Altered baseline and amphetamine-mediated behavioral profiles in dopamine transporter Cre (DAT-Ires-Cre) mice compared to tyrosine hydroxylase Cre (TH-Cre) mice

• Published in: Psychopharmacology 2020-12, Vol.237 (12), p.3553-3568
• Main Authors: Chohan, Muhammad O., Esses, Sari, Haft, Julia, Ahmari, Susanne E., Veenstra-VanderWeele, Jeremy
• Format: Article
• Language: English
• Subjects: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine - pharmacology; Agonists; Amphetamine - pharmacology; Amphetamines; Animals; Behavior; Biomedical and Life Sciences; Biomedicine; Dopamine; Dopamine - metabolism; Dopamine Agonists - pharmacology; Dopamine D1 receptors; Dopamine Plasma Membrane Transport Proteins - metabolism; Dopamine transporter; Experiments; Gene expression; Grooming; Hydroxylase; Insertion; Integrases - genetics; Locomotion; Locomotion - drug effects; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurosciences; Novelty; Original Investigation; Pharmacology/Toxicology; Phenotypes; Preservatives; Psychiatry; Recombinase; Rodents; Stereotyped behavior; Stereotyped Behavior - drug effects; Transgenic mice; Tyrosine 3-monooxygenase; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-020-05635-4

Rationale Transgenic mouse lines expressing Cre-recombinase under the regulation of either dopamine transporter (DAT) or tyrosine hydroxylase (TH) promoters are commonly used to study the dopamine (DA) system. While use of the TH promoter appears to have less liability to changes in native gene expression, transgene insertion in the DAT locus results in reduced DAT expression and function. This confound is sometimes overlooked in genetically targeted behavioral experiments. Objectives We sought to evaluate the suitability of DAT-Ires-Cre and TH-Cre transgenic lines for behavioral pharmacology experiments with DA agonists. We hypothesized that DAT-Ires-Cre expression would impact DAT-mediated behaviors, but no impact of TH-Cre expression would be observed. Methods DAT-Ires-Cre and TH-Cre mice bred on mixed 129S6/C57BL/6 and pure C57BL/6 backgrounds were evaluated for novelty-induced, baseline, and amphetamine (AMPH)–induced locomotion, and for AMPH and D1 agonist (SKF-38393)–induced preservative behaviors. Results DAT-Ires-Cre mice on both mixed 129S6/C57BL/6 and pure C57BL/6 backgrounds displayed increased novelty-induced activity and decreased AMPH-induced locomotion, with mixed results for AMPH-induced stereotypy. TH-Cre mice on both backgrounds showed typical baseline activity and AMPH-induced stereotypy, with a difference in AMPH-induced locomotion observed only on the mixed background. Both transgenic lines displayed unaltered SKF-38393-induced grooming behavior. Conclusions Our findings indicate that the DAT-Ires-Cre transgenic line may lead to confounds for experiments that are dependent on DAT expression. The TH-Cre transgenic line studied here may be a more useful option, depending on background strain, because of its lack of baseline and drug-induced phenotypes. These data highlight the importance of appropriate controls in studies employing transgenic mice.