Inhibitory actions of serotonin and fluoxetine on tuberoinfundibular dopamine (TIDA) neurons: <em>Novel mechanisms for the sexual side effects of SSRIs</em> — ASN Events

Inhibitory actions of serotonin and fluoxetine on tuberoinfundibular dopamine (TIDA) neurons: Novel mechanisms for the sexual side effects of SSRIs (#114)

Christian Broberger 1 , David J Lyons 1
  1. Karolinska Institutet, Stockholm, Sweden

Background: Sexual side effects such as impotence and amenorrhea are common causes for non-compliance during selective serotonin reuptake inhibitor (SSRI) therapy, and are associated with elevations of the hormone, prolactin. Prolactin secretion is under most circumstances under tonic inhibition by neuroendocrine tuberoinfundibular dopamine (TIDA) neurons. Here, we studied if serotonin (5-HT) and SSRI actions on TIDA neuron membrane properties can explain hyperprolactinaemia.

 

Methods: Visualized whole-cell patch clamp recordings were performed on hypothalamic slice preparations from 3-4w old male rats. TIDA neurons were identified by their electrical properties including a membrane potential oscillation (DJ Lyons et al., 2010; Neuron).

 

Results: In the presence of 5-HT (10 μM) TIDA neurons hyperpolarized (average -23 mV) and phasic discharge was abolished. In voltage clamp, 5-HT elicited an outward current that reversed negative of -100 mV. The 5-HT-induced current was attenuated by including Cs2+ in the intracellular solution and when Ba2+, the G-protein blocker, NEM, or the 5-HT1A-selective antagonist, NAD299, were bath applied. These and other data suggest that 5-HT acting on 1A-type receptors hyperpolarizes TIDA neurons by activating a GIRK-like K+ conductance. In the presence of the SSRI, fluoxetine (25 µM), the TIDA oscillation persisted (in contrast to the effects seen in 5-HT). The intrinsic excitability of TIDA neurons was, however, decreased, manifested in attenuated action potential amplitude and capacity for repetitive discharge. At higher doses of fluoxetine (100µM) oscillatory activity was gradually abolished, but with a different profile than with 5-HT.

 

Conclusions: These findings indicate that SSRI’s may inhibit dopamine release through both 5-HT-dependent and independent mechanisms, relieving the suppression of pituitary lactotrophs. Thus, modulation of TIDA membrane properties provides a novel explanation for SSRI-induced reproductive dysfunction.