The Influence of THC, Opioids, and Age on the Plasticity of Excitatory Inputs to Ventral Tegmental Area GABA Neurons
Adults exhibit significant differences in drug vulnerability, learning ability, and emotive processing than adolescents. Long-lasting synaptic changes, including long-term depression (LTD), can endure many hours and are believed to be key to encoding memories and persistent cognitive changes such as addiction. The ventral tegmental area (VTA) is the primary source of midbrain dopamine (DA) and is regulated by local inhibitory GABA neurons. GABA regulation can decrease, resulting in dis-inhibition of DA neurons and increased feelings of reward, learning, or salience attachment to memories. Endocannabinoids (eCBs) are signaling molecules that often result in synaptic plasticity changes, and the eCB system has shown pronounced cross-talk with opioid signaling and receptor pathways. We examined eCB mediated plasticity of excitatory inputs to GABA neurons within the VTA and how THC, opioids, and age influence this plasticity. We determined that direct CB1 receptor activation in the mouse results in reduced excitatory input activity to GABA, resulting in GABA depression. CB1-mediated GABA depression was lost following chronic exposure to THC, suggesting THC injection has already activated this pathway. Chronic THC occlusion of GABA LTD was then reversible following a week of drug withdrawal. Next, as adult animals tend to exhibit reduced emotive influence, learning, and drug affect when compared to adolescents we examined if LTD of VTA GABA neurons was present in adults. We determined that adult mice no longer undergo HFS-induced LTD. Interestingly, the eCB pathway is still active, as we determined that both CB1 receptor activation and mGluR5 activation still results in GABA depression in adults. We then determined that a greater electrical HFS could induce LTD of excitatory inputs to adult VTA GABA neurons, suggesting a change in adults leading to an increase in induction thresholds for GABA plasticity. Morphine was found to induce similar LTD of GABA neurons through the mu-opioid receptor in both adolescents and adults. This LTD is likely pre-synaptic, similar to THC induced LTD, and is potentially mediated through the same presynaptic pathways as CB1-dependent LTD as injection of either THC or morphine eliminates depression by the other. Chronic morphine injection eliminates HFS-induced LTD in adolescents but only results in a loss of LTD in 58% of adult experiments suggesting resistance to morphine exposure at this synapse in adults. In summary, THC and morphine appear to act pre-synaptically to induce GABA LTD within the VTA and occlude further LTD by the other drug. Additionally, development into adulthood significantly alters the propensity of GABA neurons to undergo plasticity and greater levels of stimulus are required to elicit lasting changes.
College and Department
Life Sciences; Physiology and Developmental Biology
BYU ScholarsArchive Citation
Ostlund, Isaac Brent, "The Influence of THC, Opioids, and Age on the Plasticity of Excitatory Inputs to Ventral Tegmental Area GABA Neurons" (2022). Theses and Dissertations. 9406.
Endocannabinoid, GABA, VTA, development, age, adult, opioid, THC, plasticity