Acute and chronic interactive treatments of serotonin 5HT<sub>2C</sub> and dopamine D<sub>1</sub> receptor systems for decreasing nicotine self-administration in female rats.
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A variety of neural systems are involved in the brain bases of tobacco addiction. Animal models of nicotine addiction have helped identify a variety of interacting neural systems involved in the pathophysiology of tobacco addiction. We and others have found that drug treatments affecting many of those neurotransmitter systems significantly decrease nicotine self-administration. These treatments include dopamine D1 receptor antagonist, histamine H1 antagonist, serotonin 5HT2C agonist, glutamate NMDA antagonist, nicotinic cholinergic α4β2 partial agonist and nicotinic cholinergic α3β4 antagonist acting drugs. It may be the case that combining treatments that affect different neural systems underlying addiction may be more efficacious than single drug treatment. In the current study, we tested the interactions of the D1 antagonist SCH-23390 and the serotonin 5HT2c agonist lorcaserin, both of which we have previously shown to significantly reduce nicotine self-administration. In the acute interactions study, both SCH-23390 and lorcaserin significantly reduced nicotine self-administration when given alone and had additive effects when given in combination. In the chronic study, each drug alone caused a significant decrease in nicotine self-administration. No additive effect was seen in combination because SCH-23390 given alone chronically was already highly effective. Chronic administration of the combination was not seen to significantly prolong reduced nicotine self-administration into the post-treatment period. This research shows that unlike lorcaserin and SCH-23390 interactions when given acutely, when given chronically in combination they do not potentiate or prolong each other's effects in reducing nicotine self-administration.
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Willette, Blair KA, Anica Nangia, Sarah Howard, Devon DiPalma, Collin McMillan, Sonum Tharwani, Janequia Evans, Corinne Wells, et al. (2019). Acute and chronic interactive treatments of serotonin 5HT2C and dopamine D1 receptor systems for decreasing nicotine self-administration in female rats. Pharmacology, biochemistry, and behavior, 186. p. 172766. 10.1016/j.pbb.2019.172766 Retrieved from https://hdl.handle.net/10161/29507.
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My research and teaching interests have been primarily focused on the following areas:
Alcoholism: I work with "alcoholic" rats with genetic predisposition!" We use selectively-bred alcohol preferring rats as an animal model of human alcoholism for developing better pharmacological treatments for alcoholism. Recently, we are working on several novel promising "anti-craving" compounds for the treatment of alcoholism. We are also studying the interaction between alcohol drinking and nicotine intake.
Nicotine Addiction: We have been studying age and sex differences in i.v. nicotine self-administration in rats. We have found that pattern of drug intake is both age- and sex-dependent. Our lab is also exploring different neuronal targets for developing better pharmacologic treatment for nicotine addiction.
Sustained Attention: Another aspect of our research is studying the role of the neuronal nicotinic and other neuronal systems in sustained attention using a rodent model. We have shown, nicotine (not smoking!) and nicotinic compounds improve attention in rats. A majority of people with schizophrenia smoke and they smoke heavily. Thus, it is important to understand the interaction of antipsychotic medications and nicotine in sustained attention. This has been another aspect of our research with interesting results. Presently, we are testing novel nicotinic compounds for improving pharmacologically-impaired sustained attention.
Teaching: I love to teach and interact with students. Since arriving at Duke in 1999, I have been team-teaching the popular alcohol course (Psych 206-01R; Alcohol: Brain, Society and Individual). I also enjoy mentoring undergrad students who are interested in science and enjoy working in the lab with cute little creatures!.
Community: I am a member of the Board of Directors of Triangle Residential Options for Substance Abusers (TROSA), a self-supported therapeutic community in Durham. I also give seminars and workshops on addiction around the country.
Dr. Levin is Chief of the Neurobehavioral Research Lab in the Psychiatry Department of Duke University Medical Center. His primary academic appointment is as Professor in the Department of Psychiatry and Behavioral Sciences. He also has secondary appointments in the Department Pharmacology and Cancer Biology, the Department of Psychological and Brain Sciences and the Nicholas School of the Environment at Duke. His primary research effort is to understand basic neural interactions underlying cognitive function and addiction and to apply this knowledge to better understand cognitive dysfunction and addiction disorders and to develop novel therapeutic treatments.
The three main research components of his laboratory are focused on the themes of the basic neurobiology of cognition and addiction, neurobehavioral toxicology and the development of novel therapeutic treatments for cognitive dysfunction and substance abuse. Currently, our principal research focus concerns nicotine. We have documented the basic effects of nicotine on learning memory and attention as well as nicotine self-administration. We are continuing with more mechanistic studies in rat models using selective lesions, local infusions and neurotransmitter interaction studies. We have found that nicotine improves memory performance not only in normal rats, but also in rats with lesions of hippocampal and basal forebrain connections. We are concentrating on alpha7 and alpha4beta2 nicotinic receptor subtypes in the hippocampus, amygdala , thalamus and frontal cortex and how they interact with dopamine D1 and D2 and glutamate NMDA systems with regard to memory and addiction. I am also conducting studies on human cognitive behavior. We have current studies to assess nicotine effects on attention, memory and mental processing speed in schizophrenia, Alzheimer's Disease and Attention Deficit Hyperactivity Disorder. In the area of neurobehavioral toxicology, I have continuing projects to characterize the adverse effects of prenatal and adolescent nicotine exposure. Our primary project in neurobehavioral toxicology focuses on the cognitive deficits caused by the marine toxins. The basic and applied aims of our research complement each other nicely. The findings concerning neural mechanisms underlying cognitive function help direct the behavioral toxicology and therapeutic development studies, while the applied studies provide important functional information concerning the importance of the basic mechanisms under investigation.
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