Chronic tryptophan deprivation attenuates gating deficits induced by 5-HT1A, but not 5-HT2 receptor activation

The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts a multifaceted function in the modulation of information processing, through the activation of multiple receptor families. In particular, stimulation of 5-HT1A and 5-HT2A receptors leads to sensorimotor gating impairments and perceptual perturbations. Previous evidence has shown that chronic deprivation of l-tryptophan (TRP), the precursor of 5-HT, results in marked reductions of 5-HT brain levels, as well as neuroplastic alterations in 5-HT1A and 5-HT2A expression and/or signaling. Building on these premises, in the present study we tested whether a prolonged TRP deprivation may differentially impact the roles of these receptors in the regulation of the prepulse inhibition (PPI) of the acoustic startle reflex, a dependable index of gating. Male Sprague-Dawley rats were fed for 14 days with either a regimen with negligible TRP content (TR−) or the same diet supplemented of TRP (TR+). At the end of this schedule, rats were treated with the prototypical 5-HT1A receptor agonist 8-OH-DPAT (62.5-250 μg/kg, subcutaneous, s.c.) or the 5-HT2 receptor agonist DOI (0.25-1 mg/kg, s.c.). Notably, the PPI deficits induced by 8-OH-DPAT in TR− rats were significantly milder than those observed in their TR+ counterparts; these effects were fully prevented by the 5-HT1A antagonist WAY-100135 (10 mg/kg, intraperitoneal). Conversely, TRP deprivation did not affect the PPI-disrupting properties of DOI. These findings suggest that prolonged 5-HT depletion attenuates the influence of 5-HT1A, but not 5-HT2 receptors on sensorimotor gating, confirming the distinct mechanisms of these two targets in PPI regulation.