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Title page for ETD etd-04262016-152731


Type of Document Dissertation
Author Joffe, Max Emanuel
Author's Email Address max.joffe@vanderbilt.edu
URN etd-04262016-152731
Title Nucleus accumbens n-methyl-d-aspartate receptor function and reward learning: implications for cocaine use disorders
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Christine Konradi Committee Chair
Ariel Deutch Committee Member
Brad Grueter Committee Member
Danny Winder Committee Member
Roger Colbran Committee Member
Keywords
  • cocaine
  • thalamus
  • nucleus accumbens
  • reward
  • addiction
Date of Defense 2016-04-12
Availability unrestricted
Abstract
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.

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