Endogenous Cannabinoid Control of Reward Substrates

PROJECT SUMMARY
One of the primary functions of the brain is to calculate the most adaptive action for the organism to make
under a given set of environmental conditions. This process requires learning which features in the
environment predict ethological relevance and subsequently deciding which actions to take, given the probable
outcome of those actions. Hence, neural substrates for reward prediction must interact with those controlling
behavioral output. The neuromodulator dopamine is a critical component of this interaction. Dopaminergic
neurons in the midbrain are excited by rewards not predicted by the current environment. However, when
stimuli reliably predict reward, they decrease activity time locked to the reward and shift to the environmental
predictors themselves. Therefore, dopamine is thought of as a teaching signal that broadcasts stimuli-related
reward predictions. Data from the previous funding cycles showed that endocannabinoids in the ventral
tegmentum sculpt cue-induced surges in dopamine release in the nucleus accumbens during reward seeking.
We hypothesized, but never unambiguously demonstrated, that this arises from release of the
endocannabinoid 2AG from dopamine neurons themselves, which lessens their level of inhibition. This
disinhibition mechanism is highly conserved as we found that it occurs during the pursuit of apetitive rewards
but also during the avoidance of punishment. However, the precise excitatory input to the ventral tegmentum
responsible for the on-demand release of 2AG from dopamine neurons is not known. Here, we propose
experiments to further elucidate the role of endocannabinoid signaling in encoding of reward-related cues and
its role in motivation. First, we will assess, using genetic dissection approaches, whether 2AG is indeed
released from dopamine neurons for their activity to conform to reward prediction theories and whether it can
causally influence behavior (aim 1). Next, we will determine which CB1 receptor-expressing afferents to
dopamine neurons in the VTA are responsible for the disinhibitory actions of 2AG during cue-driven reward
seeking. We will provide further mechanistic insight to these questions by studying the excitatory afferents that
give rise to 2AG-dependent dopamine neuron disinhibition during the pursuit of rewards (aim 2). Thus, we will
isolate the different components necessary for endocannabinoid signaling to modulate motivational processes
using a methodologically-integrated approach, as specific genetic control of 2AG production and CB1 receptor
expression will allow explicit tests of current hypotheses of endocannabinoid modulation of motivated behavior.
The present proposal makes use of tools not yet applied to these questions to generate new insights on
therapeutic strategies for the treatment of motivational disorders such as maladaptive drug seeking.

Grant Number: 5R01DA022340-15
NIH Institute/Center: NIH
Principal Investigator: Joseph Cheer