The effects of pertussis toxin on dopamine D2 and serotonin 5-HT1A autoreceptor-mediated inhibition of neurotransmitter synthesis: relationship to receptor reserve.
Irreversible inactivation of striatal D2 dopamine (DA) autoreceptors with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) or inactivation of striatal guanine nucleotide binding proteins (G proteins) with pertussis toxin (PT) shifted the dose-response curve for N-n-propylnorapomorphine (NPA)-mediated inhibition of gamma-butyrolactone (GBL)-induced elevation of L-3,4-dihydroxyphenylalanine (L-DOPA) to the right, with a decrease in the maximum response. For the partial agonist (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(+)-3-PPP], in contrast, there was little shift in the ED50, after inactivation of either D2 receptors or G proteins. Completely analogous effects were found at the somatodendritic 5-HT1A autoreceptor in the raphe nuclei, mediating inhibition of the synthesis of serotonin (5-HT); the full agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the partial agonist, buspirone were utilized to inhibit the synthesis of 5-HT, as measured by changes in levels of L-5-hydroxytryptophan (5-HTP). Additionally, in both systems, combined treatment with pertussis toxin, followed by EEDQ, reduced the maximum effect, when compared to either agent alone but had little further effect on the ED50. In systems exhibiting a large receptor reserve for agonists, such as those described above, the same pattern of response seen after inactivation of receptors or G proteins may reflect the operation of a common mechanism underlying the phenomenon of receptor reserve.
Millhauser Laboratories, Department of Psychiatry, New York University Medical Center, NY 10016.
K
K
Bohmaker
F
F
Bordi
E
E
Meller
D006916:5-Hydroxytryptophan / Q000378:metabolism*; D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives / Q000494:pharmacology; D001921:Brain / Q000187:drug effects; D015259:Dopamine Agents / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D007980:Levodopa / Q000378:metabolism; D008297:Male; D018377:Neurotransmitter Agents / Q000096:biosynthesis*; D037342:Pertussis Toxin; D010880:Piperidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012266:Ribose / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D015259:Dopamine Agents; D018377:Neurotransmitter Agents; D010880:Piperidines; D011804:Quinolines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D010566:Virulence Factors, Bordetella; D007980:Levodopa; C009074:N-n-propylnorapomorphine; C000470:EEDQ; D012266:Ribose; C026539:preclamol; D006916:5-Hydroxytryptophan; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D001058:Apomorphine