Alterations of central serotoninergic and dopaminergic neurotransmission in rats chronically treated with ipsapirone: biochemical and electrophysiological studies.
Inasmuch as sustained treatment with the 5-hydroxytryptamine1A (5-HT1A) agonist, ipsapirone, is necessary for inducing anxiolytic and antidepressant effects in the clinic, investigations were performed for assessing the possible changes in serotoninergic and dopaminergic neurotransmission in the brain of rats 24 hr after a 2-week treatment with this drug. Receptor binding assays with membranes and quantiative autoradiography indicated that the twice-daily administration of ipsapirone (5 mg/kg i.p.) for 14 days did not alter the characteristics of 5-HT1A sites in the hippocampus, septum and dorsal raphe nucleus. In contrast, significant decreases in the Bmax values for 5-HT2 sites (-24%) and 5-HT3 sites (-19%) were found in the frontal and posterior cortex, respectively. As expected from unchanged postsynaptic 5-HT1A receptors, inhibition of forskolin-stimulated adenylate cyclase by 5-HT1A agonists (8-hydroxy-2-(di-n-propylamino)tetralin, ipsapirone) exhibited the same characteristics in hippocampal homogenates from both control and ipsapirone-treated animals. An acute administration of 8-hydroxy-2-(di-n-propylamino)tetralin (0.5 mg/kg i.p.) or ipsapirone (1 or 5 mg/kg i.p.) 24 hr after the last injection for the chronic treatment produced a similar decrease in the rate of 5-HT turnover in various brain areas in rats treated for 2 weeks with saline or ipsapirone. At the highest dose (5 mg/kg i.p.), acute ipsapirone also increased the rate of dopamine turnover in the striatum and cerebral cortex approximately to the same extent in both treatment groups. In vitro recording of the firing of serotoninergic neurons in brain stem slices revealed a desensitization of the somatodendritic 5-HT1A receptors, which might be responsible for the increased 5-HT turnover in the brain stem and striatum of rats chronically treated with ipsapirone as compared with controls. These data demonstrated that chronically administered ipsapirone produces adaptive changes in central serotoninergic neurotransmission which might account for the anxiolytic and antidepressant properties of this drug after sustained treatment.
INSERM U 288, Neurobiologie Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
L E
LE
Schechter
F J
FJ
Bolaños
H
H
Gozlan
L
L
Lanfumey
S
S
Haj-Dahmane
A M
AM
Laporte
C M
CM
Fattaccini
M
M
Hamon
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D006916:5-Hydroxytryptophan / Q000096:biosynthesis; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites; D001679:Biogenic Amines / Q000378:metabolism / Q000502:physiology*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D001933:Brain Stem / Q000033:anatomy & histology / Q000648:ultrastructure; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D004334:Drug Administration Schedule; D004594:Electrophysiology; D006624:Hippocampus / Q000648:ultrastructure; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D008566:Membranes / Q000648:ultrastructure; D009474:Neurons / Q000502:physiology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000145:classification / Q000502:physiology; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013997:Time Factors
D001679:Biogenic Amines; D011743:Pyrimidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013764:Tetrahydronaphthalenes; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D004295:Dihydroxyphenylalanine; C043077:ipsapirone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D006916:5-Hydroxytryptophan; D000262:Adenylyl Cyclases; D004298:Dopamine; D006719:Homovanillic Acid