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Ketamine and Phencyclidine Reward and Sensitization in Adult and Adolescent Rats

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Ketamine and Phencyclidine Reward and Sensitization in Adult and Adolescent Rats CALIFORNIA STATE UNIVERSITY SAN MARCOS THESIS SIGNATURE PAGE THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE MASTER OF ARTS IN PSYCHOLOGICAL SCIENCE THESIS TITLE: KETAMINE AND PHENCYCLIDINE REWARD AND SENSITIZATION IN ADULT AND ADOLESCENT RATS AUTHOR: Talal Javed Zafar DATE OF SUCCESSFUL DEFENSE: 12/05/2017 THE THESIS HAS BEEN ACCEPTED BY THE THESIS COMMITTEE IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF ARTS IN PSYCHOLOGICAL SCIENCE. Running head: SENSITIZATION AND DISSOCIATIVES 1 Ketamine and Phencyclidine Reward and Sensitization in Adult and Adolescent Rats Talal J. Zafar California State University San Marcos SENSITIZATION AND DISSOCIATIVES 2 Abstract Dissociative drugs, a class that includes ketamine, phencyclidine and related drugs, are popularly abused, especially by teens and young adults in club and rave settings. Despite use by young people, little is known of the effects of these drugs in adolescents, and potential differences between adolescents and adults. The current thesis examined the effects of dissociatives in adolescents and adults in an animal model. Two behavioral responses, locomotor stimulation and ultrasonic vocalizations (USVs) were examined simultaneously following administration of ketamine or phencyclidine in adolescent and adult Sprague-Dawley rats. The effects of repeated administration were examined to determine if behavioral sensitization, a phenomenon that is characterized by an increase in the effect of a drug after repeated adminstration, occurs. Behavioral sensitization has been linked to drug addiction due to neural plasticity. USVs represent a new approach to measuring positive (reward) and negative (aversion) affective states. It was hypothesized that animals treated with ketamine or phencycline would show increases in locomotor activity and 50 kHz vocalizations, and that they will develop sensitization to both. Furthermore, it was hypothesized that adolescent animals would develop more rapid sensitization than adults, and the adolescents would show long-lasting effects of exposure to dissociatives when tested as adults. In Experiment 1, which examined ketamine, the first treatment induced a short-lived stimulant response that was greater in adolescents. Activity increased across days in adults and adolescents, reflecting the development of sensitization, with adolescents showing more rapid sensitization compared to adults. For 50 kHz USVs on Day 1 ketamine induced a short-lived response in adolescents, but not adults, and the adolescent group showed an upward trend in USVs across days, reflecting sensitization. In contrast, adults showed little evidence of sensitization to the USVs. Both adolescents and adults demonstrated persistent sensitization to locomotor behavior when tested 23 days later; only the adolescents showed persistent sensitization to USVs. In Experiment 2, which examined phencyclidine, the first treatment induced a stimulant response that was greater in adolescents. Locomotor activity increased across days for adults and adolescents, reflecting sensitization in both groups, with adolescents showing more rapid sensitization than adults. For 50 kHz USVs on Day 1 phencyclidine induced an increase in adolescents, but not adults. In contrast to our hypothesis USVs in adolescents decreased across days, reflecting the development of tolerance instead of sensitization. Both adolescents and adults demonstrated persistent sensitization in locomotor behavior. For USVs there was persistent tolerance in adolescents when tested 23 days later, but not in adults. The results demonstrate that adolescents are more sensitive to the stimulant and rewarding effects of dissociatives, and that changes following repeated use are dependent on the specific dissociative examined. SENSITIZATION AND DISSOCIATIVES 3 Ketamine and Phencyclidine Reward and Sensitization in Adult and Adolescent Rats Drug abuse is prevalent in the USA and around the world and is typically initiated in adolescence (Johnston, O’Malley, & Bachman, 2013; SAMHSA 2015). Adolescence is a transitional time between childhood and adulthood that is characterized by complex modifications of behavior, brain function and anatomy that mature at different ages. Therefore, the adolescent brain may be affected by drugs of abuse in ways that differ from the adult brain. Exposure to drugs during the adolescent period may increase vulnerability to drug abuse and neuropsychiatric disorders because of the immature brain development (Anthony & Petronis 1995; Ellgren, Spano, & Hurd, 2007). Drug abuse in adolescence is a cause for concern. For instance, opioid drug abuse among adolescents has led to thousands of hospitalizations annually (Unick, Rosenblum, Mars, & Ciccarone, 2013). Adolescent response to drugs of abuse is therefore a growing area of research (Spear & Brake, 1983; Belluzzi, Lee, Oliff, & Leslie, 2004; Zakharova, Leoni, Kichko, & Izenwasser, 2009; Spear & Varlinskaya 2010; Wiley, & Spear, 2013). An effective way to study the effects of drugs of abuse in a controlled scientifically rigorous manner is to utilize animal models. Human subjects have much variability that complicates research on drug responses. Moreover, conducting research on humans with drugs of abuse has ethical implications, particularly in adolescence. If the goal is to find out the long term effects of drugs on the brain, animal models are essential. Importantly, laboratory rats have behavioral, neurochemical, neuroanatomical and developmental parallels to humans, making them excellent tools for neuroscientific research (Lynch, Nicholson, Dance, Morgan, & Foley, 2010). The main goal of this proposed study is to compare the effects of repeated administration of a class of drugs known as dissociatives (including ketamine and phencyclidine) in adolescents SENSITIZATION AND DISSOCIATIVES 4 and adults. Because brain development is incomplete during adolescence it is possible that introducing drugs during this stage of development will differ from adults. For this study, ketamine and phencyclidine were administered repeatedly to compare the changes that take place in adolescence and adulthood. Ketamine and PCP Ketamine and phencyclidine are known as dissociatives because of their distinct effects, including distortion of perception of sight and sound, an experience of separation between the environment and one’s self, and out of body experiences (Dillon, Copeland, & Jansen, 2003; Jansen 2000). These drugs were developed initially as anesthetics, however their use has expanded (Jansen, 2000; Rudgley, 1998). Recreational use of ketamine started to increase in the 1970s and peaked in the 1990s when the drug became popular in the club and rave scene. Common routes of administration for recreational use of ketamine are injection, snorting, smoking (powder added to tobacco or marijuana cigarettes), or swallowing (NIDA, 2015). At low doses, ketamine users claim that the drug is rewarding and has the ability to produce stimulation and excitation, feelings of euphoria, lucid intoxication, and increased empathy (Dillon et al., 2003; Jansen, 2000; Jansen and Darracot-Cankovic, 2001). At higher doses people experience a sometimes frightening experience known as the K-hole, with distortion of space and time, derealization, depersonalization, dissociation, hallucinations, and near-death experiences (Dillon et al., 2003; Muetzelfeldt et al., 2008; Stone & Pilowski, 2006). PCP is also known recreationally as angel dust, sheet, synthetic marijuana and rocket fuel. Routes of administration for PCP are smoking in marijuana or tobacco cigarettes dipped in PCP solution, snorting, or injecting the drug. Once widely used on college campuses during the SENSITIZATION AND DISSOCIATIVES 5 1970s PCP is now relatively rare among college populations and used chiefly in large cities and urban areas (Domino, 1991; Johnston, O’Malley, & Bachman (2014). Its effects are very similar to those of ketamine, but longer lasting. Adolescence Adolescence is a transitional time between childhood and adulthood that is characterized by complex changes in physiology and behavior. Compared to people of other ages, adolescents have higher sensation seeking, risk taking, and reckless behavior. Such behaviors are beneficial to the adolescent’s development of autonomy (Spear, 2000). One of the difficulties that arises from the increased sensation seeking and risk taking is that adolescents may experiment with drugs of abuse. For example, 15-20% of teenagers in the US and several European regions have used marijuana (Cannabis sativa) in the past month (Ellgren et al., 2007). In addition, more than 90% adult smokers first started smoking during adolescence (Faraday, Elliott, & Grunberg, 2001; U.S. Department of Health and Human Services [USDHHS], 2014). The changes in behavior seen during adolescence are accompanied by changes in the brain that are thought to be responsible for the behavioral changes. These changes in brain anatomy and function peak at different ages. For instance, frontal lobe gray matter reaches its maximal volume around 11-12 years of age, temporal lobe cortical gray matter peaks around 16- 17 years, and parietal lobe cortical gray matter peaks between 10-12 years (Lenroot & Giedd, 2006; Spear, 2000). Additionally, myelenation occurs throughout the young adult’s life until roughly age 25 when myelin sheaths are fully developed (Lenroot et al., 2006). Adolescents go through marked changes in the brain and the normal trajectory of brain development
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