Altered neurotensin mrna expression in mice lacking the dopamine transporter.
Psychostimulants and antipsychotic drugs increase mRNA expression of the neuropeptide neurotensin (NT) in the striatum and nucleus accumbens. In the present study, we used mice lacking the dopamine transporter (DAT) to investigate the consequences of a chronic hyperdopaminergic state on NT gene expression. NT mRNA expression was examined under basal conditions and after administration of haloperidol or amphetamine using in situ hybridization with a digoxigenin-labeled NT cRNA probe. DAT-/- mice exhibited a striking increase in the number of NT mRNA-expressing perikarya in the substantia nigra and ventral tegmental area, as well as a less pronounced increase in the lateral septum compared with wild-type littermates. No changes were detected in other regions expressing NT mRNA. Acute administration of haloperidol (1 mg/kg) induced a significant increase in the number of NT mRNA-expressing neurons in the dorsomedial and dorsolateral striatum of wild-type mice but failed to stimulate NT gene expression in DAT mutants. In contrast, a higher dose of haloperidol (5 mg/kg) stimulated striatal NT mRNA expression both in DAT+/+ and DAT-/- mice. Amphetamine (10 mg/kg) increased the number of hybridized neurons in the nucleus accumbens shell and fundus striati of wild-type and DAT-/- mice, indicating that the drug acted through a target other than DAT, such as the serotonin or the norepinephrine transporters. The up-regulation of NT mRNA observed in DAT-/- mice may represent an adaptive mechanism in response to constitutive hyperdopaminergia. These results illustrate the profound alterations in the NT system induced by chronic stimulation of DA receptors and underscore the potential clinical relevance of NT/DA interactions in schizophrenia and drug abuse.
Roubert
C
C
INSERM U513, Neurobiology and Psychiatry, Faculté de Médecine de Créteil, 8 rue du Général Sarrail, 94000 Créteil, France.
Spielewoy
C
C
Soubrié
P
P
Hamon
M
M
Giros
B
B
Betancur
C
C
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D015870:Gene Expression / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D017403:In Situ Hybridization; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000172:deficiency*; D001523:Mental Disorders / Q000503:physiopathology*; D051379:Mice; D009419:Nerve Tissue Proteins; D009496:Neurotensin / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C493215:Slc6a3 protein, mouse; D009496:Neurotensin; D000661:Amphetamine; D006220:Haloperidol