Multiple somatostatin (SRIF) receptor subtypes, which mediate distinct biological actions of SRIF, are expressed in the rat central nervous system. In the present study, we examined the effects of local injections of SRIF and the SRIF analogs MK 678 and CGP 23996 into the anterior nucleus accumbens on locomotor activity. The binding of [125I]Tyr11-SRIF to membranes from rat nucleus accumbens was potently and monophasically inhibited by SRIF. MK 678 inhibited only 58% of specific [125I]Tyr11-SRIF binding, indicating that the nucleus accumbens expresses both SRIF1 (MK 678-sensitive) and SRIF2 (MK 678-insensitive) receptors. The inhibition of [125I]Tyr11-SRIF binding by CGP 23996 was best fit by a two-site model, and analysis indicated an approximately 100-fold selectivity of this peptide for SRIF receptor subtypes. Intra-accumbens injections of SRIF (3.2-100 ng/side) produced significant increases in locomotor activity with a maximal 212% increase relative to saline control. This effect was mediated by SRIF1 receptors, as MK 678 (1-320 ng/side) produced a dose-dependent significant increase in locomotor activity with a maximal 228% increase relative to saline control, comparable to that attained with 3 to 10 micrograms of d-amphetamine. In contrast, CGP 23996 did not affect locomotor activity at doses of 3.2 to 1000 ng/side. The retroenantiomer hexapeptide analog L363-572, which is 70-fold less potent than MK 678 to inhibit radioligand binding to SRIF1 receptors, did not affect locomotor activity at doses up to 100 ng/side. These results indicate that SRIF1 receptors mediate the locomotor-activating effects of SRIF in the nucleus accumbens of the rat.