Early L-dopa treatment initially retards but later enhances dopamine receptor supersensitivity following unilateral dopamine denervation.
Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of nigrostriatal dopamine neurons were administered 25 mg/kg L-DOPA methyl ester/2 mg/kg carbidopa once or twice per day or saline in separate treatment groups for 13 days. Treatment was initiated within 18-20 h postoperative, well-before the onset of denervation supersensitivity. Contralateral rotation emerged as a response to L-DOPA on day 7 postoperative first in the L-DOPA once/day group and then on day 9 for the L-DOPA twice/day group. Thus, early postoperative L-DOPA treatment retarded but did not prevent the development of dopamine receptor supersensitivity. Following a 14-day withdrawal period, these same L-DOPA treated groups exhibited substantially higher rates of contralateral rotation to an L-DOPA challenge as compared to a drug-naive group with comparable 6-OHDA lesions. HPLC-EC measurements of L-DOPA in striatal and cortical tissue samples showed no differences in concentration across the L-DOPA treatment groups. There were several differences, however, in the neurochemical impact of L-DOPA on frontal cortex vs. striatum. In the striatum but not the cortex, L-DOPA concentrations were higher in the 6-OHDA than the intact hemisphere and, L-DOPA increased dopamine concentrations in cortex but not in the striatum. Behaviorally, L-DOPA exerted two diametrically opposite effects linked to the state of dopamine receptors. Prior to the onset of dopamine receptor supersensitivity L-DOPA suppressed locomotor behavior and delayed the emergence of denervation supersensitivity. Once denervation supersensitivity developed, however, the L-DOPA engaged sensitization mechanisms and enhanced locomotor behavior and dopamine receptor supersensitivity. These findings suggest that the initiation of antiparkinsonian treatment prior to the onset of denervated dopamine receptor supersensitivity in the 6-OHDA model is a valuable strategy to determine if a drug treatment retards or facilitates the development of dopamine receptor supersensitivity.
Carey
R J
RJ
SUNY Health Science Center, Syracuse.
Pinheiro-Carrera
M
M
Tomaz
C
C
Huston
J P
JP
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003714:Denervation; D007839:Functional Laterality / Q000502:physiology; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008750:Methyldopa / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects*; D012399:Rotation; D013997:Time Factors
D011954:Receptors, Dopamine; D007980:Levodopa; D008750:Methyldopa; D006719:Homovanillic Acid