The role of dopamine systems in the nucleus accumbens (NA) in mediating the hyperactivity following colchicine-induced granule cell damage was investigated. In the first experiment adult Sprague-Dawley rats were bilaterally injected with 6-hydroxydopamine (6-OHDA; 8 micrograms/2 microliters) or 0.5% ascorbate into the NA. Eight days later, rats received intradentate COLCH or CSF and were tested for locomotor activity 2, 4, 6, 8, and 10 days later. Intradentate COLCH produced a significant hyperactivity which was prevented by prior injection of 6-OHDA into the NA. Neurochemical analysis revealed that 6-OHDA decreased dopamine (80%) but not norepinephrine in the NA without altering either catecholamine in the striatum. In the second experiment animals were injected with COLCH or CSF in the dentate gyrus and immediately implanted with bilateral cannulae in the NA. Animals received intraaccumbens injections of CSF or d-amphetamine (20 micrograms/l microliters) and were tested for locomotor activity. Amphetamine produced a significant increase in locomotor activity in both CSF- and COLCH-treated animals. However, COLCH produced an exaggerated response to the motor stimulating effects of amphetamine. These results suggest that the destruction of dentate granule cells following colchicine results in a "functional" hyperactivity of the mesolimbic dopamine input to the NA which might disinhibit locomotor activity.