Neurotensin (NT) is an endogenous brain tridecapeptide that exhibits selective anatomic and neurochemical interactions with rat brain dopaminergic systems. Because modulation of dopaminergic neurotransmission may underlie many of the behavioral properties of cocaine, the effects of both acute and chronic administration of cocaine on the concentration of NT-like immunoreactivity (NT-LI) in specific brain regions was determined. Adult male rats were treated with cocaine for 14 days at a dose of 40 mg/kg/day (0.118 mmoles/kg/day) administered as either 1 subcutaneous injection per day, or infused continuously using subcutaneously implanted minipumps. Neurotensin-like immunoreactivity in specific brain regions was then measured 24 hours or 8 days following drug administration. After 24 hours of withdrawal from daily subcutaneous injection, the concentration of NT-LI was significantly increased in the substantia nigra (SN) and frontal cortex. After 24 hours of withdrawal from continuous infusion with cocaine, NT-LI was increased only in the SN. After 8 days of withdrawal, NT-LI was increased in the SN of rats treated with daily subcutaneous infections of cocaine, but not in the group treated with continuous infusion. Twenty-four hours following a single acute injection of 40 mg/kg of cocaine, NT-LI was increased in the SN and nucleus accumbens. These results provide evidence consistent with a neuroanatomically selective involvement of NT systems in the behavioral and/or addictive properties of cocaine.