# Cannabinoid receptor control of a DRN to VTA pathway and its role in affective states

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $347,625

## Abstract

PROJECT SUMMARY
Dopaminergic and serotonergic systems of the brain are associated with many psychiatric conditions including
addiction and depression. However, there has been less investigation regarding how these systems
dynamically interact to modulate changes in motivation following adverse events in early life and how they
regulate responses leading to recovery and gain of function. For example, clinical and preclinical findings that
exposure to exogenous cannabinoids such as Δ9-tetrahydrocannabinol (THC, the main psychoactive
component of marijuana) during adolescence, leads to motivational deficits similar to those caused by stress
that are consistent with compromised affective states such as depression. Exciting preliminary work from our
laboratory shows that serotonin (5HT) release in the ventral tegmental area (VTA) excites dopamine (DA)
neurons, enhances phasic DA release in the nucleus accumbens (NAc) and is reinforcing. Our preliminary data
also suggests that potential counter-motivational effects of adolescent THC can arise from a decrease in the
probability of neurotransmitter release from 5HT terminals in the VTA caused by activation of CB1 receptors on
these axons. Here, we propose two experiments to investigate the functional role of CB1 receptors on 5HT
terminals in the VTA. First, we will control CB1 receptor expression via cre-lox recombination approaches
involving cell-type specific loss of function and rescue to isolate the role of CB1 receptors on VTA 5HT
terminals to probe cue-related dopaminergic encoding of motivated behavior (aim 1). Next, we will determine if
chronic adolescent exposure to THC reduces motivation and its dopaminergic correlates in adulthood and
whether these maladaptive effects require CB1 receptors expressed on 5HT terminals in the VTA (aim 2). The
present study will incorporate a combination of behavior, anatomy, electrophysiology, fast-scan cyclic
voltammetry, virally-mediated gene transfer and optogenetics. In addition, experiments will include males and
females and will be replicated in adult animals. Specific genetic control of CB1 receptors on 5HT afferents to
VTA DA neurons and optogenetic interrogation of this circuit, will allow explicit tests of current hypotheses of
endocannabinoid function in motivation and the consequences of its dysfunction following THC exposure in
adolescence. Thus, by investigating 5HT terminal/DA interactions with CB1 receptor signaling, the present
proposal makes use of tools not yet applied to these questions to respond to NIDA's mission and to generate
new insights on therapeutic strategies for the treatment of conditions involving compromised motivation.

## Key facts

- **NIH application ID:** 9876941
- **Project number:** 5R01DA045639-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Joseph F Cheer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,625
- **Award type:** 5
- **Project period:** 2019-03-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876941

## Citation

> US National Institutes of Health, RePORTER application 9876941, Cannabinoid receptor control of a DRN to VTA pathway and its role in affective states (5R01DA045639-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9876941. Licensed CC0.

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