ABSTRACT
Fluoxetine, a selective serotonin reuptake inhibitor, shows moderate efficacy and potency in the rat forced swimming depression test and the shock-induced ultrasonic vocalization anxiety test, whereas the 5-HT(1A) receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is highly efficient and potent in both models. Whereas the 5-HT(1A) receptor antagonist WAY 100,635 abolishes the effect of 8-OH-DPAT in both models, it only attenuates the antidepressant-like effect of fluoxetine. Pretreatment with the 5-HT-depleting agent parachlorophenylalanine attenuates the antidepressant-like effect of fluoxetine, but not that of 8-OH-DPAT. This suggests that the antidepressant-like effect of fluoxetine and 8-OH-DPAT results from indirect (via increased synaptic availability of 5-HT) and direct stimulation of postsynaptic 5-HT(1A) receptors, respectively; whereas the anxiolytic-like effect of fluoxetine is not mediated by 5-HT(1A) receptors. The data support the hypothesis that the antidepressant- and anxiolytic-like effect of 8-OH-DPAT is predominantly mediated by post- and presynaptic 5-HT(1A) receptors, respectively, and that 5-HT(1A) receptors are only partially involved in the antidepressant-like effect of fluoxetine.
Subject(s)
8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Anti-Anxiety Agents/pharmacology , Antidepressive Agents, Second-Generation/pharmacology , Antidepressive Agents/pharmacology , Fluoxetine/pharmacology , Receptor, Serotonin, 5-HT1A/drug effects , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin Receptor Agonists/pharmacology , Animals , Anxiety/psychology , Behavior, Animal/drug effects , Dose-Response Relationship, Drug , Fenclonine/pharmacology , Male , Piperazines/pharmacology , Pyridines/pharmacology , Rats , Rats, Wistar , Receptors, Presynaptic/drug effects , Receptors, Presynaptic/metabolism , Serotonin Antagonists/pharmacology , Swimming/psychology , Vocalization, Animal/drug effectsABSTRACT
Calcium (Ca(2+)) channels appear to be involved in the regulation of ethanol (EtOH) intake, as indicated by the effectiveness of both L-type Ca(2+) channel antagonists and agonists in reducing EtOH intake in animals. The present study was aimed to investigate rewarding/aversive and discriminative stimulus effects of the Ca(2+) channel agonist BAY k 8644, a compound showing pronounced anti-alcohol effects in rats. Therefore, a series of conditioned taste aversion (CTA), conditioned place preference (CPP) and two-lever drug discrimination (DD) experiments were conducted in Wistar rats, with (+/-)-BAY k 8644 and its enantiomers. After i.p. application, (+/-)-BAY k 8644 (0.0625-1mg/kg), (-)-BAY k 8644 (0.125-1mg/kg) and (+)-BAY k 8644 (2.5-20mg/kg) all induced a dose-dependent CTA. The minimal effective doses (MED) for (+/-)-, (-)- and (+)-BAY k 8644 were 0.25, 0.25 and 10mg/kg, respectively. In a CPP study, however, (+/-)-BAY k 8644 (0.25-2mg/kg, i.p.) showed neither aversive nor rewarding stimulus properties. Rats were trained to discriminate (-)-BAY k 8644 (0.3mg/kg, i.p.), the enantiomer acting as a high potency Ca(2+) channel agonist, from vehicle, in a two-lever DD procedure (ED(50)) value: 0.05mg/kg); full generalisation: 0.1mg/kg). The (-)-BAY k 8644 cue dose-dependently generalized to (+/-)-BAY k 8644 and (+)-BAY k 8644, the enantiomer acting as a low potency Ca(2+) channel antagonist, with ED(50) values of 0.06 and 0.28mg/kg, respectively. Both (+/-)- and (+)-BAY k 8644 produced full generalization at 1mg/kg, the latter compound showing an inverted U-shaped curve (i.e., this was the only dose showing >80% drug lever selection). The stimulus patterns of BAY k 8644 and its enantiomers appear to resemble the anti-alcohol profiles of these compounds. Therefore, commonalities between the stimulus properties of the agonistic and antagonistic enantiomers might provide a clue for the mechanism underlying the anti-alcohol effects of L-type Ca(2+) channel antagonists and agonists.
ABSTRACT
In the rat shock-induced ultrasonic vocalization test, the anxiolytic effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) obtained after systemic (IP) and intracerebral injection into the dorsal raphe nucleus (DRN) were selectively abolished by pretreatment with the 5-HT1A receptor antagonist WAY-100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclo-hexane-carboxamide trihydrochloride]. This blockade was demonstrated both after systemic and DRN application of WAY-100635. Therefore, it is concluded that the anxiolytic effects of 8-OH-DPAT are mediated by activation of somatodendritic 5-HT1A receptors.
