Postnatal changes in the expressions of serotonin 1A, 1B, and 2A receptors in ten brain stem nuclei of the rat: implication for a sensitive period.

A critical period in respiratory network development occurs in the rat around postnatal days (P) 12-13, when abrupt neurochemical, metabolic, and physiological changes were evident. As serotonin and its receptors are involved in respiratory modulation, and serotonergic abnormality is implicated in sudden infant death syndrome, we hypothesized that 5-HT receptors are significantly downregulated during the critical period. This was documented recently for 5-HT(2A)R in several respiratory nuclei. The present study represents a comprehensive analysis of postnatal development of 5-HT(1A)R and 5-HT(1B)R in 10 brain stem nuclei and 5-HT(2A)R in six nuclei not previously examined. Optical densitometric analysis of immunohistochemically-reacted neurons from P2 to P21 indicated four developmental patterns of expression: (1) Pattern I: a high level of expression at P2-P11, an abrupt and significant reduction at P12, followed by a plateau until P21 (5-HT(1A)R and 5-HT(1B)R in raphé magnus [RM], raphé obscurus [ROb], raphé pallidus [RP], pre-Bötzinger complex [PBC], nucleus ambiguus [Amb], and hypoglossal nucleus [XII; 5-HT(1A)R only]). (2) Pattern II: a high level at P2-P9, a gradual decline from P9 to P12, followed by a plateau until P21 (5-HT(1A)R and 5-HT(1B)R in the retrotrapezoid nucleus (RTN)/parafacial respiratory group (pFRG)). (3) Pattern III: a high level at P2-P11, followed by a gradual decline until P21 (5-HT(1A)R in the ventrolateral subnucleus of solitary tract nucleus [NTS(VL)] and the non-respiratory cuneate nucleus [CN]). (4) Pattern IV: a relatively constant level maintained from P2 to P21 (5-HT(1A)R in the commissural subnucleus of solitary tract nucleus (NTS(COM)); 5-HT(1B)R in XII, NTS(VL), NTS(COM), and CN; and 5-HT(2A)R in RM, ROb, RP, RTN/pFRG, NTS(VL), and NTS(COM)). Thus, a significant reduction in the expression of 5-HT(1A)R, 5-HT(1B)R, and 5-HT(2A)R in multiple respiratory-related nuclei at P12 is consistent with reduced serotonergic transmission during the critical period, thereby rendering the animals less able to respond adequately to ventilatory distress.