Neurotensin agonists block the prepulse inhibition deficits produced by a 5-HT2A and an alpha1 agonist.
BACKGROUND
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 alpha1-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.


OBJECTIVE
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 alpha1-adrenoceptor neurotransmission, we examined the effects of PD149163 and NT69L on PPI deficits induced by the alpha1-adrenoceptor agonist, cirazoline.


METHODS
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.


RESULTS
In all three experiments the PPI disruption produced by DOI and cirazoline was blocked by the NT agonists.


CONCLUSIONS
These findings provide strong evidence that NT agonists inhibit 5-HT2A and alpha1-adrenoceptor modulation of neurotransmission, pharmacological effects that, in conjunction with their known inhibition of dopamine transmission, strengthen the antipsychotic potential of NT agonists.
Shilling
P D
PD
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA.
Melendez
G
G
Priebe
K
K
Richelson
E
E
Feifel
D
D
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009496:Neurotensin / Q000819:agonists* / Q000031:analogs & derivatives* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects*; D058826:Serotonin 5-HT2 Receptor Agonists
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000662:Amphetamines; D014150:Antipsychotic Agents; D007093:Imidazoles; C117269:PD 149163; D010446:Peptide Fragments; D058826:Serotonin 5-HT2 Receptor Agonists; C407426:neurotensin 69L; D009496:Neurotensin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; C014282:cirazoline