Variability in the effects of 5-HT-related compounds in experimental models of anxiety: evidence for multiple mechanisms of 5-HT in anxiety or never ending story?
To date, more than two thousand experiments have investigated the behavioral effect of 5-HT-interacting drugs in animal models of anxiety disorders. Most of them have focused on the involvement of drugs interacting with 5-HT1A, 5-HT2A/2C and 5-HT3 receptors. Although numerous results are in line with the classic 5-HT hypothesis of anxiety, suggesting that decreased anxiety is related to decreased activity in central 5-HT neurons and vice versa, paradoxical drug effects have often been found. To explain this variability, several authors point to a determining role of the experimental paradigms used. In fact, an overview of the behavioral data arising from the vast literature indicates that conditioned procedures as well as more ethological-based tests are equal in revealing anxiolytic-like effects of drugs targetting 5-HT1A, 5-HT2A or 5-HT2C receptor subtypes. Furthermore, results obtained in ethologically-based animal models of anxiety with drugs stimulating 5-HT transmission are most consistent with the classic 5-HT hypothesis of anxiety in that they showed an increase in animals' emotional reactivity. Finally, anxiolytic-like effects of 5-HT3 receptor antagonists are in great part revealed by models based on spontaneous behaviors. Taken together, these observations lead to the conclusion that different 5-HT mechanisms, mediated by different receptor subtypes, are involved in the genesis of anxiety.
Griebel
G
G
CNS Research Department, Synthélabo Recherche, Bagneux, France.
D000818:Animals; D001007:Anxiety / Q000503:physiopathology*; D001522:Behavior, Animal / Q000187:drug effects; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects; D044263:Receptors, Serotonin, 5-HT1; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology
D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin