Enhancement of the acoustic startle response by dopamine agonists after 6-hydroxydopamine lesions of the substantia nigra pars compacta: corresponding changes in c-Fos expression in the caudate-putamen.
Rats with 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway show enhanced locomotor and stereotyped behaviors when challenged with direct and indirect dopamine (DA) agonists due to the development of postsynaptic supersensitivity. To determine if this phenomenon generalizes to other motor behaviors, we have used this rat model of Parkinson's disease to examine the effects of the direct dopamine D(1) receptor agonist SKF 82958 and the indirect DA agonist L-3,4-dihydroxyphenylalanine (L-DOPA) on the acoustic startle response. In addition, we used the expression of c-Fos protein as a marker of neuronal activity to assess any corresponding drug-induced changes in the caudate-putamen (CPu) after L-DOPA administration. Male Sprague-Dawley rats received bilateral injections of 6-OHDA into the substantia nigra pars compacta and 1 week later were tested for startle after systemic administration of SKF 82958 (0.05 mg/kg) or L-DOPA (1, 5, 10 mg/kg). SKF 82958 produced a marked enhancement of startle with a rapid onset in 6-OHDA-lesioned but not SHAM animals. L-DOPA produced a dose- and time-dependent enhancement of startle in 6-OHDA-lesioned rats that had no effect in SHAM animals even at the highest dose (10 mg/kg). Furthermore, L-DOPA produced a dramatic induction of c-Fos in the CPu in 6-OHDA-lesioned animals. Consistent with other literature, these data suggest that neurons in the CPu become supersensitive to the effects of DA agonists after 6-OHDA-induced denervation of the nigrostriatal pathway and that supersensitive dopamine D(1) receptors may mediate the enhancement of startle seen in the present study.
Meloni
E G
EG
The Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA. emeloni@emory.edu
Davis
M
M
D000161:Acoustic Stimulation; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002421:Caudate Nucleus / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D016762:Genes, fos; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D016627:Oxidopamine; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D011699:Putamen / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects* / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology*
D001552:Benzazepines; D018491:Dopamine Agonists; D016760:Proto-Oncogene Proteins c-fos; D007980:Levodopa; C071262:SK&F 82958; D016627:Oxidopamine