Effects of Early-Adolescent, Mid-Adolescent, or Adult Stress on Morphine Conditioned Place Preference

Early-life stress is correlated with negative mental health outcomes, including illicit drug abuse. One mechanism that may contribute to drug abuse is stress-induced elevation of drug reward. Place conditioning paradigms show that exposure to uncontrollable stress as an adult enhances opiate conditioned place preference, CPP. The present work addressed whether early-adolescent, mid-adolescent, or adult stress amplified morphine CPP. Male Sprague-Dawley rats were randomly assigned to stress or no stress conditions and received stress during early-, mid-adolescence, or adulthood. Stressors were unpredictable consisting of exposure to synthetic fox odor (trimethylthiazoline) and an elevated platform. Morphine place conditioning occurred during adulthood, and all animals received either morphine (15 mg/kg) on the initially non-preferred side or saline (1 ml/kg) on the initially preferred side. A post-test was conducted and time on non-preferred side was analyzed. A 2 (S/NS) x 2 (pre-/post-test) x 3 (early-adolescent/mid-adolescent/adult) mixed ANOVA revealed a significant main effect of test, F(1,42)=115.90, p \u3c .001

Opiate Drug Seeking and Addiction: The Influence of Sucrose Consumption on the Acquisition and Expression of Morphine-induced Conditioned Place Preferences (CPP)

Sucrose intake may lead to changes in brain and behavior similar to the effects of abused drugs. For example, sucrose may agonize endogenous opiate systems and modulate opiate-seeking behavior. Previous research reported equivocal outcomes where sucrose may either enhance (i.e., cross-sensitization) or attenuate (i.e., cross-tolerance) drug seeking as measured by morphine-induced CPP. The present experiment extends from past work and evaluated the impact of sucrose administered prior to place conditioning. Additionally, unique groups received sucrose prior to tests for CPP to measure sucrose influences on CPP expression. Sprague-Dawley rats (n=24) were assigned to sucrose (15% w/v) or water pre-exposure conditions. Subsequently, subjects received morphine place conditioning where morphine (10mg/kg) was administered on the initially non-preferred side of the apparatus. Three post-tests were conducted and, prior to each test, animals within each pre-exposure group (sucrose or water) received either sucrose or water. Factorial ANOVA was used to analyze data. Results showed robust morphine-induced CPP. Although animals in the sucrose pre-exposure condition displayed enhanced CPP, the outcomes were not statistically significant. The present findings support the value of CPP techniques to measure opiate drug-seeking behavior. Future work may discover the sufficient conditions for detecting sucrose cross-sensitization of morphine CPP

Behavioral and Neural Pharmacology of Drug-Seeking Behavior and Addiction

This sabbatical allowed me to secure a Visiting Scientist position in the Behavioral Neuroscience Department at OHSU where I collaborated with Dr. Christopher L. Cunningham and his research team. His laboratory employs conditioning paradigms to explore genetic factors, brain systems, neurotransmitters and information processing mechanisms that drive alcohol seeking behavior and alcohol dependence. Our research questions extended from earlier studies that implicated endogenous opiate systems in alcohol’s neuropharmacological effects. For example, the opiate receptor antagonist Naloxone, when administered prior to test, reduced expression of previously learned alcohol-induced conditioned place preferences (CPP) and facilitated extinction of CPP. Naloxone’s capacity to augment reduction of alcohol-seeking behavior in DBA/2J mice may yield important translational research applications to curb alcohol-seeking behavior in humans. An equally important problem related to opiate systems is the potential impact of opiate agonists on expression and extinction of alcohol-induced CPP. Opiate use and abuse is a significant public health problem impacting individuals and society. Potentially, opiate agonists may interact with other drug use, like alcohol, in unique ways, and alcohol-induced place conditioning affords an opportunity to experimentally evaluate that question. More specifically, will morphine, an opiate agonist, alter either expression or extinction of alcohol-induced CPP? Preliminary outcomes suggest that opiate agonists may enhance expression of ethanol-induced CPP as well as slow extinction of CPP. Further, at least in DBA/2J mice, opiate enhancement of ethanol CPP may be mediated by the activity-suppressing impact of morphine. Importantly, these projects may contribute to findings that will be applied to human drug addiction and add to our understanding of opiate use risk factors that may contribute to alcohol abuse and alcoholism

Adolescent Stress Enhances Morphine Conditioned Place Preference in Rats

Past research using rat models suggests that uncontrollable stress experienced as an adult enhances morphine’s rewarding properties using place conditioning techniques (Will, Watkins \u26 Maier, 1997; Der-Avakian et al., 2007). Recent work using a new peripubertal stress paradigm indicates that exposure to fear inducing stressors, synthetic fox odor (TMT) and an elevated platform (EP), during postnatal days 28 through 42 (P28-P42) increases aggression in adulthood (Marquez et al., 2013). Few studies have explored whether adolescent stress enhances morphine-induced conditioned place preference (CPP), and the present work adapts a new stress paradigm to explore modulation of opiate reward. Adolescent Sprague-Dawley rats (n=12) arrived P25 and the stress phase commenced P28. Half of the animals remained in the homecage (No Stress, NS). The remaining animals received two stressors (Stress, S), exposure to fox urine (TMT) and an elevated platform (EP). The S treatment continued 7 days starting P28 (EP only), P29 (EP, TMT), P30 (TMT, EP), P31 (TMT only), P33 (EP only), P34 (EP, TMT) and P35 (EP only). TMT exposure occurred in a cage containing a small cloth saturated with 10 mls of TMT for 25 mins. EP exposure occurred by placing each animal on a 12x12 cm platform atop a 95 cm tall column for 25 mins. Two days after the stress phase, all rats received morphine place conditioning. Subjects received a 15-minute preference test (Pre-test) to determine the initially nonpreferred side of the apparatus followed by 8 conditioning days. On alternating days, each animal received either morphine (15 mg/kg, IP) in the initially nonpreferred side of the apparatus (B/G+ (black/grid) or W/H+ (white/hole)) or saline solution (1 ml/kg, IP) in the non-drug paired side of the apparatus for 15 minutes. After the last day of conditioning, a place preference test (Post-test) was conducted identical to the pre-test. Time on the nonpreferred side of the apparatus served as the primary dependent measure. A 2 (S v. NS) X 2 (Pre- v. Post-test) mixed ANOVA revealed significant main effects of stress (F(1,10)=6.854, p=.026) and test (F(1,10)=49.47, p=.000). A statistically significant interaction showed a unique effect of stress during post-test indicating that adolescent stress increases morphine CPP (F(1,10)=6.981, p=.025). Similar to uncontrollable stress as an adult, adolescent stress enhances the rewarding properties of opiates