Bridgeside Labs Addiction Research: Molecular Psychiatry, The Journal of Neuroscience, & Psychopharmacology

The Huang, McClung, and Torregrossa Labs at the University of Pittsburgh’s Bridgeside Point II facility are part of the Department of Psychiatry’s Translational Neuroscience Program, which seeks to understand the neurobiological basis for complex human cognitive and emotional functions, and the manner in which alterations in the brain give rise to the types of disturbances in these functions that characterize psychiatric disorders.

Below, three recent Bridgeside studies investigate the association among drug exposure and sleep, circadian rhythms, or neural development.

Molecular Psychiatry: Cocaine Use, Rapid Eye Movement Sleep, and Relapse after Withdrawal

In a study recently published in Molecular Psychiatry researchers including lead author Yao Wang, PhD (Research Assistant Professor of Psychiatry), Rong Guo, PhD (Department of Psychiatry postdoctoral scholar), Marianne Seney, PhD (Assistant Professor of Psychiatry), and senior author Yanhua Huang, PhD (Associate Professor of Psychiatry) investigated the relationship between sleep and addiction, specifically whether and how cocaine use produces  persistent changes in rapid eye movement (REM) sleep. They focused on the melanin-concentrating hormone neurons in the lateral hypothalamus. 

Dr. Wang explained, “We know that chronic drug users often experience fragmented sleep. But the underlying mechanism remains unclear. It has been reported that hypothalamic melanin-concentrating hormone neurons became active during REM sleep, and the acute activation of melanin-concentrating hormone neurons during REM sleep could increase the duration of these sleep episodes. We wanted to see how cocaine changed gene expressions in melanin-concentrating hormone neurons, as well as in their functions.”

Using adult male rats trained to self-administer intravenous cocaine, the team did transcriptome profiling of melanin-concentrating hormone neurons in the lateral hypothalamus neurons after long-term withdrawal using RNA-sequencing. They found that cocaine exposure persistently altered gene expression profiles and electrophysiological properties of the lateral hypothalamus melanin-concentrating hormone neurons. Counteracting cocaine-induced hypoactivity of these neurons selectively in sleep enhanced REM sleep quality and quantity after long-term withdrawal. 

“Because of the broad impact of the melanin-concentrating hormone system throughout the brain, the new findings reveal new possibilities by which cocaine experience may induce maladaptive changes in the brain that leads to behavioral consequences. By leveraging the melanin-concentrating hormone system, we hope to find out next whether the benefits go beyond having better REM sleep,” Dr. Huang said.

Cocaine-induced neural adaptations in the lateral hypothalamic melanin-concentrating hormone neurons and the role in regulating rapid eye movement sleep after withdrawal 
Wang Y, Guo R, Chen B, Rahman T, Cai L, Li Y, Dong Y, Tseng GC, Fang J, Seney ML, Huang YH

Molecular Psychiatry (2020).

The Journal of Neuroscience: Circadian Disruption and Drug Use

The McClung lab, led by Colleen McClung, PhD (Professor of Psychiatry and Clinical and Translational Science), conducts research focused on how circadian rhythms and individual circadian genes regulate mood and addiction. Circadian disruptions are a common symptom of substance use disorders and chronic exposure to drugs of abuse alters circadian rhythms, which may contribute to subsequent substance use. Research has shown that the circadian transcription factor neuronal PAS domain protein 2 (Npas2) is enriched in reward-related brain regions and regulates reward, but its role in substance use is unclear. A recent paper published in The Journal of Neuroscience from investigators including Lauren DePoy, PhD (postdoctoral scholar), and Dr. McClung, reports findings from a study designed to examine the role of Npas2 in drug-taking. The scientists measured intravenous cocaine self-administration in wild-type and Npas2 mutant mice at different times of day.

“This study finds that when there is a disruption in Npas2, a gene important in circadian rhythms, this generally leads to increases in addiction-like behavior,” said Dr. McClung, the paper’s senior author. “We also found some unexpected sex differences in response in that females were more vulnerable to these effects than males.”

“This sex difference was particularly present during the dark, or active, phase, with Npas2 mutation increasing self-administration, reinforcement, motivation, extinction responding and reinstatement in females, but only reinforcement in males,” added Dr. DePoy, the study’s lead author.

Dr. McClung concluded, “Taken together, this study identifies some of the important mechanistic links between circadian rhythm disruption and vulnerability for substance abuse.” 

*The Journal of Neuroscience featured this study as a most-discussed article in December 2020.*

Circadian- and sex-dependent increases in intravenous cocaine self-administration in Npas2 mutant mice
DePoy LM, Becker-Krail DD, Zong W, Petersen K, Shah NM, Brandon JH, Miguelino AM, Tseng GC, Logan RW, McClung CA

J Neurosci. 2020 Nov 24:JN-RM-1830-20. doi: 10.1523/JNEUROSCI.1830-20.2020. Epub ahead of print. PMID: 33268545.

Psychopharmacology: The Effects of Adolescent Δ-9-Tetrahydrocannabinol (THC) Exposure

Because initial exposure to cannabinoids often occurs during adolescence, and long-lasting deficits in cognitive function can occur as a result of adolescent cannabis use, Pitt Psychiatry investigators Sierra Stringfield, PhD (Department of Psychiatry postdoctoral scholar), and Mary Torregrossa, PhD (Associate Professor of Psychiatry), sought to establish a novel procedure for achieving intravenous THC self-administration in adolescent rats to determine if volitional THC intake in adolescence produced indices of addiction-related behavior, altered working memory performance in adulthood, or altered the expression of proteins associated with these behaviors across several brain regions. 

In a recent Psychopharmacology study, they reported that both male and female adolescent rats self-administered THC and exhibited cue-induced lever pressing throughout abstinence. THC-exposed males exhibited slightly enhanced working memory performance in adulthood, and better performance positively correlated with total THC self-administered during adolescence, but this was not true in females. Adolescent THC-exposed rats exhibited reductions in cannabinoid receptor type 1, gamma-aminobutyric acid, and glutamate receptor protein, primarily in the prefrontal cortex, dorsal hippocampus, and ventral tegmental area.

“Cannabis use often begins during adolescence, coinciding with the maturation of multiple neural systems. This study investigated how exposure to the primary psychoactive component of cannabis, THC, influences the way these systems develop and contribute to behavior,” said Dr. Stringfield, the study’s lead author. “We conclude that the effects of adolescent THC exposure may depend on sex or the amount of drug taken, and they can persist into adulthood even after a period of abstinence.”

Intravenous self-administration of delta-9-THC in adolescent rats produces long-lasting alterations in behavior and receptor protein expression
Stringfield SJ, Torregrossa MM

Psychopharmacology 238, 305–319 (2021).