Neurotensin receptor 1 deletion suppresses methamphetamine self-administration and the associated reduction in dopamine cell firing

Abstract

We previously reported that pharmacological blockade of neurotensin receptors in the ventral tegmental area (VTA) decreases methamphetamine (METH) self-administration in mice. Here we explored the consequences of genetic deletion of neurotensin receptor 1 (NtsR1) in METH self-administration and VTA dopamine neuron firing activity. We implanted mice with an indwelling jugular catheter and trained them to nose-poke for intravenous infusions of METH. Mice with NtsR1 deletion (KO) acquired selfadministration similar to wildtype (WT) and heterozygous (HET) littermates. However, in NtsR1 KO and HET mice, METH intake and motivated METH seeking decreased when the response requirement was increased to a fixed ratio 3 and when mice were tested on a progressive ratio protocol. After completion of METH self-administration, single cell in vivo extracellular recordings of dopamine firing activity in the VTA were obtained in anesthetized mice. In WT METH-experienced mice, dopamine cell firing frequency dramatically decreases compared to WT drug-naive mice. NtsR1 KO and HET mice did not exhibit this decline of dopamine cell firing activity after prolonged METH selfadministration. We also observed an increase in population activity following METH selfadministration that was strongest in the WT group. Our results suggest a role for NtsR1 in METH-seeking behavior, and ablation of NtsR1 receptors prevents the detrimental effects of prolonged METH self-administration on VTA dopamine cell firing frequency.