Abstract

The brain is an intricate network of neurons that communicate via synapses. Synaptic plasticity, which is the ability to strengthen or weaken synaptic connections, plays a key role in learning, memory, and reward learning. Disruptions to synaptic plasticity play a central role in addiction, particularly in brain circuits involved in reward and motivation. The mesolimbic reward system, which includes the ventral tegmental area (VTA) and its dopaminergic projections, is a primary target of drugs of abuse, including opioids and cannabinoids. However, the physiological consequences of combined exposure to opioids and cannabinoids and the potential for psychedelics to reverse drug-induced neuroadaptations remain poorly understood. Polysubstance use, particularly the combined use of opioids and cannabis, is common among people with opioid use disorder. However, the effects of polydrug use are not well understood. Both drugs increase dopamine release by disinhibiting VTA dopamine neurons, yet their combined effects on synaptic plasticity remain unclear. We show that morphine and THC together enhance dopamine neuron firing and bursting while suppressing VTA GABA neuron activity, eliminating LTD at excitatory synapses. Behavioral analyses reveal distinct anxiety-related phenotypes in polysubstance-treated mice. Because age is a key variable to consider when assessing the effects of drugs of abuse, we sought to determine whether young mice undergo THC-induced alterations to VTA GABA cell plasticity after fewer exposures than their adult counterparts. Experiments were done in young (P14-P54) and adult (P66-P240) mice treated with THC or vehicle control for 3 days, to assess age-dependent variability in THC effects on synaptic plasticity and gene expression. Plasticity was eliminated in young but not adult mice after 3 days of THC treatment. Quantitative real-time PCR revealed no THC-induced changes for young or adult mice but did show several differences between young and adult control mice. These age-dependent differences could reveal a physiological mechanism underlying increased sensitivity of adolescents to THC. Psychedelics such as LSD show promise in reversing drug-induced neuroadaptations, like the ones caused by exposure to drugs of abuse. Our findings demonstrate that a single LSD treatment restores LTD in VTA GABA cells of morphine-exposed mice and reduces morphine preference in a conditioned place preference paradigm, suggesting a role for psychedelics in reversing maladaptive plasticity related to drug dependence. These suggest a potential physiological mechanism behind the therapeutic potential of psychedelics for substance use disorders and other neuropsychiatric conditions.

Degree

PhD

College and Department

Life Sciences; Neuroscience

Rights

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