Selective serotonin reuptake inhibitors reduce the spontaneous activity of dopaminergic neurons in the ventral tegmental area.
Electrophysiological techniques were used to study the effects of paroxetine, sertraline, and fluvoxamine on the basal activity of dopaminergic neurons in the ventral tegmental area (VTA) of rats. Acute i.v. administrations of paroxetine (20-1280 microg/kg), sertraline (20-1280 microg/kg), and fluvoxamine (20-1280 microg/ kg) caused a slight but significant reduction in the firing rate of the VTA dopaminergic cells studied. Paroxetine produced a maximal inhibitory effect of 10 +/- 11% at the cumulative dose of 160 microg/kg. Sertraline induced a dose-related inhibition of VTA dopaminergic neurons, which reached its maximum (10 +/- 7%) at the cumulative dose of 1280 microg/kg. The effect of fluvoxamine on the basal firing rate of VTA dopaminergic neurons was more pronounced as compared to that of paroxetine and sertraline, in that it produced a maximal inhibition of 17 +/- 12% at the cumulative dose of 1280 microg/kg. Acute i.v. injections of paroxetine (20-1280 microg/kg), sertraline (20-1280 microg/kg), and fluvoxamine (20-5120 microg/kg) caused a dose-dependent decrease in the basal firing rate of serotonergic neurons in the dorsal raphe nucleus (DRN). Paroxetine and sertraline stopped the spontaneous firing of serotonergic neurons at the cumulative dose of 1280 microg/kg, whereas fluvoxamine reached the same effect only at the cumulative dose of 5120 microg/kg. Pretreatment with the 5-HTA1A receptor antagonist tertatolol (1 mg/kg, i.v.) reduced the inhibitory effects of paroxetine, fluvoxamine, and sertraline on the basal activity of serotonergic neurons in the DRN. Administration of tertatolol induced a 15-fold increase in the ED50 for fluvoxamine. The antagonistic effect of tertatolol was much less evident in blocking the inhibitory action exerted by paroxetine and sertraline on the activity of serotonergic neurons. Pretreatment with tertatolol (1 mg/kg, i.v.) potentiated the inhibitory effect of fluvoxamine on the basal activity of VTA dopaminergic neurons. Tertatolol did not affect the inhibitory action exerted by paroxetine and sertraline on these neurons. It is concluded that inhibition of the basal firing rate of dopaminergic neurons in the VTA is a common characteristic of selective serotonin reuptake inhibitors (SSRIs). The effects of SSRIs on VTA dopaminergic cell activity might be relevant for their therapeutic action and may explain the origin of the reported cases of akathisia.
Di Mascio
M
M
Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Santa Maria Imbaro (Chieti), Italy.
Di Giovanni
G
G
Di Matteo
V
V
Prisco
S
S
Esposito
E
E
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D004298:Dopamine / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D016666:Fluvoxamine / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D017374:Paroxetine / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000493:pharmacokinetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline / Q000494:pharmacology; D013876:Thiophenes; D017557:Ventral Tegmental Area / Q000166:cytology* / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D004298:Dopamine; D016666:Fluvoxamine; D017374:Paroxetine; D011412:Propanolamines; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; D013876:Thiophenes; C005632:tertatolol