Control of behavior by cocaine-sounds encoded in the auditory brainstem and a potential role for the locus coeruleus
Creators: name: Presker, Mark A.
Publisher: name: No Publisher Supplied
Year: 2024

description: Cocaine addiction is a chronic relapsing disorder characterized by the inability to regulate cocaine intake or discontinue use, despite negative health or social consequences. Over the course of initial cocaine use and the transition to addiction, associative-learning processes link sensory stimuli and drug taking to underlie the formation and expression of sensory-cued cocaine memories. Such “maladaptive” memories can initiate, control, and maintain maladaptive stimulus-initiated addiction behaviors like drug seeking and taking, or by inhibiting or otherwise disrupting naturally-motivated behavior (e.g., food and water consumption). Animal models of cocaine conditioning have identified cocaine-dependent plasticity and stimulus encoding in the mesocorticolimbic system as central to the dysregulation of motivation observed in cocaine addiction. However, the neural basis of stimulus control of behavior by cocaine-associated sensory cues remains largely unexplored, despite an extant body of literature on experience-dependent plasticity in primary sensory systems, e.g., like the auditory system, which can encode learned stimulus (sound cue) associations.This thesis reports a novel auditory cocaine conditioning (AuCC) paradigm in rats that blends standard auditory fear conditioning (AFC) and cocaine conditioned place preference (CPP) paradigms, in which cocaine is paired with exposure to a sound stimulus, producing cocaine-sound associative memories. AuCC was used to investigate the stimulus control properties of the cocaine-paired sound on multiple behavioral and neurobiological assays of auditory and neuromodulatory system function in the brainstem. The specificity of effects to cocaine were determined between-subjects conditioned with saline instead of cocaine, or within-subjects in rats conditioned with multiple tones, one paired with cocaine and another paired with saline. The specificity of effects to the stimulus features of the cocaine-paired sound were determined by comparing responses to paired, unpaired, or novel sound stimuli. Several key findings are reported that link cocaine-sound controlled behavior to neuroplasticity in the auditory brainstem and noradrenergic locus coeruleus (LC) activity that together may dynamically encode stimulus features of cocaine-associated sounds.First, AuCC successfully produces cocaine-sound associations, revealed in multiple forms of cocaine-sound control over spontaneous and motivated behaviors. Second, AuCC induces multiple forms of plasticity in auditory brainstem physiology that include general increases in evoked thresholds in the auditory brainstem response (ABR) across sounds, as well as stimulus-specific changes to sound-evoked amplitude and latency unique to cocaine-paired sounds. Third, cocaine-paired sound cues uniquely activate the LC while animals are in a drug-free state and this activation correlates with the cue-evoked modulation of spontaneous behaviors. Altogether, the significance of the findings herein indicates a role for the auditory brainstem and LC in associative learning processes underlying the control of natural behaviors by cocaine-associated sounds.These findings are consistent with an overarching model wherein sensory-drug associations are encoded by neuroplasticity in sensory systems and mediated by neuromodulator systems that enable cues to gain control of behavior and subserve addiction phenotypes.