Effects of long-term desipramine administration on noradrenergic neurotransmission: electrophysiological studies in the rat brain.
The present studies were undertaken to assess in vivo the effects of repeated administration of the norepinephrine (NE) reuptake blocker desipramine (DMI) (5 or 10 mg/kg/day x 14 days) on five subsets of adrenoceptors and on the effectiveness of the NE reuptake process in the rat central nervous system. These receptors were: 1) the postsynaptic alpha-2 adrenoceptors which signal the suppressant effect of microiontophoretically applied NE on the firing activity of dorsal hippocampus pyramidal neurons; 2) the postsynaptic alpha-1 adrenoceptors which mediate the short-latency suppressant effect of endogenous NE, released by the electrical stimulation of the locus ceruleus (LC), on the firing activity of these same neurons; 3) the postsynaptic beta adrenoceptors which mediate the long-latency excitatory effect of LC stimulation on hippocampus pyramidal neurons; 4) the alpha-2 autoreceptors located on NE terminals in the hippocampus; and 5) the alpha-2 autoreceptors located on the cell body of LC NE neurons. The suppressant effect of microiontophoretic applications of NE on dorsal hippocampus pyramidal neurons was not changed by the long-term DMI treatments. The recovery time of the firing activity of these neurons after microiontophoretic application of NE, an index of the activity of the NE reuptake process, was the same in control and DMI-treated rats. However, the prolongation of this recovery time by the acute i.v. administration of DMI reached a plateau at a lower cumulative dose in long-term DMI-treated than in control rats. These results thus suggest that long-term administration of DMI did not affect the function of the NE transporter but reduced the number of DMI binding sites. The effectiveness of the 1 Hz stimulation of the LC in suppressing of the firing activity of pyramidal neurons was unchanged by either long-term DMI treatment (5 or 10 mg/kg/day), whereas that of the 5 Hz stimulation was enhanced only in rats on the 10-mg/kg regimen. This suggests that the function of terminal alpha-2 autoreceptors was decreased after this latter DMI regimen, because the reduction of the efficacy of the stimulation obtained by increasing the frequency from 1 to 5 Hz has been shown to be due to the activation of terminal alpha-2 adrenergic autoreceptors. In keeping with this interpretation, the reduction of the effectiveness of the stimulation of the LC by the systemic administration of the alpha-2 adrenoceptor agonist clonidine was attenuated in rats treated with the 10-mg/kg/day regimen of DMI, but not in those with the 5-mg/kg/day regimen.(ABSTRACT TRUNCATED AT 400 WORDS)
Lacroix
D
D
Department of Psychiatry, McGill University, Montreal, Canada.
Blier
P
P
Curet
O
O
de Montigny
C
C
D000818:Animals; D001921:Brain / Q000187:drug effects*; D003000:Clonidine / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004558:Electric Stimulation; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects; D008125:Locus Coeruleus / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D005680:gamma-Aminobutyric Acid; D003000:Clonidine; D003891:Desipramine; D009638:Norepinephrine