Discriminative stimulus effect of flesinoxan: effect of 5-HT1A antagonists and PCPA.

Rats were trained to discriminate 0.3 mg/kg (IP) flesinoxan from saline in a standard two-lever operant procedure and thereafter subjected to generalization and antagonism tests with the 5-HT1A receptor agonist ipsapirone and the beta-adrenergic/5-HT1 receptor antagonist pindolol. Ipsapirone (3.0 mg/kg) completely substituted for flesinoxan. Both the flesinoxan (0.3 mg/kg) and the ipsapirone cue (3.0 mg/kg) were dose-dependently blocked by (+/-)-pindolol. In a second group of rats, trained to discriminate 0.5 mg/kg (IP) of flesinoxan from saline, the putative 5-HT1A antagonist NAN-190 (in the dose range of 1.0 to 6.0 mg/kg) partially blocked the cue of flesinoxan. Generalization studies revealed that the flesinoxan cue could not be mimicked by NAN-190 (3.0 mg/kg). Finally, rats were pretreated with the 5-HT depletor parachlorophenylalanine (PCPA) and thereafter tested with the flesinoxan training dose (0.5 mg/kg). PCPA pretreatment did not significantly attenuate the recognition of the flesinoxan cue. The present results are in agreement with previous findings concerning the stimulus effect of flesinoxan and point to a mechanism that involves the activation of 5-HT1A receptors in the brain. Depletion of 5-HT did not significantly affect the stimulus effect of flesinoxan, suggesting that presynaptic 5-HT1A receptors do not play a crucial role in the mechanism underlying the stimulus effect of flesinoxan.

Adrenoceptors and dopamine receptors are not involved in the discriminative stimulus effect of the 5-HT1A receptor agonist flesinoxan.

Using a two-lever operant drug discrimination procedure, rats were trained to discriminate the 5-HT1A receptor agonist, flesinoxan (0.5 mg/kg i.p.), from saline. Hereafter, several non-serotonergic drugs were tested in generalization and antagonism tests. The flesinoxan stimulus did not generalize to the stimuli of either the alpha 1-adrenoceptor antagonist, prazosin, the alpha 2-adrenoceptor agonist, clonidine, the dopamine receptor agonist, apomorphine, the dopamine receptor antagonists, haloperidol and pimozide, the benzodiazepine receptor agonist, chlordiazepoxide, nor to the peripherally acting vasodilator, hydralazine. In antagonism studies, prazosin, haloperidol, pimozide and the alpha 2-adrenoceptor antagonist, idazoxan, failed to block the flesinoxan stimulus. In substitution tests, however, flesinoxan partially generalized to idazoxan and completely to the alpha 2-adrenoceptor antagonist, yohimbine. The affinities of yohimbine and idazoxan for the 5-HT1A receptor may explain the latter result. The present findings suggest that the central mechanism through which flesinoxan exerts its discriminative stimulus effects does not involve alpha 1- and alpha 2-adrenoceptors, dopamine and benzodiazepine receptors. Finally, the results with the blood pressure lowering agents, hydralazine, clonidine and prazosin do not support the suggestion that the centrally mediated blood pressure lowering effects of flesinoxan contribute to its internal stimulus effect.

Dose-dependent discriminative stimulus properties of 8-OH-DPAT.

Separate groups of rats were trained to discriminate either 0.1mg/kg (low dose; L) or 2.5mg/kg (high dose; H) of 8-OH-DPAT from saline, in a standard operant task. Both cues were found to be dose, time and route dependent and generalized completely to the 5-HT(1A) agonists ipsapirone and flesinoxan. Buspirone substituted completely for 8-OH-DPAT in L and partially in H, whereas the 5-HT(1A/1B) receptor agonist eltoprazine substituted completely for 8-OH-DPAT in H but only partially in L. The 5-HT(1A/1B) receptor agonist RU24969, the 5-HT(1B/2C/1A) receptor agonist TFMPP and the 5-HT reuptake blocker fluvoxamine did not completely mimic the effect of 8-OH-DPAT in either L or H and the 5-HT(1A) mixed agonists/antagonists BMY 7378 and NAN-190 produced partial generalization in L, but no generalization in H. In antagonism tests, NAN-190 and BMY 7378 only partially blocked the 8-OH-DPAT cue in both groups. The non-selective 5-HT receptor antagonist methysergide did not completely block the 8-OH-DPAT cue in in L or H. However, in generalization studies, it completely mimicked the 8-OH-DPAT cue in L and produced partial generalization in H. The beta-adrenergic/5-HT(1A/1B) receptor antagonist pindolol completely blocked the 8-OH-DPAT cue in L and H and did not mimic the 8-OH-DPAT cue in either condition. The alpha(2)-adrenoceptor blocker yohimbine substituted fully for the 8-OH-DPAT cue in L and partially in H. Idazoxan did not substitute for the cue of 8-OH-DPAT in H, but produced nearly 80% generalization in L. The dopamine receptor antagonist pimozide neither blocked nor mimicked the cue of 8-OH-DPAT in either group. A number of other drugs (i.e. m-CPP, S(-)-propranolol, DOI, ketanserin, clonidine and apomorphine) were only tested in H. S(-)-Propranolol blocked the 8-OH-DPAT cue but the other compounds produced neither stimulus generalization nor antagonism. The present study demonstrates that the cues produced by the low and the high training dose of 8-OH-DPAT are quantitatively different and mediated by the agonistic activity of 8-OH-DPAT at 5-HT(1A) receptors. Although the results suggest that the 8-OH-DPAT cue (both L and H) is mediated via postsynaptic 5-HT(1A) receptors, the involvement of presynaptic 5-HT(1A) receptors cannot yet be ruled out.

Discriminative stimulus properties of the serotonergic compound eltoprazine.

The 5-hydroxytryptamine-1a/1b (5-HT1a/1b) agonist eltoprazine is the main representative of the so-called "serenics," a group of drugs sharing a specific antiaggressive activity. Rats were trained to discriminate an i.p. dose of 0.5 mg/kg of eltoprazine from saline in a two-lever operant drug discrimination task using a fixed ratio 10 schedule of food reinforcement. The cue of eltoprazine was found to be dose and time dependent. The eltoprazine stimulus generalized to the structurally related experimental drug fluprazine, the mixed 5-HT1a/1b agonist 5-methoxy-3-(1,2,3,6-tetrahydropyridinyl)-1H indole, (RU 24969), the 5-HT1b/1c agonist 1-[3-(trifluoromethyl)phenyl]piperazine, (TFMPP), the 5-HT1a agonist 8-hydroxy-2-(di-n-propylamino)tetralin-HB, (8-OH-DPAT), and the beta adrenergic/5-HT1 antagonists (+/-)-pindolol and (+/-)-propranolol. The eltoprazine cue partially generalized to the cues of the 5-HT1a agonists flesinoxan and buspirone, (m-CPP), the 5-HT1b/1c agonist 1,3-chlorophenyl-piperazine dihydrochloride and the 5-HT1c/2 antagonist mesulergine, and did not generalize to the 5-HT2/1c agonist DOI. During tests of antagonism, neither mesulergine, the nonspecific 5-HT antagonist methysergide, the 5-HT2 antagonist ketanserin, the 5-HT3 antagonist tropisetron (ICS 205-930), nor (+/-)-pindolol and (+/-)-propranolol attenuated the stimulus effect of eltoprazine. The specific beta adrenergic antagonist timolol did not substitute for eltoprazine. The present data show that eltoprazine can serve as a discriminative stimulus in rats and suggest that specifically 5-HT1 (i.e., 5-HT1a and 5-HT1b) receptors are involved in the stimulus properties of eltoprazine.(ABSTRACT TRUNCATED AT 250 WORDS)

Discriminative stimulus properties of flesinoxan.

Different groups of rats were trained to discriminate either 0.3 mg/kg of flesinoxan (N = 13) or 0.1 mg/kg of 8-OH-DPAT (N = 7) from saline in a two-lever operant drug discrimination task using a fixed ratio 10 schedule of reinforcement. Once trained, animals in both groups displayed a dose-related decrease in discriminative performance upon administration of lower doses of the drug used in training. In generalization tests, flesinoxan generalized to 8-OH-DPAT in 8-OH-DPAT-trained animals and 8-OH-DPAT substituted for flesinoxan in flesinoxan-trained animals. Buspirone substituted partially for both the flesinoxan and the 8-OH-DPAT cue. The results of the present study indicate similarity between the discriminative stimulus effects of flesinoxan and the stimulus produced by the 5-HT1A agonist 8-OH-DPAT. These results, coupled with the finding that flesinoxan has a significant affinity and selectivity for 5-HT1A binding sites, suggest that the stimulus effects of flesinoxan are mediated by a 5-HT1A mechanism.