Dysregulation of the mesolimbic dopamine (DA) system is a hallmark of the pathophysiology of drug addiction and many other prevalent diseases. The nucleus accumbens (NAc), a region essential for the incentive and hedonic properties of drugs of abuse, is a key biological substrate. At least 90% of the neurons in the NAc are medium spiny neurons (MSNs), which provide the sole projections from the region. MSNs can divided into two classes by biochemistry and anatomy: D1(+) MSNs project primarily to midbrain DA areas, while A2A/D2(+) MSNs send afferents to the ventral pallidum. MSNs generally rest at relatively hyperpolarized membrane potentials, so excitatory drive is essential to governing the output of the NAc and subsequent complex behavioral outcomes. The prefrontal cortex (PFC), ventral hippocampus, and basolateral amygdala provide major excitatory inputs to the NAc and have been examined recently in the context of cocaine exposure. However, despite its comparable anatomical denseness, little is known about how afferents from the midline nuclei of the thalamus (mThal) to the NAc modulate reward-related behaviors and learning and memory processes.
While much remains to be understood, drug-induced modifications of excitatory signaling (i.e. synaptic plasticity) in the NAc have been suggested to underlie the maladaptive behaviors observed in addiction. N-methyl-D-aspartate receptors (NMDARs) are of paramount importance in regulating excitatory synaptic strength and learning and memory. Therefore we aimed to assess the function of NMDARs in NAc core D1(+) MSNs, with a particular emphasis on mThal inputs. We determined that cocaine sensitization and abstinence enhances NMDAR function at mThal-D1(+), mThal-D1(-), and PFC-D1(+) synapses. At mThal-D1(+) synapses specifically, we demonstrated that cocaine enhances GluN2C/D function and NMDAR-dependent synaptic plasticity. The role for these NMDARs cocaine-conditioned behaviors is evidenced by the finding that mice with a D1-specific GluN1 genetic deletion did not reinstate a place preference to cocaine. Collectively these data emphasize the emerging role for D1-NMDARs in reward learning, and highlight mThal inputs and GluN2C/D subunits as novel targets for the treatment of psychostimulant use disorders.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-04262016-152731 |
| Date | 26 April 2016 |
| Creators | Joffe, Max Emanuel |
| Contributors | Brad Grueter, Christine Konradi, Roger Colbran, Ariel Deutch, Danny Winder |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-04262016-152731/ |
| Rights | restrictsix, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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