Systemic PD149163, a neurotensin receptor 1 agonist, decreases methamphetamine self-administration in DBA/2J mice without causing excessive sedation

Abstract

Methamphetamine (METH) is a psychostimulant that exhibits significant abuse potential. Although METH addiction is a major health and societal concern, no drug is currently approved for its therapeutic management. METH activates the central dopaminergic “reward” circuitry, and with repeated use increases levels of the neuromodulatory peptide neurotensin in the nucleus accumbens and ventral tegmental area. Previous studies in rats suggest that neurotensin agonism decreases METH self-administration, but these studies did not examine the effect of neurotensin agonism on the pattern of self-administration or open field locomotion. In our studies, we established intravenous METH self-administration in male, DBA/2J mice (fixed ratio 3, 2 hr sessions) and examined the effect of pretreatment with the NTS1 receptor agonist PD149163 on METH self-administration behavior. Locomotion following PD149163 was also measured up to 2 hours after injection on a rotarod and in an open field. Pretreatment with PD149163 (0.05 and 0.10 mg/kg, s.c.) significantly decreased METH self-administration. The pattern of responding suggested that PD149163 decreased motivation to self-administer METH initially in the session with more normal intake in the second hour of access. Voluntary movement in the open-field was significantly decreased by both 0.05 and 0.10 mg/kg (s.c.) PD149163 from 10–120 minutes after injection, but rotarod performance suggested that PD149163 did not cause frank sedation. These results suggest that a systemically delivered NTS1 receptor agonist decreases METH self-administration in mice. The pattern of self-administration suggests that PD149163 may acutely decrease motivation to self-administer METH before the drug is experienced, but cannot rule out that depression of voluntary movement plays a role in the decreased self-administration.

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

“…Interestingly, systemic administration of SR48692 does not modify METH self-administration in experienced rats ( Frankel et al, 2011 ; Hanson et al, 2012 , 2013 ). Work from our laboratory and others suggests that the selective NTS1 receptor agonist PD149163 reduces METH self-administration and METH drug-seeking behavior ( Frankel et al, 2011 ; Hanson et al, 2012 , 2013 ; Sharpe et al, 2017 ); however, locomotor deficits may contribute to this effect ( Vadnie et al, 2014 ).…”

“…At least 2 weeks after arrival, mice were implanted with an indwelling catheter in the right jugular vein as previously described ( McCall et al, 2017 ; Sharpe et al, 2017 ). After the catheter was secured, mice were moved to a stereotaxic instrument (Kopf Instruments) for placement of bilateral cannulae (10.0 mm, 26-gauge stainless steel hypodermic tubing).…”

“…To assess catheter patency, catheters were flushed with sterile saline before each operant session and with heparinized saline after the session. Two-hour operant sessions were conducted daily as previously described ( McCall et al, 2017 ; Sharpe et al, 2017 ). Two nose-poke holes were located on one wall of the modular mouse operant chamber (Lafayette Instruments), and the correct nose poke was illuminated by a dim green light located inside of the hole.…”

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

“…Consistent with this, midbrain neurotensin promotes dopamine release in striatal terminals [18,19], and is itself reinforcing [20,21]. Indeed, we previously described that systemic administration of the selective NtsR1 agonist PD149163 transiently decreases motivation to self-administer METH in mice [22]. Furthermore, we also reported that a five-day treatment with microinfusions of the NtsR1/NtsR2 receptor antagonist SR142948A directly into the VTA acutely delays METH self-administration acquisition and produces a prolonged decrease in METHseeking behavior [23].…”

Diverse actions of the modulatory peptide neurotensin on central synaptic transmission

“…In this model, mice are trained to self‐administer methamphetamine through an intravenous catheter by responding operantly through a nose poke (Sharpe et al ., , ). We have observed that mice that are treated systemically with a NT receptor agonist or given an intra‐VTA NT receptor antagonist self‐administer less methamphetamine than controls (Dominguez‐Lopez et al ., ; Sharpe et al ., ). Thus, NT in the VTA appears to increase, while NT in other brain regions may decrease, the reinforcing effects of methamphetamine.…”