Differential responsiveness of the rat dorsal and median raphe 5-HT systems to 5-HT1 receptor agonists and p-chloroamphetamine.
The dorsal and median raphe 5-HT neurons give rise to projections that differ in axon morphology and in vulnerability to certain amphetamine derivatives. The present study was undertaken to determine if these two 5-HT systems possess different functional properties. To this end, we studied the effects of selective 5-HT1A or 5-HT1A/5-HT1B receptor agonists and of p-chloroamphetamine on extracellular levels of indoleamines, as measured by differential pulse voltammetry with extracellular levels of indoleamines, as measured by differential pulse voltammetry with electrochemically pretreated carbon fiber electrodes, in cell body and nerve terminal regions of these subsets of 5-HT neurons in the rat brain. The selective 5-HT1A agonist 8-OH-DPAT produced a gradual decrease in the height of the 300 mV oxidation peak in the dorsal raphe and in the frontal cortex, reaching a maximum of 60% 3 h after the i.v. injection of 30 micrograms/kg. However, the same dose of 8-OH-DPAT was ineffective in the median raphe and in the dentate gyrus that receives its 5-HT innervation exclusively from the median raphe. A higher dose of 8-OH-DPAT (150 micrograms/kg, i.v.) produced a 60% decrease in the height of the 300 mV oxidation peak in the median raphe, whereas only a 20% decrease was obtained in the dentate gyrus. In contrast, the non-selective 5-HT1 agonist RU 24,969 (10 mg/kg, i.p.) caused a 70% reduction of the 300 mV peak height in both the dorsal and median raphe and a 50% decrease in both the frontal cortex and the dentate gyrus. Moreover, although a high dose of 8-OH-DPAT (150 micrograms/kg, i.v.) given alone reduced by 20% the amplitude of the oxidative peak in the dentate gyrus, subsequent administration of RU 24,969 (10 mg/kg, i.p.) caused a further 30% diminution of the oxidative peak height. The greater responsiveness of dorsal as compared to median raphe 5-HT systems to 5-HT1A receptor agonists was confirmed in two further series of experiments. First, the microiontophoretic application of 8-OH-DPAT directly onto 5-HT neurons was three times more potent in suppressing the firing rate of dorsal raphe 5-HT neurons than that of their median raphe congeners. Second, 8-OH-DPAT and buspirone were ten and four times, respectively, more potent in decreasing 5-HT synthesis in the frontal cortex than in the hippocampus.(ABSTRACT TRUNCATED AT 400 WORDS)
Blier
P
P
Biology Department Synthélabo Recherche-L.E.R.S., Bagneux, France.
Serrano
A
A
Scatton
B
B
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000200:Action Potentials / Q000187:drug effects; D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D010133:p-Chloroamphetamine / Q000494:pharmacology*
D000662:Amphetamines; D007211:Indoles; D009281:Naphthalenes; D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes; C025145:5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H indole; D012701:Serotonin; D010133:p-Chloroamphetamine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin