Date of Award

2020

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Thomas C. Jhou

Second Advisor

Brett Froeliger

Third Advisor

Dorothea Jenkins

Fourth Advisor

Peter Kalivas

Fifth Advisor

Bryan Tolliver

Abstract

Decades of studies have examined the mechanisms by which drugs of abuse produce strong rewarding effects that drive addictive behavior. However, these drugs also produce aversive effects that are less well understood, but that also strongly influence drug-seeking, and may contribute to individual variation in addiction liability. For example, individuals with particularly strong aversive responses to nicotine or alcohol may be less likely to acquire smoking or drinking habits, with these protective effects arising from specific biological differences in nicotinic receptor function or alcohol metabolism, respectively. These aversive effects can also be exploited therapeutically, as in widely available treatments for alcoholism and smoking. We and others found that cocaine also produces aversive effects that can slow or block drug-seeking, and that the magnitudes of these protective aversive effects also vary widely between individuals. However, the molecular substrates of cocaine's aversive effects, and of their variation between individuals, are almost entirely unknown. To examine these substrates, we examined functions of the rostromedial tegmental nucleus (RMTg), a major GABAergic input to midbrain dopamine neurons that plays key roles in aversive learning from cocaine and other stimuli. In particular, we found that RMTg neural activity is necessary for cocaine's conditioned aversive effects, and is correlated with aversion magnitude. Furthermore, in collaboration with a slice electrophysiologist in the lab (Dr. Jeffrey Parrilla-Carrero), we identified several molecular drivers of this activity showing that cocaine drives RMTg activation via glutamatergic signaling through calcium permeable AMPA receptors (CP-AMPARs) residing on RMTg neurons. Additional data showed that this receptor undergoes differential plasticity in response to cocaine, as it is downregulated in low cocaine-avoider rats having especially low aversive responses to cocaine, relative to high cocaine avoider rats with stronger aversive responses. We also showed that this modulation may be driven by the phosphatase enzyme, PTEN, which has been previously implicated in synaptic depotentiation. In particular, we found that inhibition of PTEN increases glutamate signaling in RMTg and reduces cocaine-seeking, suggesting PTEN as a novel therapeutic target for cocaine addiction. Because RMTg neurons send strong inhibitory projections to DA neurons in the ventral tegmetal area (VTA), which in turn project to the nucleus accumbens (NAc), and because of extensive prior studies implicating D2 medium spiny neurons (D2 MSNs) in avoidance behavior, we also looked at whether high- and low-avoiders have differences in D2 MSNs properties of the nucleus accumbens shell (NAshell) after exposure to cocaine. We found that aversion to cocaine in high-avoiders correlated with increased neuronal excitability, enhanced glutamate transmission and impaired long term depression (LTD) at excitatory synapse in D2-MSNs of the NAshell, and demonstrated that RMTg plays a role in modulating dopamine levels in the NAshell in response to noxious stimuli.

Rights

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