title: Quantitative pharmacologic MRI: mapping the cerebral blood volume response to cocaine in dopamine transporter knockout mice.
abstract: The use of pharmacologic MRI (phMRI) in mouse models of brain disorders allows noninvasive in vivo assessment of drug-modulated local cerebral blood volume changes (ΔCBV) as one correlate of neuronal and neurovascular activities. In this report, we employed CBV-weighted phMRI to compare cocaine-modulated neuronal activity in dopamine transporter (DAT) knockout (KO) and wild-type mice. Cocaine acts to block the dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT) that clear their respective neurotransmitters from the synapses, helping to terminate cognate neurotransmission. Cocaine consistently reduced CBV, with a similar pattern of regional ΔCBV in brain structures involved in mediating reward in both DAT genotypes. The largest effects (-20% to -30% ΔCBV) were seen in the nucleus accumbens and several cortical regions. Decreasing response amplitudes to cocaine were noted in more posterior components of the cortico-mesolimbic circuit. DAT KO mice had significantly attenuated ΔCBV amplitudes, shortened times to peak response, and reduced response duration in most regions. This study demonstrates that DAT knockout does not abolish the phMRI responses to cocaine, suggesting that adaptations to loss of DAT and/or retained cocaine activity in other monoamine neurotransmitter systems underlie these responses in DAT KO mice.
authors.affiliation: Biological Imaging Center, Beckman Institute, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Teodora-Adriana
authors.initials: TA
authors.lastname: Perles-Barbacaru
authors.forename: Daniel
authors.initials: D
authors.lastname: Procissi
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Demyanenko
authors.forename: F Scott
authors.initials: FS
authors.lastname: Hall
authors.forename: George R
authors.initials: GR
authors.lastname: Uhl
authors.forename: Russell E
authors.initials: RE
authors.lastname: Jacobs
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005260:Female; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D003042:Cocaine