Abstract Three experiments investigated the suppression of hypothalamic self-stimulation in rats by neuroleptics and its restoration by centrally acting anticholinergic agents. Scopolamine (0.1–1.0 mg/kg i.p) and benztropine (1.0–10.0 mg/kg i.p.) each enhanced self-stimulation when administered alone, and partially restored performance suppressed by spiroperidol (0.05–0.15 mg/kg i.p.). Benztropine strongly inhibits transmitter reuptake at DA synapses but scopolamine does not, thus inhibition of DA reuptake cannot fully account for the stimulant or antineuroleptic action of anticholinergic drugs. Neuroleptic and anticholinergic effects on self-stimulation rate were mutually subtractive, and statistical evidence of interaction was not obtained. Scopolamine was shown also to restore performance extinguished by discontinuation of the stimulating current. Smaller doses of scopolamine (50 nmol; 19 μg) injected directly into the nucleus accumbens septi partially restored responding suppressed by spiroperidol, though similar doses of scopolamine injected bilaterally into the caudate-putamen were ineffective. These findings suggest that hypothalamic self-stimulation may be influenced by ACh- and DA-containing systems which exert independent effects on a third system controlling performance. These effects appear to reflect the level of arousal or motivation rather than the reinforcement process itself.