Cocaine sensitization is a progressive and long-lasting enhancement of the motor stimulant effect induced by a subsequent cocaine challenge. The goal of this work is to elucidate the role of alpha adrenergic receptors at the VTA and RFC in the development and expression of cocaine sensitization. There are three specific Aims: 1) Assess whether microinjections of alpha noradrenergic receptor agonists and antagonists into the VTA or RFC modulate the process of cocaine sensitization. Using the model of cocaine sensitization, intra-VTA or -RFC microinjections of selective alpha-noradrenergic receptor agonists and antagonists will be used to localize the anatomical structure mediating the pharmacological actions of these drugs. 2) Identify changes in alpha noradrenergic receptors at the VTA and RFC induced by behavioral sensitization. We will investigate alpha-1 and alpha-2 adrenergic receptor mediated G protein activation in cocaine-sensitized rats using agonist-stimulated [35S] GTPyS binding as a functional assay. The hypothesis is that development of cocaine sensitization involves an increase in alpha-1 and a decrease in alpha-2 receptor functional sensitivity in both VTA and RFC areas, which will promote cocaine sensitization. Correlations will be made between changes in functionality and number/affinities of receptors in each structure using an in vitro receptor autoradiography assay. We will also assess whether changes in these noradrenergic receptors play a role in the initiation or expression of behavioral sensitization by comparing animals after a 7days withdrawal period. 3) Determine the role of alpha-2 receptors in the modulation of glutamate release at .the VTA. In vitro whole cell patch clamp recordings will be employed to study the role of alpha-2 receptors in the modulation of glutamate release onto VTA dopamine cells. The effects of alpha-2 adrenoreceptor agonists on glutamate-induced excitatory postsynaptic currents (EPSCs) will be assessed. Paired-pulse ratios and miniature EPSCs will be employed to provide evidence that the EPSC's alterations are localized at the presynaptic terminal. The hypothesis is that presynaptic alpha-2 receptors control glutamate release onto VTA neurons. A sub-hypothesis is that there is a decreased alpha-2 -induced inhibition of glutamate release in cocaine sensitized rats. Changes in alpha adrenoceptor modulation of glutamate release into VTA cells after a withdrawal period will also be determined. Understanding of alpha adrenoceptor modulatory changes in cocaine sensitization will increase our knowledge of the role of the noradrenergic system in cocaine addiction and might provide possible avenues for therapeutic pharmacological interventions.. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Enhancement Award (SC1)
Project #
1SC1GM084854-01
Application #
7498601
Study Section
Special Emphasis Panel (ZGM1-MBRS-0 (NP))
Program Officer
Fabian, Miles
Project Start
2008-09-01
Project End
2012-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
1
Fiscal Year
2008
Total Cost
$311,250
Indirect Cost
Name
University of Puerto Rico Med Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
948108063
City
San Juan
State
PR
Country
United States
Zip Code
00936
Velásquez-Martínez, Maria C; Vázquez-Torres, Rafael; Rojas, Legier V et al. (2015) Alpha-1 adrenoreceptors modulate GABA release onto ventral tegmental area dopamine neurons. Neuropharmacology 88:110-21
Vélez-Hernández, M E; Padilla, E; Gonzalez-Lima, F et al. (2014) Cocaine reduces cytochrome oxidase activity in the prefrontal cortex and modifies its functional connectivity with brainstem nuclei. Brain Res 1542:56-69
Santos-Vera, Bermary; Vazquez-Torres, Rafael; Marrero, Hermes G Garcia et al. (2013) Cocaine sensitization increases I h current channel subunit 2 (HCNýýý) protein expression in structures of the mesocorticolimbic system. J Mol Neurosci 50:234-45
Arencibia-Albite, Francisco; Vazquez, Rafael; Velasquez-Martinez, Maria C et al. (2012) Cocaine sensitization inhibits the hyperpolarization-activated cation current Ih and reduces cell size in dopamine neurons of the ventral tegmental area. J Neurophysiol 107:2271-82
Inyushin, M U; Arencibia-Albite, F; Vazquez-Torres, R et al. (2010) Alpha-2 noradrenergic receptor activation inhibits the hyperpolarization-activated cation current (Ih) in neurons of the ventral tegmental area. Neuroscience 167:287-97