Neurotensin (NT) agonists have been proposed as potential antipsychotics based exclusively upon their ability to inhibit dopamine-2 (D2) receptor transmission. Several other pharmacological mechanisms have been implicated in enhancing the antipsychotic profile produced by D2 inhibition alone. These include inhibition of 5-HT2A and α1-adrenoceptors. Recently, we reported that systemic administration of the neurotensin agonist PD149163 blocks deficits in prepulse inhibition (PPI) of the startle reflex produced by the 5-HT2A receptor agonist DOI. This suggested that NT agonists could inhibit 5-HT2A modulation of neurotransmission.
To determine if other peripherally administered NT agonists shared this effect, we examined the effects of NT69L, another NT agonist, on DOI-induced PPI deficits. In addition, to determine if NT agonists also inhibit α1-adrenoceptor neurotransmission, we examined the effects of PD149163 and NT69L on PPI deficits induced by the α1-adrenoceptor agonist, cirazoline.
In the NT69L/DOI study, rats received subcutaneous (SC) injections of NT69L (0, 0.1, 1, or 2 mg/kg) followed 30 min later by SC saline or DOI (0.5 mg/kg). In the NT agonist/cirazoline studies, animals received SC injections of either PD149163 (0, 0.01, 0.1, or 1 mg/kg) or NT69L (0, 0.01, 0.1, or 1 mg/kg) followed 30 min later by SC saline or cirazoline (0.7 mg/kg). Animals were tested in startle chambers 20 min later.
In all three experiments the PPI disruption produced by DOI and cirazoline was blocked by the NT agonists.
These findings provide strong evidence that NT agonists inhibit 5-HT2A and α1-adrenoceptor modulation of neurotransmission, pharmacological effects that, in conjunction with their known inhibition of dopamine transmission, strengthen the antipsychotic potential of NT agonists.
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D.F. and P.D.S. were supported in part by NIMH grant (MH62451). E.R. was supported by MH27692, The Forrest C. Lattner Foundation, and the Mayo Foundation for Medical Education and Research. The experiments described here comply with the current laws of the USA. We are grateful to the NIH Chemical Synthesis Program and SRI International for providing PD149163.
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Shilling, P.D., Melendez, G., Priebe, K. et al. Neurotensin agonists block the prepulse inhibition deficits produced by a 5-HT2A and an α1 agonist. Psychopharmacology 175, 353–359 (2004). https://doi.org/10.1007/s00213-004-1835-5
- Antipsychotic drugs