Electrophysiological evidence for putative subtypes of neurotensin receptors in guinea-pig mesencephalic dopaminergic neurons

• Published in: Neuroscience Vol. 86; no. 3; pp. 799 - 811
• Main Authors: Nalivaiko, E, Michaud, J.-C, Soubrié, P, Le Fur, G
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-10-1998; Elsevier
• Subjects: 8-Bromo Cyclic Adenosine Monophosphate - pharmacology; Action Potentials - drug effects; Action Potentials - physiology; Animals; Biological and medical sciences; brain slices; Central nervous system; Dopamine - pharmacology; Dopamine - physiology; dopaminergic neurons; Electrophysiology; firing rate; Fundamental and applied biological sciences. Psychology; Guinea Pigs; In Vitro Techniques; Isoquinolines - pharmacology; Kinetics; Membrane Potentials - drug effects; Membrane Potentials - physiology; Mesencephalon - physiology; Microelectrodes; Neurons - drug effects; Neurons - physiology; Neurotensin - chemistry; Neurotensin - pharmacology; neurotensin antagonists; neurotensin receptors; Patch-Clamp Techniques; Peptide Fragments - pharmacology; Pyrazoles - pharmacology; Quinolines - pharmacology; Receptors, Neurotensin - agonists; Receptors, Neurotensin - antagonists & inhibitors; Receptors, Neurotensin - physiology; Second Messenger Systems - physiology; Sulfonamides; Vertebrates: nervous system and sense organs; SFR, spontaneous firing rate; SN, substantia nigra; VTA, ventral tegmental area; 8-Br-cAMP, 8-bromoadenosine 3′,5′-cyclic monophosphate; cAMP, adenosine 3′,5′-cyclic monophosphate; SR48692 and SR142948, selective non-peptide neurotensin receptor antagonists; neurotensin receptors; brain slices; ACSF, artificial cerebrospinal fluid; firing rate; neurotensin antagonists; DA, dopaminergic; dopaminergic neurons; T 1/2, half-time of recovery; AHP, afterhyperpolarization; Vertebrata; Mammalia; Guinea pig; Rodentia; Central nervous system; Discharge pattern; Electrophysiology; Peptidergic receptor; Midbrain; Dopaminergic neuron; Neurotensin; Neuropeptide
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/S0306-4522(98)00084-0

Electrophysiologically identified mesencephalic dopaminergic neurons were examined by means of extra- and intracellular microelectrodes in coronal slices of guinea-pig brain. Neurotensin and its C-terminal fragment (8–13) were equipotent in the enhancement of spontaneous neuronal firing rate (
ec
50 values 81.9 and 72.6
nM, respectively). The duration of response was significantly longer and more variable for neurotensin compared to neurotensin fragment (8–13) (mean half-time of recovery 423±44 and 100±14
s, respectively, for peptides applied at 300
nM). The initial fast phase of excitatory responses to neurotensin receptor agonists was associated with membrane depolarization (when assessed in current-clamp mode) or with inward currents (when assessed in voltage-clamp mode), whereas prolonged excitation was associated with a slowly occurring and long-lasting change in the late afterhyperpolarization. Two kinetically distinct components were revealed in responses to neurotensin and neurotensin fragment (8–13) by the use of SR48692 and SR142948, two selective non-peptide neurotensin receptor antagonists. SR142948 (100
nM) potently antagonized responses to both agonists [response was reduced by 66±5% and 74±9% for neurotensin and neurotensin fragment (8–13), respectively] and caused a rightward shift in the concentration–response curve for neurotensin. On the other hand, SR48692 (100
nM) selectively inhibited the slow (late afterhyperpolarization-dependent) component, without altering the response amplitude; the half-time of recovery was reduced by 71±6% and 65±5% of control values for responses induced by neurotensin (300
nM) and neurotensin fragment (8–13) (300
nM), respectively. In addition, neurotensin, but not neurotensin fragment (8–13), provoked SR48692-sensitive and long-lasting attenuation of dopamine-induced inhibitory responses.
It is suggested that two subtypes of neurotensin receptors are present in dopaminergic neurons, based on the differences in agonist and antagonist sensitivity, kinetic properties and the membrane mechanisms involved.