Some of the highest concentrations of substance P in forebrain are found in areas where dopaminergic neurons arise or terminate. In the rat, native substance P has been injected directly into brain areas where interactions between substance P and dopamine are suspected. In the ventral tegmental area (A10 dopamine neurons), bilateral infusions of substance P induce locomotor activity and exploration. It is concluded that substance P activates A10 dopamine neurons innervating the limbic system because (i) the behavioural effects resemble those seen after systemic treatment with low doses of d-amphetamine, a drug response known to depend on the integrity of the A10 dopamine neurons; (ii) lesions to the A10 dopamine neurons abolish the behavioural response to intracerebrally infused substance P; and (iii) dopamine antagonist drugs abolish the response to substance P. In parallel experiments substance P was injected into the origins of the nigrostriatal (A9 dopamine neurons) system and found to produce stereotyped behaviour. Substance P analogues protected from enzymic degradation have been studied in these model systems. The prolongation of the behavioural effects is correlated with the presence of undegraded substance P in the ventral tegmental area. Unrelated behavioural responses are also observed, which appear not to be mediated by dopamine neurons, and probably reflect the spread of stable substance P from the ventral tegmental area to other brain sites.