Pindolol excites dopaminergic and adrenergic neurons, and inhibits serotonergic neurons, by activation of 5-HT1A receptors.
Pindolol accelerates the clinical actions of selective serotonin reuptake inhibitors (SSRIs) in man, and modulates extracellular levels of monoamines in corticolimbic structures in rats. Herein, we examined its influence upon electrical activity of serotonergic, dopaminergic and adrenergic perikarya in the dorsal raphe nucleus (DRN), ventral tegmental area (VTA) and locus coeruleus (LC) of anaesthetized rats. In analogy to the serotonin1A (5-HT1A) agonist, 8-OH-DPAT (-100%), pindolol dose-dependently (0.063- 1.0 mg/kg) decreased (-70%) the firing rate of serotonergic neurons. The inhibitory action of pindolol was abolished by the selective 5-HT1A antagonist, WAY-100,635 (0.031 mg/kg). In contrast, 8-OH-DPAT (+26%) and pindolol (0.25-4.0 mg/kg, +60%) dose-dependently increased the firing rate of dopaminergic cells. Of 57 neurons recorded (pindolol, 2.0 mg/kg), 36 (63%) were excited, 11 (19%) were unaffected and 10 (18%) were inhibited. This variable influence could be attributed to regularly firing neurons in the parabrachial subdivision, inasmuch as all neurons in the paranigral subnucleus were excited. The facilitation of firing by pindolol was accompanied by an increase in burst firing throughout the VTA. Both the increases in burst firing and in firing rate were reversed by WAY-100,635 (0.031 mg/kg). Finally, the electrical activity of adrenergic neurons was dose-dependently enhanced by 8-OH-DPAT and pindolol (+99% and +83%, respectively). WAY-100,635 reversed this excitation and, itself, inhibited the activity of adrenergic neurons. In conclusion, via engagement of 5-HT1A receptors, pindolol inhibits serotonergic, and activates dopaminergic and adrenergic, neurons in anaesthetized rats. Such actions may contribute to its influence upon mood, both alone and in association with antidepressant agents.
Lejeune
F
F
Institut de Recherches Servier, Centre de Recherches de Croissy, Department of Psychopharmacology, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, Paris, France.
Millan
M J
MJ
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004298:Dopamine / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000502:physiology; D008125:Locus Coeruleus / Q000166:cytology; D008297:Male; D009474:Neurons / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology*; D010869:Pindolol / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000166:cytology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000166:cytology
D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D010869:Pindolol; D004298:Dopamine; D004837:Epinephrine