Antagonism of Neurotensin Receptors in the Ventral Tegmental Area Decreases Methamphetamine Self-Administration and Methamphetamine Seeking in Mice

• Published in: The international journal of neuropsychopharmacology Vol. 21; no. 4; pp. 361 - 370
• Main Authors: Dominguez-Lopez, Sergio, Piccart, Elisabeth, Lynch, William B, Wollet, Mackenna B, Sharpe, Amanda L, Beckstead, Michael J
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01-04-2018
• Subjects: Animals; Behavior, Animal - drug effects; Central Nervous System Stimulants - administration & dosage; Central Nervous System Stimulants - pharmacology; Male; Methamphetamine - administration & dosage; Methamphetamine - pharmacology; Mice; Mice, Inbred DBA; Neurotensin - metabolism; Receptors, Neurotensin - antagonists & inhibitors; Regular s; Self Medication; Ventral Tegmental Area - drug effects; Ventral Tegmental Area - metabolism; mouse; VTA; Neurotensin; methamphetamine; self-administration
• ISSN: 1461-1457; 1469-5111
• DOI: 10.1093/ijnp/pyx117

Abstract
Background
Neurotensin is a peptide that modulates central dopamine neurotransmission and dopamine-related behaviors. Methamphetamine self-administration increases neurotensin levels in the ventral tegmental area, but the consequences for self-administration behavior have not been described. Here we test the hypothesis that antagonizing neurotensin receptors in the ventral tegmental area attenuates the acquisition of methamphetamine self-administration and methamphetamine intake.
Methods
We implanted mice with an indwelling catheter in the right jugular vein and bilateral cannulae directed at the ventral tegmental area. Mice were then trained to nose-poke for i.v. infusions of methamphetamine (0.1 mg/kg/infusion) on a fixed ratio 3 schedule.
Results
Mice receiving microinfusions of the neurotensin NTS1/NTS2 receptor antagonist SR142948A in the ventral tegmental area (10 ng/side) prior to the first 5 days of methamphetamine self-administration required more sessions to reach acquisition criteria. Methamphetamine intake was decreased in SR142948A-treated mice both during training and later during maintenance of self-administration. Drug seeking during extinction, cue-induced reinstatement, and progressive ratio schedules was also reduced in the SR142948A group. The effects of SR142948A were not related to changes in basal locomotor activity or methamphetamine psychomotor properties. In both SR142948A- and saline-treated mice, a strong positive correlation between methamphetamine intake and enhanced locomotor activity was observed.
Conclusion
Our results suggest that neurotensin input in the ventral tegmental area during initial methamphetamine exposure contributes to the acquisition of methamphetamine self-administration and modulates later intake and methamphetamine-seeking behavior in mice. Furthermore, our results highlight the role of endogenous neurotensin in the ventral tegmental area in the reinforcing efficacy of methamphetamine, independent of its psychomotor effects.