Kaplan Lab
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Background Information

Opioid Addiction

Addiction is defined by American Psychiatric Association in the Diagnosistic and Statistic Manual 5 (DSM-5) as chronic disease of brain reward, motivational, executive and cognitive-related circuitry leading to this illness. It is defined by a problematic pattern of drug use leading to clinically significant impairment or distress, as manifested: Drug is often taken in larger amounts or over a longer period than was intended. There is a persistent desire or unsuccessful efforts to cut down or control drug use. A great deal of time is spent in activities necessary to obtain drug, use drug, or recover from its effects. Craving, or a strong desire or urge to use drug. Recurrent drug use resulting in a failure to fulfill major role obligations at work, school, or home. Recurrent drug use in situations in which it is physically hazardous. Drug use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by drug. Tolerance, as defined by markedly increased amounts of drug to achieve intoxication or desired effect and/or markedly diminished effect with continued use of the same amount of drug. There is a Withdrawal, as manifested by either of characteristic aversive withdrawal syndrome in which the drug is taken to relieve withdrawal symptoms. Our group studies animal models of opioid addiction to understand it neurobiological pathophsiology and to define new and effect approaches for this deadly condition. 

Opioids are addictive substance that produce pain relief and pleasure. While some opioids are legally prescribed to help manage severe pain, some users spiral to abusing their prescription, and seeking opioids beyond their prescribed time. The percentage abuse of prescription opiates is greater than heroin or cocaine abuse. Opioid addiction is a chronic disease with great morbidity and mortality can lead to death by overdose.

National drug overdose deaths number among all ages, 199-2017. From NIDA Overdose Death Rates.

National drug overdose deaths number among all ages, 199-2017. From NIDA Overdose Death Rates.

National drug overdose deaths involving prescription opioids, number among all ages, 1999-2017. From NIDA Overdose Death Rates

National drug overdose deaths involving prescription opioids, number among all ages, 1999-2017. From NIDA Overdose Death Rates


Post-Traumatic Stress Disorder (PTSD)

From: National Institute of Health Website

From: National Institute of Health Website

Post-traumatic stress disorder (PTSD) as described by American Psychiatric Association is a psychiatric disorder that occurs in people who have witnessed a traumatic event. There are four types of PTSD symptoms (although varies per person): reliving the event, avoiding reminders of the event, negative changes in beliefs and feelings, and hyperarousal. These symptoms can last from months to years. The exact neurobiology of PTSD is not fully understood, but it is well documented that prefrontal cortex, amygdala, hippocampus, and anterior cingulate cortex are involved. We study animal models of PTSD in order to better understand this condition and to define more effective treatments for this disabling disorder.


Traumatic Brain Injury (TBI)

 
 
From Department of Defense Special Report

From Department of Defense Special Report

TBI can result blunt force trauma to the head where the severity leads to altered or loss of consciousness. Depending on the severity of injury, TBI can range from mild (loss of conscious is brief of few seconds to minutes) to moderate (loss of consciousness last minutes to hours) to severe (skull gets crushed or seriously fractured). Mild severity TBI is most common version suffered by Veterans, therefore it is what we focus on. Symptoms of mild TBI include but not limited to: headaches, sensitivity to sound & light, sleep disturbances, impaired concentration & memory, increase in anxiety and depression. Complete recovery of mild TBI takes days to weeks, but symptoms can persist for months and years

 
 
 

Impact on Veterans

From Veterans Affairs Public Health Website

From Veterans Affairs Public Health Website

At Veteran Affairs Healthcare System, we focus our research to help support Veterans with TBI and PTSD. Unfortunately, the current Iraqi & Afghanistani wars with the advanced explosives and intensive combat in war zones, have lead to almost quarter of the Veteran population suffering TBI, and 40-50% demonstrated PTSD symptoms. Often, the injury leading to TBI comes with traumatic experience causing PTSD.  In fact, 44% of TBI inflicted U.S Army soldiers returning from Iraq had met the criteria for PTSD.

In military and VA settings, soldiers and Veterans face acute or chronic pain that is managed by opiate narcotics. Unfortunately, due the addictive properties of opioids, many Veterans are misuse prescribed opioids, consistent with an Opioid Use Disorder. A study showing over 500,000 veterans who met the criteria for chronic opioid treatment, only 7.5% discontinued opioid use after year. We are examining mechanisms underlying the comorbidity of TBI and potential novel and more effective treatments for both.

 
 

Current projects

 

TBI & PTSD

Using Lateral Fluid Percussion for TBI and Fear Conditioning for PTSD on mouse model to see the full spectrum of the comorbid effects: from behavior to neuronal plasticity

PTSD & Opioid Addiction

With the rise of opioid epidemic, it is imperative to see how the PTSD population are more vulnerable to opioids. We use Fear Conditioning with Opioid Conditioned Place Preference on mouse model to represent the comorbid human condition.

 
 
 

Previous Research

 
 

Fear conditioning increased BLA spine density, reversed by extinction

Figure 1. From: Heinrichs SC, Leite-Morris KA, Guy MD, Goldberg LR, Young AJ, Kaplan GB. Dendritic structural plasticity in the basolateral amygdala after fear conditioning and its extinction in mice. Behavioural brain research. 248:80-4, 2013

Figure 1. From: Heinrichs SC, Leite-Morris KA, Guy MD, Goldberg LR, Young AJ, Kaplan GB. Dendritic structural plasticity in the basolateral amygdala after fear conditioning and its extinction in mice. Behavioural brain research. 248:80-4, 2013

CB57/6BJ mice were exposed to tone-shock fear paradigm, undergo extinction of the fear, and then Golgi stained to trace neurons for structural plasticity changes in the basal lateral amygdala (BLA). The structural plasticity measures were spine density and Sholl analysis. We found that fear conditioning increase spine density in the BLA but went back to normal levels after extinction (Figure 1A). More specifically these increases in spine density was found in the 2nd through 4th branch order (Figure 1B). Sholl analysis continued to show increase in structural plasticity for the fear conditioned mice only, with increased dendritic branch intersections (Figure 2C). 

*p < 0.05, **p < 0.01 for differences between the unconditioned/extinction control group and the fear conditioned/sham extinction group and #p < 0.05 for differences between the fear conditioned/sham extinction group and the fear conditioned/extinction group (n = 15 neurons/treatment group).

 
 

Morphine CPP increases NAc core spine density, not NAc shell

CB57/6BJ mice undergo conditioned place preference (CPP) paradigm to morphine (10 mg/kg) for nine days. After final preference test, mice were Golgi stained to trace neurons for structural plasticity changes in the nucleus accumbens (NAc) in both core and shell. The structural plasticity measures were total dentitric length, number of dendrites, and spine density. Mice exposed to morphine CPP had higher dendritic length and number in NAc compare to both saline and morphine homecage controls (Figure 2A & 2B). There were no significant difference in NAc shell (Figure 2C & 2D). Spine density was also shown to increase in NAc core for morphine CPP compared to saline and morphine homecage controls.

*p<0.05

Figure 2. From: Kobrin KL, Moody O, Arena DT, Moore CF, Heinrichs SC, Kaplan GB. Acquisition of morphine conditioned place preference increases the dendritic complexity of nucleus accumbens core neurons. Addiction biology. 21(6):1086-96, 2016

Figure 2. From: Kobrin KL, Moody O, Arena DT, Moore CF, Heinrichs SC, Kaplan GB. Acquisition of morphine conditioned place preference increases the dendritic complexity of nucleus accumbens core neurons. Addiction biology. 21(6):1086-96, 2016


Intermittent morphine increased FosB in motivational, stress, and associative learning pathways

Figure 3. From: Kaplan GB, Leite-Morris KA, Fan WY, Young AJ, Guy MD. Opiate sensitization induces FosB/ΔFosB expression in prefrontal cortical, striatal and amygdala brain regions. PLoS One 6(8):e23574, 2011

Figure 3. From: Kaplan GB, Leite-Morris KA, Fan WY, Young AJ, Guy MD. Opiate sensitization induces FosB/ΔFosB expression in prefrontal cortical, striatal and amygdala brain regions. PLoS One 6(8):e23574, 2011

CB57/B6J mice had 6 pre-treatment administrations of either morphine (10mg/kg) or saline (vehicle). After all mice had motor activity test, the mice were sacrificed and the FosB/ΔFosB levels were quantitatively analyzed. FosB/ΔFosB were measured in control motor region (M1/2), prelimic (PL), infralimbic (IL), nucleus accumbens core & shell (NAcC & NAcS), medial caudate-putamen (CPU), basolateral amygdala (BLA), and central nucleus of amygdala (CNA). There was increase of FosB/ΔFosB expression in the motivational (NAc), stress (CNA), and associative learning (PL, IL, BLA) pathways for the morphine treated mice (Figure 3). No changes in FosB/ΔFosB expression in the motor pathways (M1/M2).

*p<0.05, **p<0.01, and ***p<0.001 vs. vehicle pre-treatment group.