Neural substrates of antipsychotic drug action: Simultaneous projections from prefrontal cortex to dopaminergic and serotonergic nuclei

VÁZQUEZ BORSETTI P, CELADA P, CORTÉS R, ARTIGAS F.

INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY

CAMBRIDGE UNIV PRESS

Año: 2011 vol. 14 p. 289 - 302

1461-1457

Derangements of  the prefrontal cortex  (PFC) and of brainstem monoaminergic systems  occur  in  depression  and  schizophrenia.  Anatomical  and  functional evidence  supports  a  PFC  control  of  the  brainstem  monoaminergic  systems. Likewise,  the PFC  contains  a high  density  of monoamine  receptors  for which antipsychotic  drugs  exhibit  high  affinity.  This  raises  the  possibility  that pathological  or  drug-induced  changes  in  PFC  may  subsequently  alter monoaminergic  activity.  Recent  data  (Vázquez-Borsetti  et  al.,  2009)  indicate that a substantial proportion of PFC pyramidal neurons projecting to the ventral tegmental  area  (VTA)  or  the  dorsal  raphe  nucleus  (DR)  express  the  5-HT2A receptor  mRNA,  which  suggests  that  atypical  antipsychotic  drugs  affect serotonergic  and  dopaminergic  function  by  targeting  PFC  5-HT2A  receptors. Using  electrophysiological  and  tract-tracing  techniques  here  we  examined whether PFC  pyramidal  neurons  projecting  to DR  are  segregated  from  those projecting  to  the  VTA.  Sequential  electrical  stimulation  of  these  nuclei  in anesthetized  rats  evoked  antidromic  potentials  from  both  areas  in  the  same pyramidal neurons of the medial PFC (60%, n=30). A similar percentage of dual DR+VTA projection neurons  (50%) was obtained using  the  reciprocal collision test (n=85). Likewise,  tracer application (fluorogold  in VTA and cholera  toxin B in DR, or viceversa)  retrogradely  labeled pyramidal neurons  in PFC projecting to VTA (81±18), to DR (52±9) and to both nuclei (31±4; n=5 rats). Overall, these results  indicate  that  the  PFC  may  simultaneously  coordinate  the  activity  of dopaminergic  and  serotonergic  systems  within  a  short  temporal  domain, supporting  a  concerted  modulation  of  the  ascending  serotonergic  and dopaminergic activity during antipsychotic drug treatment.