Date of Award
Master of Science (MS)
Dr. Chris Bishop
Dr. Yaoying Ma
Dopamine (DA) transmission in the striatum influences the motivated pursuit of rewarding stimuli. Pharmacological and opto- and chemo-genetic studies have suggested that the release of DA onto D2+/A2A+-expressing striatopallidal neurons, plays a role in this process. To determine the potentially dissociable roles of DA-releasing ventral midbrain and striatopallidal neurons on motivational processes, we employed double transgenic mice that expressed inhibitory DREADDs—designer receptors that are activated only by otherwise inert ligands—only in dopamine transporter (DAT) or A2A adenosine receptor (A2A) expressing neurons, allowing us to transiently inhibit either DA-releasing neurons (DATcre/DREADD) or striatopallidal neurons (A2Acre/DREADD) during various tests. In the first experiment, locomotor activity in a familiar environment was measured after mice received an injection of the DREADD ligand CNO (1 or 2.5 mg/kg) or vehicle. Both lines of mice exhibited decreases in spontaneous activity in response to the high dose of CNO. Second, voluntary consumption of sweetened condensed milk (SCM) was assessed. Both doses of CNO caused a significant decrease in SCM consumption in A2Acre/DREADD, but not DATcre/DREADD, mice. Finally, mice were trained and tested on a progressive ratio task, wherein increasing numbers of lever presses were required to obtain access to SCM. We found that CNO and Compound 21 (3 mg/kg) reduced active lever pressing in A2Acre/DREADD mice but not DATcre/DREADD mice. In none of these experiments were effects of CNO or Compound 21 detected in littermate control mice that were not double transgenic, supporting the idea that the effects observed were not due to back metabolization of CNO or other "off target" effects. Thus, inhibition of A2A-expressing (presumably striatopallidal) neurons suppresses free and effortful reward pursuit and consumption; the degree to which this is attributable solely to impaired motor activity requires further study. Further studies will also assess the opposite effects of activating these same neural populations using excitatory DREADD (Gq) construct. Overall, these data do not support the idea that dopaminergic neural activity plays a major role in motivation for a palatable reward, but does implicate A2A-expressing neurons in both motor and motivational phenotypes.
Wherry, James D., "Effects of Chemogenetic Inhibition of Dopamine Transporter- or A2A-Expressing Neurons On Spontaneous Activity and Motivation to Consume a Palatable Food Reward" (2018). Graduate Dissertations and Theses. 31.