (3.2 ng/side). In the reference memory task, intrahippocampal injection of CPP at doses up to 32 ng/side had no effect on the number of errors. Intrahippocampal (+)-MCPG at doses up to 3.2 micrograms/side did not affect the number of reference memory errors, whether administered alone or together with 3.2 ng/side of CPP. These results indicate that blockade of hippocampal metabotropic glutamate receptors aggravates impairment of working memory resulting from deficiency of N-methyl-D-aspartate receptor-mediated glutamatergic neurotransmission, suggesting that mechanisms regulated by co-activation of hippocampal metabotropic glutamate and N-methyl-D-aspartate receptors are involved in working memory performance of rats.

Localization of dopamine receptor subtypes occupied by intra-accumbens antagonists that reverse cocaine-induced locomotion

The purpose of this study was to examine whether blockade of either dopamine D1-like or D2-like receptors by selective antagonist administration into the nucleus accumbens (NAc) is sufficient to reverse cocaine-induced locomotion, and to develop a new technique that enables the population of receptors occupied by the antagonists to be quantified. Locomotor activity was assessed in rats that had received bilateral intra-accumbens injections of the D1-selective antagonist SCH-23390 (0–3.0 μg/0.5 μl/side) or the D2/D3-selective antagonist sulpiride (0–1.0 μg/0.5 μl/side), followed 15 min later by injections of saline or cocaine (15 mg/kg, i.p.). To assess receptor occupancy by the antagonists, 105 min prior to sacrifice the rats received intra-accumbens injections of the antagonist, followed 15 min later by an injection of the non-selective irreversible antagonist, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 10 mg/kg, i.p.). Receptors were labeled with [ 3H]SCH-23390 or [ 3H]sulpiride in sections containing the NAc, and the autoradiograms allowed quantitation of receptors occupied (i.e. protected from EEDQ) by the antagonist given in vivo. Only a dose of 3 μg/side SCH-23390 reversed cocaine-induced locomotion, whereas a dose of 0.5 μg/side did not alter cocaine-induced locomotion despite occupying the same amount of [ 3H]SCH-23390 binding sites in the NAc. Intermediate doses of 0.1 and 0.3 μg/side sulpiride reversed cocaine-induced locomotion, and also occupied the greatest number of [ 3H]sulpiride binding sites in the NAc. The results suggest that blockade of D2-like, but not D1-like, receptors in the NAc is sufficient to reverse cocaine-induced locomotion, and also demonstrate the importance of quantifying receptors occupied by drugs administered intracranially.

Mechanisms by which cancer chemotherapeutic drugs induce emesis.

Because the area postrema seems essential for chemotherapy-induced vomiting, both circulating and/or neurally mediated stimuli in this area could trigger the emetic response. In our laboratories results of cross-circulation and direct intracerebroventricular infusion experiments in dogs do not support a role for circulating substances. The large increases in serum vasopressin induced by cisplatin were not blocked by inhibitors of the angiotensin-converting enzyme. In the ferret inhibition of serotonin synthesis with p-chloro-phenylalanine, administration of selective antagonists of 5-hydroxy-tryptamine3 (5-HT3) receptors, or visceral deafferentation inhibited the emetic response evoked by cisplatin or high-dose cyclophosphamide. The results suggest that serotonin plays an important role and that peripheral neural mechanisms are involved in the emetic response. The strong antiemetic efficacy of selective 5-HT3 antagonists also has been confirmed in humans. In cancer patients high-dose cisplatin increased the plasma and urinary levels of 5-hydroxy-indoleacetic acid (5-HIAA), but did not affect platelet and free plasma serotonin. The changes in 5-HIAA levels paralleled the onset and development of vomiting. No evidence of serotonin depletion has been obtained after high-dose cisplatin. Dacarbazine, another strongly emetogenic agent, increased urinary 5-HIAA; however, only small increases in 5-HIAA were produced with low-dose cisplatin or cyclophosphamide-containing regimens. Thus, emetogenicity appears to be directly related to the ability of the cytotoxic agent to release serotonin. In humans, antiemetics such as ondansetron, metoclopramide, and dexamethasone did not effect high-dose cisplatin-induced increases in serotonin metabolism. Therefore, these antiemetics seem not to affect the amount of serotonin released. The mechanism by which chemotherapeutic drugs induce serotonin release is unknown; however, release may occur by direct cytotoxicity on the gastrointestinal mucosa, including the enterochromaffin cells. Delayed emesis appears to be mediated by 5-HT3-independent mechanisms. It is proposed that emesis that develops despite high-dose ondansetron (residual emesis) should be considered delayed emesis. Residual and delayed episodes of emesis have similar time courses, are characterized by very mild emetic episodes and poor response to 5-HT3 antagonists, and are not associated with increases in serotonin metabolism.