Differential Effects of Neurotensin NTS1 and NTS2 Receptors on Locomotion

Neurotensin (NT) is an endogenous neuropeptide with diverse central and peripheral effects, particularly as related to modulation of central nervous system dopaminergic activity. For example, interactions between dopamine and NT have been associated with the motivation to use, and the motor consequences of drugs abuse, including nicotine. However, the relative contribution of the two subtypes of cell surface G-protein coupled NT receptors (NTS1 and NTS2) to dopamine-related drug-induced effects is unclear.

We investigated the locomotor behavior and exploratory drive of C57BL/6J mice deficient in either NTS1 (NTS1 -/-) or NTS2 (NTS2 -/-) compared to wild-type C57BL/6J (WT +/+) mice in an open-field. In addition, the effect of nicotine on locomotion and intra-session habituation to a novel open field was compared in each of these genetic strains.

When compared to WT (+/+) mice, the results demonstrated less intra-session habituation across time (i.e., less accommodation (as assessed by distanced travelled, horizontal activity, and vertical activity) in mice deficient in the NTS1 receptor. In contrast, mice deficient in the NTS2 receptor accommodated more rapidly. Nicotine injection reduced all three parameters of locomotor activity in WT (+/+) and NTS1 (-/-) mice. In contrast to effects in both WT (+/+) and NTS1 (-/-) mice, NIC exposure had a negligible effect on TD in the NTS2 (-/-) mice.

These results suggest opposing effects of the NTS1 and NTS2 receptor subtypes in modulating natural and nicotine-induced dopaminergic transmission and consequent locomotor behavior.