We attempt to provide evidence that the projection from the guinea pig auditory cortex (AC) to the inferior colliculus (IC) may contain glutamatergic or GABAergic fibers. Seven days after unilateral AC aspiration, histological studies indicated almost complete AC destruction and preterminal degeneration of fibers and terminal fields in the dorsal cortex (DCIC), external cortex (ECIC), and central nucleus (CNIC) of the IC ipsilateral to the ablated AC. Contralaterally, degeneration appeared in the DCIC. AC ablation depressed the electrically evoked Ca(2+)-dependent release of D-[3H]aspartate (D-[3H]Asp) in the ipsilateral DCIC, ECIC, and CNIC, and D-[3H]Asp uptake in the CNIC. Together with other evidence that the corticocollicular pathway is excitatory, these findings suggest that this projection may contain glutamatergic and/or aspartatergic (Glu/Asp-ergic) fibers. Glutamic acid decarboxylase immunoreactivity was not apparent in presumed pyramidal cells of layer V of the AC retrogradely labeled with biotinylated dextran injected into the ipsilateral IC. Thus, corticocollicular neurons probably do not synthesize GABA and may not be GABAergic. However, AC ablation depressed [14C]GABA release from the ipsilateral DCIC and ECIC, and [14C]GABA uptake in the DCIC. These findings are consistent with the atrophy or down-regulation of some subcortical neurons that mediate GABAergic transmission in the IC.