The Discriminative Stimulus Effects of the Neurotensin NTS₁ Receptor Agonist PD149163 in Rats: Stimulus Generalization Testing with Dopamine D₁ and D₂ Receptor Ligands

Abstract

Brain-penetrant neurotensin NTS1 receptor agonists produce antipsychotic drug-like effects in animal models, including inhibition of conditioned avoidance responding and reversal of psychostimulant-induced hyperactivity and stereotypy. Allosteric interactions between NTS1 receptors and dopamine D2 receptors may account for some of these antipsychotic effects. In order to determine the role that dopamine receptors may play in the behavioral effects produced by activation of NTS1 receptors, a drug discrimination approach was used in rats to evaluate the potential mediation of NTS1 receptor agonist stimulus effects by dopamine D1 and D2 receptors. Rats were trained to discriminate either the NTS1 receptor agonist PD149163, the D1 receptor agonist SKF81297, or the D2 receptor agonist quinpirole from vehicle in a two choice drug discrimination task. Full stimulus generalization occurred from PD149163 to the typical antipsychotic drug and D2 receptor-preferring antagonist haloperidol. However, stimulus generalization did not occur from SKF81297 or quinpirole to PD149163. The discriminative cue for SKF91297 and quinpirole was fully blocked the D1 receptor antagonist SCH23390 and the D2/3 receptor antagonist raclopride, respectively. Cross generalization did not occur between SKF91297 and quinpirole. Based on these findings, the stimulus effects of PD149163 may be mediated, in part, through D2 receptor antagonism, but this may only be evident when PD149163 is used as the training drug.

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

“…Behaviorally, neurotensin signaling modulates dopamine-related processes such as cognition, food intake, and the effects of psychostimulants [ 8 – 11 ]. Dopaminergic neurons and their downstream targets are known to express surface neurotensin NTS1 receptors [ 12 – 14 ], and rats trained to discriminate a neurotensin receptor agonist show full generalization to the D2-like receptor antagonist haloperidol [ 15 ]. Neurotensin receptor agonism is known to decrease self-administration of food [ 16 – 19 ], nicotine [ 20 ] and METH [ 7 ].…”