Neurotensin antagonist acutely and robustly attenuates locomotion that accompanies stimulation of a neurotensin-containing pathway from rostrobasal forebrain to the ventral tegmental area

Neurotensin exerts complex effects on the mesolimbic dopamine system that alter motivation and contribute to neuroadaptations associated with psychostimulant drug administration. Activation of abundant neurotensin receptors in the ventral tegmental area (VTA) enhances dopamine neuron activity and associated release of dopamine in the nucleus accumbens (Acb) and cortex. In view of recent anatomical studies demonstrating that 70% of all neurotensin-containing neurons projecting to the VTA occupy the lateral preoptic area-rostral lateral hypothalamus (LPH) and lateral part of the medial preoptic area (MPOA), the present study examined functionality in the LPH-MPOA neurotensinergic pathway in the rat. Disinhibition (resulting ultimately in stimulation-like effects) of LPH-MPOA neurons with microinjected bicuculline (50 or 100 ng in 0.25 mu L) produced locomotor activation that was considerably attenuated by systemic administration of the neurotensin antagonist SR 142948 A (0.03 and 0.1 mg/kg). In contrast, locomotion elicited in this manner was completely blocked by SR 142948 A infused directly into the VTA (5.0 and 15.0 ng in 0.25 mu L). Baseline locomotion was unaffected by systemic or intra-VTA administration of SR 142948 A and LPH-MPOA-elicited locomotion was unaffected by infusion of SR 142948 A into the substantia nigra pars compacta and sites rostral and dorsal to the VTA. Locomotion was not elicited by infusions of bicuculline into the lateral hypothalamus at sites caudal to the LPH-MPOA, where neurotensin neurons projecting to the VTA are fewer. The results demonstrate the capacity of a neurotensin-containing pathway from LPH-MPOA to VTA to modulate locomotion. This pathway may be important in linking hippocampal and mesolimbic mechanisms in normal behaviour and drug addiction.