Blockade of neurotensin receptor by SR 48692 potentiates the facilitatory effect of haloperidol on the evoked in vivo dopamine release in the rat nucleus accumbens.
The present experiments assessed the effects of SR 48692, a selective nonpeptide antagonist of neurotensin receptors, on mesolimbic dopaminergic neurotransmission. Dopamine release evoked by the electrical stimulation of the median forebrain bundle (20 Hz, 10 s) was measured in the nucleus accumbens of urethane-anesthetized rats using differential pulse amperometry combined with carbon fiber electrodes. SR 48692 (0.1 mg/kg, i.p.) alone did not affect this release, whereas it dose-dependently (0.03-1 mg/kg, i.p.) enhanced the haloperidol (50 micrograms/kg, i.p.)-induced facilitation of the electrically evoked DA release. The increase induced by haloperidol (92 +/- 26% above control values 30 min after injection) was potentiated by SR 48692 (264 +/- 75% at 0.03 mg/kg, 428 +/- 113% at 0.1 mg/kg, and 480 +/- 135% at 1 mg/kg). Effects identical to those of SR 48692 were obtained with SR 48527, a chemically related compound with a high affinity for neurotensin receptors, but not with SR 49711, its low-affinity antipode. The potentiating effects of SR 48692 were positively related to the stimulation frequency (from 6 to 20 Hz) and to the dose of haloperidol (from 12.5 to 50 micrograms/kg) and were abolished after prior kainic acid lesion (1 microgram/1 microliter) of the nucleus accumbens. Thus, the effects of SR 48692 required the integrity of postsynaptic elements of the nucleus accumbens and occurred under the combination of two, at least partly, interdependent conditions: strong D2 autoreceptor blockade and high-intensity stimulation likely to release neurotensin. It is interesting that these potentiating effects of SR 48692 did not appear in the striatum. In conclusion, these findings suggest that endogenous neurotensin may attenuate the facilitation of D2 receptor blockade on mesolimbic but not nigrostriatal dopamine transmission.
Brun
P
P
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, USA.
Steinberg
R
R
Le Fur
G
G
Soubrié
P
P
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004558:Electric Stimulation; D004566:Electrodes; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors*
D011720:Pyrazoles; D011804:Quinolines; D018028:Receptors, Neurotensin; C079087:SR 48692; D006220:Haloperidol; D007608:Kainic Acid; D004298:Dopamine