title: When the party is over: depressive-like states in rats following termination of cortical D1 receptor overexpression.
abstract: BACKGROUND
  Increased activity of prefrontal D1 dopamine receptors (D1R) is involved in reward-related behavior found in bipolar disorder and drug addiction. While the effects of elevated D1R are known, depressive-like behaviors also occur in these disorders after reward-seeking ends.
  
  
  OBJECTIVE
  The goal is to characterize how termination of D1R overexpression influences depressive-like behaviors.
  
  
  METHODS
  An inducible (Tet.On), lentiviral vector was used to manipulate the expression of the DRD1 gene in glutamate neurons within the prefrontal cortex in male, adult rats. Sexual activity and sucrose preference were studied in both D1R elevated ON and relatively reduced OFF states. Following termination of the D1R ON state, depressive-like behavior was determined in the OFF state. Expression of the transcriptional regulator, cyclic AMP-responsive element-binding protein (CREB), was used as an indication of downstream effects in the nucleus accumbens (NA).
  
  
  RESULTS
  ON D1R expression increased sexual activity that returned to baseline in the OFF state. Sucrose preferences increased ~6 % in ON state but fell 11 % below control levels when OFF. Consistent with a depressive-like phenotype, D1R OFF decreased activity by 40 %, impaired the ability to control (43 %) and motivation to escape shock (27 % more impaired) relative to dsRed OFF. CREB increased 29 % in the NA in the D1R OFF state relative to the ON state.
  
  
  CONCLUSIONS
  This novel approach demonstrates that elevated D1R expression increased hedonic behavior, whereas the termination of D1R overexpression often resulted in depressive-like behavior. These observations support a role for D1R expression cycling in bipolar-associated behaviors and addiction.
authors.affiliation: Laboratory for Developmental Neuropharmacology, McLean Hospital and Harvard Medical School, Belmont, MA, 02478, USA. nadja.freund@med.uni-tuebingen.de.|Klinik für Psychiatrie und Psychotherapie, Calwerstr. 14, 72076, Tübingen, Germany. nadja.freund@med.uni-tuebingen.de.
authors.forename: Nadja
authors.initials: N
authors.lastname: Freund
authors.affiliation: Laboratory for Developmental Neuropharmacology, McLean Hospital and Harvard Medical School, Belmont, MA, 02478, USA.
authors.forename: Britta S
authors.initials: BS
authors.lastname: Thompson
authors.affiliation: Laboratory for Developmental Neuropharmacology, McLean Hospital and Harvard Medical School, Belmont, MA, 02478, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Sonntag
authors.affiliation: Laboratory for Developmental Neuropharmacology, McLean Hospital and Harvard Medical School, Belmont, MA, 02478, USA.
authors.forename: Shirisha
authors.initials: S
authors.lastname: Meda
authors.affiliation: Laboratory for Developmental Neuropharmacology, McLean Hospital and Harvard Medical School, Belmont, MA, 02478, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Andersen
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D003863:Depression / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D009714:Nucleus Accumbens / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D012201:Reward
chemical_list: D017447:Receptors, Dopamine D1; D018698:Glutamic Acid
keywords: Addiction; Bipolar disorder; Hedonia; Lentivirus; Prefrontal cortex; Rat