Dr. Roberto I. Meléndez Aponte
Med Sci Campus Main Bldg, Lab A570/A505/A544/A530
Interests: Neurobiology of Addictions (Drug and Alcohol Abuse), Extracellular Glutamate Homeostasis (In-vivo Microdialysis and HPLC), Glutamate Transporters (Synatosomal versus Glial [3H]-Glutamate Uptake), Gene Expression Profiling (Brain Microarray and Bioinformatics)
Project 1: Modeling Excessive Alcohol Drinking in C57BL/6J Mice
Alcoholism continues to be a substantial medical, social, and financial problem in the United States and Puerto Rico. Animal models that reflect the transition to compulsive or excessive alcohol drinking are necessary to understand the addiction process from a neurobiological perspective. The goal of this project is to develop an optimal C57BL/6J (C57) mouse model of drinking that captures the fundamental characteristics of drug addiction. Notably, there is a wealth of available genetic information about the C57 strain, which provides the unique opportunity to test various transgenic models (i.e., knock-outs) in the future.
Project 2: Role of Extracellular Glutamate Levels in Excessive Drug Use and Dependence
Understanding the neurochemical factors involved in excessive drug use will lead to the development of effective pharmacotherapy′s for the prevention of addiction and relapse. Of particular interest and relevant to this project is acamprosate (Campral@), a non-selective NMDA receptor antagonist which has been approved by the FDA to help maintain alcohol abstinence through restoring glutamate homeostasis (i.e., normalization of a hyperglutamatergic state). The goal of this project is to combine the ′C57 driknking model′ with in-vivo microdialysis/HPLC and site-specific microinjection techniques to determine the role of glutamate homeostasis in the prefrontal cortex, basolateral amygdala, and nucleus accumbens circuitry in mediating excessive alcohol drinking and vulnerability to relapse.
Project 3: Neuroadaptations between Neuronal and Glial Glutamate Transporters
Elevated glutamate levels may result in impaired glutamatergic signaling and excitotoxic neuronal cell death, which may have implications in the neurobiology of major diseases affecting glutamate neurotransmission. The major mechanism of control of brain glutamate levels, are the high affinity, sodium dependent excitatory amino acid transporters (EAATs). EAAT1 and EAAT2 are predominantly located in glia cells, whereas EAAT3 is located in neurons. Although the bulk of glutamate uptake occurs in glial, the neurons themselves significantly contribute to the process. The goal of this project is to elucidate the role of neuronal [3H]-glutamate uptake and the protein expression of EAATs 1-3 in excessive alcohol-drinking mice.
Project 4: Gene Expression Profiling (Microarray) and Bioinformatics
A major challenge in the neurobiology of addiction is to understand the many interconnected molecular networks that govern the neuronal functions involved and the recruitment of brain-regional specific responses. Microarray technologies have made it possible to monitor changes in the simultaneous response of thousands of genes of interest. In collaboration with the Center for Drug and Alcohol Problems at the Medical University of South Carolina, the aim of this project is to use high-density oligonucleotide microarrays and bioinformatics methods to characterize patterns of gene expression in the prefrontal cortex, hippocampus, nucleus accumbens, and amygdala of alcohol dependent C57 mice.
Present Funding: NIH R01
- Melendez RI, Roman C, Capo-Velez CM, Lasalde-Dominicci JA (2016) Decreased glial and synaptic glutamate uptake in the striatum of HIV-1 gp120 transgenic mice. J Neurovirol. 22(3):358-65.
- Quiñones-Laracuente K, Hernández-Rodríguez MY, Bravo-Rivera C, Melendez RI, Quirk GJ. (2015) The effect of repeated exposure to ethanol on pre-existing fear memories in rats. Psychopharmacology (Berl) 232(19):3615-22.
- Root DH, Melendez RI, Zaborszky L, Napier TC (2015) The ventral pallidum: Subregion-specific functional anatomy and roles in motivated behaviors. Prog Neurobiol 130:29-70.
Lopez MF, Griffin WC 3rd, Melendez RI, Becker HC (2012) Repeated Cycles of Chronic Intermittent Ethanol Exposure Leads to the Development of Tolerance to Aversive Effects of Ethanol in C57BL/6J Mice. Alcohol Clin Exp Res. 36(7): 1180-1187.
- Ballester LY, Capó-Vélez CM, García-Beltrán WF, Ramos FM, Vázquez-Rosa E, Ríos R, Mercado JR, Meléndez RI, Lasalde-Dominicci JA (2012). Up-regulation of the neuronal nicotinic receptor α7 by HIV glycoprotein 120: potential implications for HIV-associated neurocognitive disorder. J Biol Chem 287:3079-86.
- Melendez RI, Kalivas PW, McGinty JF, Becker HB (2012) Brain Region-Specific Gene Expression Changes After Chronic Intermittent Ethanol Exposure and Early Withdrawal in C57BL/6J Mice. Addiction Biology 17:351-54.
- Melendez RI (2011) Intermittent (every-other-day) drinking induces rapid escalation of ethanol intake and preference in adolescent and adult C57BL/6J mice. Alcohol Clin Exp Research, 35: 1-7.
- Knackstedt LA, Melendez RI, Kalivas PW (2010) Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biol Psychiatry. 67, 81-84.
- Pacchioni AM, Vallone J, Melendez RI, Shih A, Murphy TH, Kalivas PW (2007) Nrf2 gene deletion fails to alter psychostimulant-induced behavior or neurotoxity. Brain Research 1127: 26-35.
- Melendez RI, Middaugh LD, and Kalivas PW (2006) Expression of an alcohol deprivation and escalation effect in C57BL/6J mice. Alcoholism Clinical and Experimental Research, 30:2017-25.
- Melendez RI, Hicks MP, Cagles S, Kalivas PW (2005) Ethanol exposure decreases glutamate uptake in the nucleus accumbens. Alcoholism Clinical and Experimental Research, 29:326-33.
- Moran M, McFarland K, Melendez RI, Kalivas PW, and Seamans J (2005) Cystine/ glutamate exchange regulates mGluR presynaptic inhibition of excitatory transmission and vulnerability to cocaine-seeking. Journal of Neuroscience, 25:6389-93.
- Melendez RI, Vuthiganon J, Kalivas PW (2005) Regulation of extracellular glutamate in the prefrontal cortex: focus on cystine glutamate exchange and group I metabotropic glutamate receptors. Journal of Pharmacology and Experimental Therapeutics,
- Melendez RI, Rodd ZA, McBride WJ and Murphy JM (2005) Dopamine receptor regulation of ethanol intake and extracellular dopamine levels in the ventral pallidum of alcohol preferring (P) rats. Drug and Alcohol Dependence, 77:293-301.
- Melendez RI and Kalivas PW (2004) Last call for adenosine transporters. Nature Neuroscience, 7:795-796.
- Melendez RI, Gregory ML, Bardo MT and Kalivas PW (2004) Impoverished rearing environment alters metabotropic glutamate receptor expression and function in the prefrontal cortex. Neuropsychopharmacology, 29:1980-87.
- Rodd ZA, Melendez RI, Bell RL, Kuc KA, Zhang Y, Murphy JM and McBride WJ (2004) Intracranial self-administration of ethanol within the ventral tegmental area of male Wistar rats: evidence for involvement of dopamine neurons. Journal of Neuroscience, 24:1050-57.
- Rodd ZA, Bell RL, Melendez RI, Kuc KA, Lumeng L, Li TK, Murphy JM and McBride WJ (2004) Comparison of intracranial self-administration of ethanol within the posterior ventral tegmental area between alcohol-preferring and Wistar rats. Alcoholism Clinical and Experimental Research, 28:1212-19.
- Melendez RI, Rodd ZA, McBride WJ and Murphy JM (2004) Involvement of the mesopallidal dopamine system in ethanol reinforcement. Alcohol, 32:137-44.
- Melendez RI and Kalivas PW (2003) Metabotropic glutamate receptor regulation of extracellular glutamate levels in the prefrontal cortex. Annals New York Academy of Sciences, 1003:443-4.
- Melendez RI, Rodd-Henricks ZA, McBride WJ and Murphy JM (2003) Alcohol stimulates the release of dopamine in the ventral pallidum but not in the globus pallidus: a dual-probe microdialysis study. Neuropsychopharmacology, 28:939-946.
- Rodd-Henricks ZA, McKinzie DL, Melendez RI, Berry N, Murphy JM and McBride WJ(2003) Effects of serotonin-3 receptor antagonists on the intracranial self-administration of ethanol within the ventral tegmental area of Wistar rats. Psychopharmacology,
- Rodd-Henricks ZA, Melendez RI, Zaffaroni A, Goldstein A, McBride WJ and Li TK (2002) The reinforcing effects of acetaldehyde in the posterior ventral tegmental area of alcohol-preferring rats. Pharmacology Biochemistry and Behavior, 72:55-64.
- Melendez RI, Rodd-Henricks ZA, Engleman EA, Li TK, McBride WJ and Murphy JM (2002) Microdialysis of dopamine in the nucleus accumbens of alcohol-preferring (P) ratsduring anticipation and operant self-administration of ethanol. Alcoholism Clinical and Experimental Research, 26:318-25.
Swithers SE, Melendez RI, Watkins BA and Davis RJ (2001) Metabolic and behavioral responses in pre-weanling rats following alteration of maternal diet. Physiology and Behavior, 72:147-57.
Melendez RI and Kalivas PW (2008) Basic Science of Addiction, in Pain and Chemical Dependency (Smith H and Passick S, eds), pgs. 33-38. Oxford University Press, New York.
Melendez RI, Griffin WC, Yanke AB, Overstreet MP, Olive MF, Becker HC (2007) Deletion of NR2A subunit enhances neuronal glutamate uptake in the prefrontal cortex. Society for Neuroscience, 682.10.
- Melendez RI, Fernandes K, Becker HC (2007) Effects of ethanol on neuronal glutamate uptake in C57Bl/6J mice Alcoholism Clinical & Experimental Research Supp 31(6): 201A.
- Rodd-Henricks ZA, Melendez RI, Zhang Y, Zaffaroni A, Goldstein A, McBride WJ, Li T-K (2002) Alcohol-preferring rats self-administer salsolinol directly into the nucleus accumbens shell. Alcoholism Clinical & Experimental Research Supp 26(5): 104A.
- Melendez RI, Rodd-Henricks ZA, Zhang Y, McBride WJ, Murphy JM (2001) Interaction between the reinforcing effects of cocaine and ethanol in the posterior ventral tegmental area (VTA) of rats. Society for Neuroscience, 981.16.
- Rodd-Henricks ZA, Bell RL, Kuc KA, Melendez RI, Murphy JM, McBride WJ, Lumeng L, Li T-K (2001) Access to multiple ethanol concentrations by high alcohol-drinking (HAD) rats contribute to the expression of a robust alcohol deprivation effect which is enhanced with repeated deprivations. Alcohol Clin Exp Res Supp, 25(5): 20A.
Rodd-Henricks ZA, Bell RL, Melendez RI, Jones AR, Murphy JM, McBride WJ, Lumeng L, Li T-K (2000) Repeated deprivations enhance operant alcohol self-administration in the P rat. Alcohol Clin Exp Res, Supp 24(5): 52A.