Psychostimulants act by increasing synaptic dopamine levels, principally in the nucleus accumbens. When taken repeatedly, constant psychostimulant doses produce an increasing behavioral response - known as psychostimulant sensitization. This animal model of drug dependence is mediated by neuroplastic changes both at the level of the dopamine neuron cell bodies in the ventral tegmental area and a their synapses in the nucleus accumbens. These changes require glutamatergic synaptic transmission. Recently, this laboratory has made the striking observation that dopamine neurons corelease glutamate. If so, glutamatergic synapses of dopamine neurons are likely to be important in sensitization. To test this, mice generated in this laboratory with fluorescent dopamine neurons will be used to examine the relationship between the dopaminergic ami glutamatergic terminals of single dopamine neurons and to assess the plastic capabilities of the glutamatergic synapses as a basis for sensitization. To address the role of the glutamatergic cotransmission in the behaving animal, another line of mice have been made that lack glutaminase - the enzyme principally responsible for Ihe production of neurotransmitter glutamate. Preliminary results confirming the importance of glutaminase will be extended to test this definitively. Interestingly, mice heterozygous for glutaminase appear to be already in a sensitized state, as they show an exaggerated response to stimulants. Using tissue-specific rescue and deletion approaches, the final aim is to identify the crucial glutamatergic circuits underlying the sensitized phenotype. Finally, the role of glutamatergic cotransmission by dopamine neurons in the development of sensitization will be tested in mice lacking glutaminase in their dopamine neurons. This integrated approach should help to elucidate the crucial glutamatergic circuits underlying sensitization, and offer new targets lor the pharmacological reduction of sensitization and thus of drug dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA017978-04
Application #
7460595
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Frankenheim, Jerry
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$276,734
Indirect Cost
Name
New York State Psychiatric Institute
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Mingote, Susana; Chuhma, Nao; Kalmbach, Abigail et al. (2017) Dopamine neuron dependent behaviors mediated by glutamate cotransmission. Elife 6:
Chuhma, Nao; Mingote, Susana; Moore, Holly et al. (2014) Dopamine neurons control striatal cholinergic neurons via regionally heterogeneous dopamine and glutamate signaling. Neuron 81:901-12
Mihali, Andra; Subramani, Shreya; Kaunitz, Genevieve et al. (2012) Modeling resilience to schizophrenia in genetically modified mice: a novel approach to drug discovery. Expert Rev Neurother 12:785-99
Gaisler-Salomon, Inna; Wang, Yvonne; Chuhma, Nao et al. (2012) Synaptic underpinnings of altered hippocampal function in glutaminase-deficient mice during maturation. Hippocampus 22:1027-39
Chuhma, Nao; Tanaka, Kenji F; Hen, René et al. (2011) Functional connectome of the striatal medium spiny neuron. J Neurosci 31:1183-92
Hnasko, Thomas S; Chuhma, Nao; Zhang, Hui et al. (2010) Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. Neuron 65:643-56
Chuhma, N; Choi, W Y; Mingote, S et al. (2009) Dopamine neuron glutamate cotransmission: frequency-dependent modulation in the mesoventromedial projection. Neuroscience 164:1068-83
Masson, Justine; Darmon, Michele; Conjard, Agnes et al. (2006) Mice lacking brain/kidney phosphate-activated glutaminase have impaired glutamatergic synaptic transmission, altered breathing, disorganized goal-directed behavior and die shortly after birth. J Neurosci 26:4660-71