Neurotensin Gene Expression and Behavioral Responses Following Administration of Psychostimulants and Antipsychotic Drugs in Dopamine D3 Receptor Deficient Mice

Exposure to psychostimulants and antipsychotics increases neurotensin (NT) gene expression in the striatum and nucleus accumbens. To investigate the contribution of D3 receptors to these effects we used mice with targeted disruption of the D3 receptor gene. Basal NT mRNA expression was similar in D3 receptor mutant mice and wild-type animals. Acute administration of haloperidol increased NT gene expression in the striatum in D3+/+, D3+/− and D3−/− mice. Similarly, acute cocaine and amphetamine induced NT mRNA expression in the nucleus accumbens shell and olfactory tubercle to a comparable extent in D3 mutants and wild-type mice. Daily injection of cocaine for seven days increased NT mRNA in a restricted population of neurons in the dorsomedial caudal striatum of D3+/+ mice, but not in D3−/− and D3+/− animals. No differences were observed between D3 receptor mutant mice and wild-type littermates in the locomotor activity and stereotyped behaviors induced by repeated cocaine administration. These findings demonstrate that dopamine D3 receptors are not necessary for the acute NT mRNA response to drugs of abuse and antipsychotics but appear to play a role in the regulation of NT gene induction in striatal neurons after repeated cocaine. In addition, our results indicate that the acute locomotor response to cocaine and development of psychostimulant-induced behavioral sensitization do not require functional D3 receptors.