RATS BRED FOR ENHANCED APOMORPHINE SUSCEPTIBILITY HAVE ELEVATED TYROSINE-HYDROXYLASE MESSENGER-RNA AND DOPAMINE D-2-RECEPTOR BINDING-SITES IN NIGROSTRIATAL AND TUBEROINFUNDIBULAR DOPAMINE SYSTEMS

From a Wistar population two rat lines were generated using as criteri on the behavioral response to the dopamine agonist apomorphine. Rats o f the apomorphine-susceptible (apo-sus) line revealed a vigorous gnawi ng response to apomorphine administration while the other rat line, th e apomorphine-unsusceptible (apo-unsus) line, was selected for lack of response to the drug. In the present study using the 12th and 13th ge neration of these genetically selected lines, we have investigated whe ther this difference in apomorphine responsiveness was correlated with changes in dopamine neurochemistry. Therefore, we measured tyrosine h ydroxylase (TH), the rate limiting enzyme in dopamine synthesis, as we ll as dopamine D-1 and D-2 receptor mRNA levels in discrete brain regi ons by in situ hybridization. Dopamine (D-2/D-3) receptor binding was assessed with [I-125]iodosulpride in a membrane binding assay and by q uantitative autoradiography on tissue sections. [H-3]SCH 23390 was use d to analyze D-1 receptor binding. Apo-sus rats displayed significantl y higher TH mRNA levels in the A(9) cell group of the substantia nigra pars compacta and in the A(12) cell group of the arcuate nucleus. No difference was found in the A(10) cell group of the VTA and the A(6) c ell group of the locus coeruleus. The density of D-2/3 binding sites a s well as D-1 receptor mRNA levels in the striatal projection area of the A(9) substantia nigra neurons, were significantly elevated in apo- sus rats. Dopamine D-2 receptor mRNA and D-1 receptor binding levels i n caudate putamen and nucleus accumbens, however, were similar in rats of both lines. In conclusion, high apomorphine susceptibility is rela ted to a potentially enhanced dopamine responsiveness selective for th e nigrostriatal and tuberoinfundibular pathways.