Behavioral effects of dopamine agonists and antagonists in MPTP-lesioned D3 receptor knockout mice.
To test the modulatory role of D(3) receptors in normal and dopamine-depleted mice, D(3) receptor KO mice and wild-type (WT) littermates were administered saline, L-dopa/carbidopa (20/2 mg/kg ip), a preferential D(3)>D(2) agonist S32504, a D1+D(2)/D(3) agonist apomorphine, a selective D(3) antagonist S33084, or apomorphine with S33084 prior to and after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We monitored lines crossed in a 55-min session, average number of rears, and average number of grooming bouts. MPTP treatment produced equivalent 70% losses of dopamine fibers in the caudate putamen (CPu) and nucleus accumbens (NAC) of WT and D(3) KO mice as compared to their control (vehicle injected) counterparts. D(3) receptors were absent in KO mice, and the number of D(3) receptors was unaffected by MPTP-induced loss of DA terminals in WT mice. The results support a lack of involvement of the D(3) receptor for D1:D2 receptor-mediated behavioral activity (synergy). First, S32504 inhibited all behaviors and to a similar degree in D(3) KO and WT mice. Second, S33084 at the higher concentration increased number of lines crossed in response to high dose apomorphine in both D(3) KO and WT mice. Third, in nonlesioned mice, apomorphine-induced gnawing stereotypies were inhibited by S33084 in both D(3) KO and WT mice. Interestingly, the inhibition of apomorphine-induced gnawing was not apparent in MPTP-lesioned mice, and this stereotypy was elevated in D(3) KO-MPTP-lesioned mice. Thus, the suppressive effects of S32504 could be via D2 autoreceptor inhibition of DA release, and D2 receptor blockade by S33084 leads to release of that inhibition. This may be more apparent in MPTP-lesioned partially DA denervated mice.
Yarkov
Alex V
AV
Thomas H. Christopher Center for Parkinson's Disease Research, Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA. Alex.Yarkov@sunhealth.org
Hanger
Diane
D
Reploge
Maria
M
Joyce
Jeffrey N
JN
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology; D002230:Carbidopa / Q000494:pharmacology; D003042:Cocaine / Q000031:analogs & derivatives; D015259:Dopamine Agents / Q000633:toxicity*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D006120:Grooming / Q000187:drug effects; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010078:Oxazines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D050637:Receptors, Dopamine D3; D013239:Stereotyped Behavior / Q000187:drug effects
D001578:Benzopyrans; D015259:Dopamine Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; C493594:Drd3 protein, mouse; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010078:Oxazines; D011758:Pyrroles; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C478818:S 32504; C408389:S 33084; D007980:Levodopa; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D003042:Cocaine; D002230:Carbidopa; D001058:Apomorphine