PICOLINIC-ACID BLOCKS THE NEUROTOXIC BUT NOT THE NEUROEXCITANT PROPERTIES OF QUINOLINIC ACID IN THE RAT-BRAIN - EVIDENCE FROM TURNING BEHAVIOR AND TYROSINE-HYDROXYLASE IMMUNOHISTOCHEMISTRY

Previous results suggest that the tryptophan metabolite, picolinic acid may have the unusual properties of antagonizing the neurotoxic but not the neuroexcitant effects of another tryptophan metabolite, quinolinic acid in the central nervous system. The present experiments tested this possibility utilizing behavioural and tyrosine hydroxylase immunohistochemical techniques. In the first series of experiments, rats received injections of relatively high concentrations of 6-hydroxydopamine (12 mu g in 1 or 2 mu 1), quinolinic acid (120 nmol in 0.5 mu 1), picolinic acid (480 nmol in 0.5 mu 1) or co-treatments (0.5 mu 1) with quinolinic (120 nmol) plus picolinic acid (480 nmol) into the region of the substantia nigra. Results revealed that 6-hydroxydopamine and quinolinic acid alone produced a large loss of tyrosine hydroxylase-positive cells in the pars compacta of the substantia nigra. Behavioural results for all 6-hydroxydopamine (n = 10) and for some quinolinate-treated rats (n = 5) revealed ipsi- and contraversive circling following amphetamine (1 mg/kg, i.p.) and apomorphine (0.5 mg/kg, s.c.), respectively, consistent with unilateral loss of dopamine cells in the substantia nigra. The remaining quinolinate-treated rats (n = 9) circled ipsiversively following either stimulant suggesting damage to the pars reticulata. Groups treated with picolinic acid alone (n = 6) or co-injected (n = 6) showed no loss of tyrosine hydroxylase-positive cells in the substantia nigra and no circling response to the stimulants. In the second series of experiments, low concentrations of quinolinic acid (2.5, 5.0, 7.5 nmol), picolinic acid (10, 20, 30 nmol), or the two together (7.5 plus 30 nmol, respectively) were microinjected (0.5 mu 1) into the dorsal striatum and circling behaviour evaluated. These results revealed dose-dependent contralateral circling with either quinolinate or picolinate; co-injection of the two tryptophan metabolites also produced contralateral circling. It was concluded that picolinic acid blocks the neurotoxic but not the neuroexcitant effects of quinolinic acid.