An elucidation of the neural mechanisms of action of cocaine is required if we are to identify medications which might block its psychotropic and toxic effects. While the focus has been on dopamine (DA) mesolimbic involvement, cocaine also interferes with serotonin (5-HT) function; specific alterations in 5-HT control of DA,: mesolimbic systems may in part affect the consequences of acute and chronic cocaine. The goals of the present proposal are: (1) to assess the role of 5-HT in the behavioral effects of cocaine (i.e., discriminative stimulus effects, hyperactivity, stereotypy and sensitization); (2) to study further the mechanism(s) by which acute and chronic cocaine interact with 5-HT raphe systems; and (3) to characterize 5-HT modulatory control of DA mesolimbic systems. The behavioral effects of cocaine will be quantified following systemic and intracranial administration of 5-HT agonists and antagonists as well as 5- HT lesions. Single unit recording, microiontophoresis and stimulation techniques will be used to characterize the cellular effects of cocaine on 5-HT-containing neurons which project to DA neurons of the ventral tegmental area (VTA) or their limbic terminals in accumbens. We will also analyze the electrophysiological effects of 5-HT on DA-containing VTA neurons and assess whether acute and/or chronic cocaine modify the normal action of 5-HT on DA neurons. In addition to this continuing theme, we have initiated a study of the role of female steroid hormones in the regulation of central 5-HT systems and how this 5-HT-steroid interrelationship determines the neural response to cocaine. Importantly, this research is designed to provide fundamental knowledge about 5-HT-DA and 5-HT-steroid interactions and how these interactions are altered by cocaine, perhaps suggesting new strategies for pharmacological intervention in abusers. The lack of 5-HT compounds which exhibit selectivity for specific 5-HT receptors has been a significant limitation to this field. However, antisense oligonucleotides have proven to be useful tools for blocking production of specific receptors following central microinjection. Under this RSDA, I propose to gain training in molecular biology in order to implement the use of this antisense strategy as a potentially powerful approach to address the goals of this grant and, hopefully, obviate the need for receptor-specific drugs. Training is also sought in (1) in situ hybridization as one approach to colocalize 5-HT and DA receptors in monoamine cell bodies and their terminal neurons and (2) Northern analysis in order to establish the impact of cocaine and hormone treatments on steady state levels of mRNA for 5-HT transporters and receptors. With this RSDA, release time and salary support would be provided for development of these new methodologies necessary for enhancement of my ongoing research program.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02DA000260-03
Application #
2700799
Study Section
Special Emphasis Panel (SRCD (11))
Program Officer
Lynch, Minda
Project Start
1996-05-01
Project End
2001-04-30
Budget Start
1998-05-15
Budget End
1999-04-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Herin, David V; Bubar, Marcy J; Seitz, Patricia K et al. (2013) Elevated Expression of Serotonin 5-HT(2A) Receptors in the Rat Ventral Tegmental Area Enhances Vulnerability to the Behavioral Effects of Cocaine. Front Psychiatry 4:2
Anastasio, Noelle C; Gilbertson, Scott R; Bubar, Marcy J et al. (2013) Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior. J Neurosci 33:1615-30
Anastasio, Noelle C; Stoffel, Erin C; Fox, Robert G et al. (2011) Serotonin (5-hydroxytryptamine) 5-HT(2A) receptor: association with inherent and cocaine-evoked behavioral disinhibition in rats. Behav Pharmacol 22:248-61
Lanfranco, Maria Fe; Anastasio, Noelle C; Seitz, Patricia K et al. (2010) Quantification of RNA editing of the serotonin 2C receptor (5-HT(?C)R) ex vivo. Methods Enzymol 485:311-28
Anastasio, Noelle C; Lanfranco, Maria Fe; Bubar, Marcy J et al. (2010) Serotonin 5-HT2C receptor protein expression is enriched in synaptosomal and post-synaptic compartments of rat cortex. J Neurochem 113:1504-15
Cunningham, Kathryn A; Bubar, Marcy J; Anastasio, Noelle C (2010) The serotonin 5-HT2C receptor in medial prefrontal cortex exerts rheostatic control over the motivational salience of cocaine-associated cues: new observations from preclinical animal research. Neuropsychopharmacology 35:2319-21
Lanfranco, Maria Fe; Seitz, Patricia K; Morabito, Michael V et al. (2009) An innovative real-time PCR method to measure changes in RNA editing of the serotonin 2C receptor (5-HT(2C)R) in brain. J Neurosci Methods 179:247-57
Nic Dhonnchadha, B A; Fox, R G; Stutz, S J et al. (2009) Blockade of the serotonin 5-HT2A receptor suppresses cue-evoked reinstatement of cocaine-seeking behavior in a rat self-administration model. Behav Neurosci 123:382-96
Leggio, Gian Marco; Cathala, Adeline; Moison, Delphine et al. (2009) Serotonin2C receptors in the medial prefrontal cortex facilitate cocaine-induced dopamine release in the rat nucleus accumbens. Neuropharmacology 56:507-13
Navailles, Sylvia; Moison, Delphine; Cunningham, Kathryn A et al. (2008) Differential regulation of the mesoaccumbens dopamine circuit by serotonin2C receptors in the ventral tegmental area and the nucleus accumbens: an in vivo microdialysis study with cocaine. Neuropsychopharmacology 33:237-46

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