Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


In this review we describe how highly addictive psychostimulants such as cocaine and methamphetamine actions might underlie hypoexcitabilty in frontal cortical areas observed in clinical and preclinical models of psychostimulant abuse. We discuss new mechanisms that describe how increments on synaptic dopamine release are linked to reduce calcium influx in both pre and postsynaptic compartments on medial PFC networks, therefore modulating synaptic integration and information. Sustained DA neuromodulation by addictive psychostimulants can "lock" frontal cortical networks in deficient states. On the other hand, other psychostimulants such as modafinil and methylphenidate are considered pharmacological neuroenhancement agents that are popular among healthy people seeking neuroenhancement. More clinical and preclinical research is needed to further clarify mechanisms of actions and physiological effects of cognitive enhancers which show an opposite pattern compared to chronic effect of addictive psychostimulants: they appear to increase cortical excitability. In conclusion, studies summarized here suggest that there is frontal cortex hypoactivity and deficient inhibitory control in drug-addicted individuals. Thus, additional research on physiological effects of cognitive enhancers like modafinil and methylphenidate seems necessary in order to expand current knowledge on mechanisms behind their therapeutic role in the treatment of addiction and other neuropsychiatric disorders. © 2016 Elsevier Ltd. All rights reserved.


Documento: Artículo
Título:Cognitive enhancers versus addictive psychostimulants: The good and bad side of dopamine on prefrontal cortical circuits
Autor:Bisagno, V.; González, B.; Urbano, F.J.
Filiación:Instituto de Investigaciones Farmacológicas, Universidad de Buenos Aires - Consejo Nacional de Investigaciones Cientificas y Tecnicas, Ciudad Autónoma de Buenos Aires, Junín 956, Piso 5, Buenos Aires, C1113, Argentina
Laboratorio de Fisiología y Biología Molecular, Instituto de Fisiología, Biología Molecular y Neurociencias, Departamento de Fisiologia, Biologia Molecular y Celular Prof. Dr. Hector Maldonado, Universidad de Buenos Aires - Consejo Nacional de Investigaciones Cientificas y Tecnicas, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
Palabras clave:Calcium channels; Cocaine; Dopamine; Hyperpolarization-activated cation current; Methamphetamine; Methylphenidate; Modafinil; Prefrontal cortex; AMPA receptor; calcium channel L type; calcium channel N type; calcium channel P type; calcium channel Q type; calcium channel R type; calcium channel T type; calcium ion; cocaine; delayed rectifier potassium channel; dopamine; dopamine 1 receptor; dopamine 2 receptor; dopamine receptor; dopamine transporter; hyperpolarization activated cyclic nucleotide gated channel; inwardly rectifying potassium channel; metabotropic receptor; methamphetamine; methylphenidate; modafinil; n methyl dextro aspartic acid receptor; noradrenalin transporter; serotonin transporter; voltage gated calcium channel; benzhydryl derivative; central stimulant agent; cocaine; dopamine; methamphetamine; methylphenidate; modafinil; nootropic agent; brain function; calcium transport; cognition; dopamine release; dopaminergic nerve cell; dopaminergic transmission; drug dependence; drug mechanism; human; nerve cell excitability; nerve cell plasticity; neuromodulation; neuroprotection; nonhuman; prefrontal cortex; priority journal; protein expression; protein function; Review; schizophrenia; animal; drug effects; metabolism; pathophysiology; physiology; prefrontal cortex; Animals; Benzhydryl Compounds; Central Nervous System Stimulants; Cocaine; Dopamine; Humans; Methamphetamine; Methylphenidate; Nootropic Agents; Prefrontal Cortex; Substance-Related Disorders
Página de inicio:108
Página de fin:118
Título revista:Pharmacological Research
Título revista abreviado:Pharmacol. Res.
CAS:calcium ion, 14127-61-8; cocaine, 50-36-2, 53-21-4, 5937-29-1; dopamine, 51-61-6, 62-31-7; methamphetamine, 28297-73-6, 51-57-0, 537-46-2, 7632-10-2; methylphenidate, 113-45-1, 298-59-9; modafinil, 68693-11-8; Benzhydryl Compounds; Central Nervous System Stimulants; Cocaine; Dopamine; Methamphetamine; Methylphenidate; modafinil; Nootropic Agents


  • Repantis, D., Schlattmann, P., Laisney, O., Heuser, I., Modafinil and methylphenidate for neuroenhancement in healthy individuals: A systematic review (2010) Pharmacol. Res., 62 (3), pp. 187-206
  • Maher, B., Poll results: Look who's doping (2008) Nature, 452 (7188), pp. 674-675
  • Battleday, R.M., Brem, A.K., Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review (2015) Eur. Neuropsychopharmacol., 25 (11), pp. 1865-1881
  • Bromberg-Martin, E.S., Matsumoto, M., Hikosaka, O., Dopamine in motivational control: Rewarding, aversive, and alerting (2010) Neuron, 68 (5), pp. 815-834
  • Goldstein, R.Z., Volkow, N.D., Dysfunction of the prefrontal cortex in addiction: Neuroimaging findings and clinical implications (2011) Nat. Rev. Neurosci., 12 (11), pp. 652-669
  • Minzenberg, M.J., Carter, C.S., Modafinil: A review of neurochemical actions and effects on cognition (2008) Neuropsychopharmacology, 33 (7), pp. 1477-1502
  • Mere, M., Bonci, A., Newman, A.H., Tanda, G., The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders (2013) Psychopharmacology (Berlin), 229 (3), pp. 415-434
  • Zolkowska, D., Jain, R., Rothman, R.B., Partilla, J.S., Roth, B.L., Setola, V., Prisinzano, T.E., Baumann, M.H., Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil (2009) J. Pharmacol. Exp. Ther., 329 (2), pp. 738-746
  • Madras, B.K., Xie, Z., Lin, Z., Jassen, A., Panas, H., Lynch, L., Johnson, R., Fischman, A.J., Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro (2006) J. Pharmacol. Exp. Ther., 319 (2), pp. 561-569
  • Scoriels, L., Jones, P.B., Sahakian, B.J., Modafinil effects on cognition and emotion in schizophrenia and its neurochemical modulation in the brain (2013) Neuropharmacology, 64, pp. 168-184
  • Urbano, F.J., Leznik, E., Llinás, R.R., Modafinil enhances thalamocortical activity by increasing neuronal electrotonic coupling (2007) Proc. Natl. Acad. Sci. U. S. A, 104, pp. 12554-12559
  • Raineri, M., Peskin, V., Goitia, B., Taravini, I.R., Giorgeri, S., Urbano, F.J., Bisagno, V., Attenuated methamphetamine induced neu- rotoxicity by modafinil administration in mice (2011) Synapse, 65 (10), pp. 1087-1098
  • Raineri, M., Gonzalez, B., Goitia, B., Garcia-Rill, E., Krasnova, I.N., Cadet, J.L., Urbano, F.J., Bisagno, V., Modafinil abrogates methamphetamine-induced neuroinflammation and apoptotic effects in the mouse striatum (2012) PLoS One, 7 (10), p. e46599
  • Lindenmayer, J.P., Nasrallah, H., Pucci, M., James, S., Citrome, L., A systematic review of psychostimulant treatment of negative symptoms of schizophrenia: Challenges and therapeutic opportunities (2013) Schizophr. Res., 147 (2-3), pp. 241-252
  • Gruber, O., Chadha Santuccione, A., Aach, H., Magnetic resonance imaging in studying schizophrenia, negative symptoms, and the glutamate system (2014) Front. Psychiatry, 5, p. 32
  • Andrade, C., Kisely, S., Monteiro, I., Rao, S., Antipsychotic augmentation with modafinil or armodafinil for negative symptoms of schizophrenia: Systematic review and meta-analysis of randomized controlled trials (2015) J. Psychiatr. Res., 60, pp. 14-21
  • Wood, S., Sage, J.R., Shuman, T., Anagnostaras, S.G., Psychostimulants and cognition: A continuum of behavioral and cognitive activation (2013) Pharmacol. Rev., 66 (1), pp. 193-221
  • Faraone, S.V., Biederman, J., Spencer, T., Mick, E., Murray, K., Petty, C., Adamson, J.J., Monuteaux, M.C., Diagnosing adult attention deficit hyperactivity disorder: Are late onset and subthreshold diagnoses valid? (2006) Am. J. Psychiatry, 163 (10), pp. 1720-1729
  • Biederman, J., Faraone, S.V., The effects of attention-deficit/hyperactivity disorder on employment and household income (2006) Med. Gen. Med., 8 (3), p. 12
  • Kooij, S.J., Bejerot, S., Blackwell, A., Caci, H., Casas-Brugué, M., Carpentier, P.J., Edvinsson, D., Ginsberg, Y., European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD (2010) BMC Psychiatry, 10, p. 67
  • Engert, V., Pruessner, J.C., Dopaminergic and noradrenergic contributions to functionality in ADHD: The role of methylphenidate (2008) Curr. Neuropharmacol., 6 (4), pp. 322-328
  • Kuczenski, R., Segal, D.S., Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: Comparison with amphetamine (1997) J. Neurochem., 68 (5), pp. 2032-2037
  • Markowitz, J.S., DeVane, C.L., Pestreich, L.K., Patrick, K.S., Muniz, R.A., Comprehensive in vitro screening of d-, l-, and dl-threo-methylphenidate: An exploratory study (2006) J. Child Adolesc. Psychopharmacol., 16 (6), pp. 687-698
  • Sandoval, V., Riddle, E.L., Hanson, G.R., Fleckenstein, A.E., Methylphenidate alters vesicular monoamine transport and prevents methamphetamine-induced dopaminergic deficits (2003) J. Pharmacol. Exp. Ther., 304 (3), pp. 1181-1187
  • Volkow, N.D., Wang, G.J., Ma, Y., Fowler, J.S., Wong, C., Ding, Y.S., Hitzemann, R., Kalivas, P., Activation of orbital and medial prefrontal cortex by methylphenidate in cocaine-addicted subjects but not in controls: Relevance to addiction (2005) J. Neurosci., 25 (15), pp. 3932-3939
  • Fowler, J.S., Volkow, N.D., Logan, J., Alexoff, D., Telang, F., Wang, G.J., Wong, C., Apelskog, K., Fast uptake and long-lasting binding of methamphetamine in the human brain: Comparison with cocaine (2008) Neuroimage, 43 (4), pp. 756-763
  • Bright, G.M., Abuse of medications employed for the treatment of ADHD: Results from a large-scale community survey (2008) Medscape J. Med., 10 (5), p. 111
  • Frauger, E., Amaslidou, D., Spadari, M., Allaria-Lapierre, V., Braunstein, D., Sciortino, V., Thirion, X., Micallef, J., Patterns of methylphenidate use and assessment of its abuse among the general population and individuals with drug dependence (2016) Eur. Addict. Res., 22 (3), pp. 119-126
  • Humphreys, K.L., Eng, T., Lee, S.S., Stimulant medication and substance use outcomes: A meta-analysis (2013) JAMA Psychiatry, 70 (7), pp. 740-749
  • Dalsgaard, S., Mortensen, P.B., Frydenberg, M., Thomsen, P.H., ADHD, stimulant treatment in childhood and subsequent substance abuse in adulthood - A naturalistic long-term follow-up study (2014) Addict. Behav., 39 (1), pp. 325-328
  • Breyer, J.L., Lee, S., Winters, K.C., August, G.J., Realmuto, G.M., A longitudinal study of childhood ADHD and substance dependence disorders in early adulthood (2014) Psychol. Addict. Behav., 28 (1), pp. 238-246
  • Jasinski, D.R., An evaluation of the abuse potential of modafinil using methylphenidate as a reference (2000) J. Psychopharmacol., 14 (1), pp. 53-60
  • Rush, C.R., Kelly, T.H., Hays, L.R., Wooten, A.F., Discriminative-stimulus effects of modafinil in cocaine-trained humans (2002) Drug Alcohol Depend., 67 (3), pp. 311-322
  • Volkow, N.D., Wang, G.J., Fowler, J.S., Tomasi, D., Addiction circuitry in the human brain (2012) Annu. Rev. Pharmacol. Toxicol., 52, pp. 321-336
  • Cadet, J.L., Bisagno, V., Milroy, C.M., Neuropathology of substance use disorders (2014) Acta Neuropathol., 127, pp. 91-107
  • Rice, M.E., Cragg, S.J., Dopamine spillover after quantal release: Rethinking dopamine transmission in the nigrostriatal pathway (2008) Brain Res. Rev., 58, pp. 303-313
  • Ross, S.B., Renyi, A.L., Inhibition of the uptake of tritiated 5-hydroxytryptamine in brain tissue (1969) Eur. J. Pharmacol., 7 (3), pp. 270-277
  • Wilson, M.C., Bedford, J.A., Buelke, J., Kibbe, A.H., Acute pharmacological activity of intravenous cocaine in the rhesus monkey (1976) Psychopharmacol. Commun., 2, pp. 251-261
  • Baumann, M.H., Rothman, R.B., Chronic cocaine exposure potentiates prolactin and head shake responses to 5-HT2 receptor stimulation in rats (1996) Neuropharmacology, 35 (3), pp. 295-301
  • Filip, M., Nowak, E., Papla, I., On the role of serotonin2A/2C receptors in the sensitization to cocaine (2001) J. Physiol. Pharmacol., 52 (3), pp. 471-481
  • Fletcher, P.J., Grottick, A.J., Higgins, G.A., Differential effects of the 5-HT(2A) receptor antagonist M100907 and the 5-HT(2C) receptor antagonist SB242084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding (2002) Neuropsychopharmacology, 27 (4), pp. 576-586
  • Burmeister, J.J., Lungren, E.M., Kirschner, K.F., Neisewander, J.L., Differential roles of 5-HT receptor subtypes in cue and cocaine reinstatement of cocaine-seeking behavior in rats (2004) Neuropsychopharmacology, 29 (4), pp. 660-668
  • Huang, C.C., Liang, Y.C., Lee, C.C., Wu, M.Y., Hsu, K.S., Repeated cocaine administration decreases 5-HT(2A) receptor-mediated serotonergic enhancement of synaptic activity in rat medial prefrontal cortex (2009) Neuropsychopharmacology, 34 (8), pp. 1979-1992
  • Goitia, B., Raineri, M., González, L.E., Rozas, J.L., Garcia-Rill, E., Bisagno, V., Urbano, F.J., Differential effects of methylphenidate and cocaine on GABA transmission in sensory thalamic nuclei (2013) J. Neurochem., 124 (5), pp. 602-612
  • Goitia, B., Rivero-Echeto, M.C., Weisstaub, N.V., Gingrich, J.A., Garcia-Rill, E., Bisagno, V., Urbano, F.J., Modulation of GABA release from the thalamic reticular nucleus by cocaine and caffeine: Role of serotonin receptors (2016) J. Neurochem., 136 (3), pp. 526-535
  • Sulzer, D., Rayport, S., Amphetamine and other psychostimulants reduce pH gradients in midbrain dopaminergic neurons and chromaffin granules: A mechanism of action (1990) Neuron, 5 (6), pp. 797-808
  • Sulzer, D., Sonders, M.S., Poulsen, N.W., Galli, A., Mechanisms of neurotransmitter release by amphetamines: A review (2005) Prog. Neurobiol., 75 (6), pp. 406-433
  • Johnson, M., Sonsalla, P.K., Letter, A.A., Hanson, G.R., Gibb, J.W., Role of the 5-HT2 receptor in the methamphetamine-induced neurochemical alterations (1994) J. Pharmacol. Exp. Ther., 270 (1), pp. 97-103
  • Berger, U.V., Gu, X.F., Azmitia, E.C., The substituted amphetamines 3,4-methylenedioxymethamphetamine, methamphetamine, p-chloroamphetamine and fenfluramine induce 5-hydroxytryptamine release via a common mechanism blocked by fluoxetine and cocaine (1992) Eur. J. Pharmacol., 215 (2-3), pp. 153-160
  • Di Chiara, G., Imperato, A., Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats (1988) Proc. Natl. Acad. Sci. U. S. A., 85 (14), pp. 5274-5278
  • Hyman, S.E., Addiction: A disease of learning and memory (2005) Am. J. Psychiatry, 162 (8), pp. 1414-1422
  • Gamo, N.J., Lur, G., Higley, M.J., Wang, M., Paspalas, C.D., Vijayraghavan, S., Yang, Y., Arnsten, A.F., Stress impairs prefrontal cortical function via D1 dopamine receptor interactions with hyperpolarization-activated cyclic nucleotide-gated channels (2015) Biol. Psychiatry, 78 (12), pp. 860-870
  • Wise, R.A., Drive incentive, and reinforcement: The antecedents and consequences of motivation (2004) Neb. Symp. Motiv., 50, pp. 159-195
  • Wise, R.A., Dual roles of dopamine in food and drug seeking: The drive-reward paradox (2013) Biol. Psychiatry, 73 (9), pp. 819-826
  • Berridge, K.C., Robinson, T.E., What is the role of dopamine in reward: Hedonic impact, reward learning, or incentive salience? (1998) Brain Res. Rev., 28 (3), pp. 309-369
  • Berridge, K.C., Kringelbach, M.L., Pleasure systems in the brain (2015) Neuron, 86 (3), pp. 646-664
  • Schultz, W., Multiple dopamine functions at different time courses (2007) Annu. Rev. Neurosci., 30, pp. 259-288
  • Grace, A.A., Floresco, S.B., Goto, Y., Lodge, D.J., Regulation of firing of dopaminergic neurons and control of goal-directed behaviors (2007) Trends Neurosci., 30 (5), pp. 220-227
  • Barchas, J.D., Akil, H., Elliott, G.R., Holman, R.B., Watson, S.J., Behavioral neurochemistry: Neuroregulators and behavioral states (1978) Science, 200 (4344), pp. 964-973
  • Cragg, S.J., Nicholson, C., Kume-Kick, J., Tao, L., Rice, M.E., Dopamine-mediated volume transmission in midbrain is regulated by distinct extracellular geometry and uptake (2001) J. Neurophysiol., 85 (4), pp. 1761-1771
  • Rice, M.E., Patel, J.C., Somatodendritic dopamine release: Recent mechanistic insights (2015) Philos. Trans. R. Soc. Lond. B. Biol. Sci., 370 (1672). , pii: 20140185
  • Tritsch, N.X., Sabatini, B.L., Dopaminergic modulation of synaptic transmission in cortex and striatum (2012) Neuron, 76 (1), pp. 33-50
  • Beaulieu, J.M., Gainetdinov, R.R., The physiology, signaling, and pharmacology of dopamine receptors (2011) Pharmacol. Rev., 63 (1), pp. 182-217
  • Felder, C.C., Jose, P.A., Axelrod, J., The dopamine-1 agonist SKF 82526, stimulates phospholipase-C activity independent of adenylate cyclase (1989) J. Pharmacol. Exp. Ther., 248, pp. 171-175
  • Friedman, E., Jin, L.Q., Cai, G.P., Hollon, T.R., Drago, J., Sibley, D.R., Wang, H.Y., D1-like dopaminergic activation of phosphoinositide hydrolysis is independent of D1A dopamine receptors: Evidence from D1A knockout mice (1997) Mol. Pharmacol., 51 (1), pp. 6-11
  • Sahu, A., Tyeryar, K.R., Vongtau, H.O., Sibley, D.R., Undieh, A.S., D5 dopamine receptors are required for dopaminergic activation of phospholipase C (2009) Mol. Pharmacol., 75, pp. 447-453
  • Lee, S.P., So, C.H., Rashid, A.J., Varghese, G., Cheng, R., Lança, A.J., O'Dowd, B.F., George, S.R., Dopamine D1 and D2 receptor Co-activation generates a novel phospholipase C-mediated calcium signal (2004) J. Biol. Chem., 279, pp. 35671-35678
  • Rashid, A.J., So, C.H., Kong, M.M., Furtak, T., El-Ghundi, M., Cheng, R., O'Dowd, B.F., George, S.R., D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum (2007) Proc. Natl. Acad. Sci. U. S. A., 104 (2), pp. 654-659
  • De Mei, C., Ramos, M., Iitaka, C., Borrelli, E., Getting specialized: Presynaptic and postsynaptic dopamine D2 receptors (2009) Curr. Opin. Pharmacol., 9 (1), pp. 53-58
  • Sokoloff, P., Diaz, J., Le Foll, B., Guillin, O., Leriche, L., Bezard, E., Gross, C., The dopamine D3 receptor: A therapeutic target for the treatment of neuropsychiatric disorders (2006) CNS Neurol. Disord. Drug Targets, 5 (1), pp. 25-43
  • Bentivoglio, M., Morelli, M., The organization and circuits of mesencephalic dopaminergic neurons and the distribution of dopamine receptors in the brain (2005) Dopamine, pp. 1-107. , S.B. Dunnett, M. Bentivoglio, A. Bjorklund, T. Hokfelt, Elsevier San Diego, CA
  • Goldman-Rakic, P.S., Castner, S.A., Svensson, T.H., Siever, L.J., Williams, G.V., Targeting the dopamine D1 receptor in schizophrenia: Insights for cognitive dysfunction (2004) Psychopharmacology (Berlin), 174 (1), pp. 3-16
  • Lidow, M.S., Goldman-Rakic, P.S., Gallager, D.W., Rakic, P., Distribution of dopaminergic receptors in the primate cerebral cortex: Quantitative autoradiographic analysis using 3H raclopride, 3H spiperone and 3H SCH23390 (1991) Neuroscience, 40, pp. 657-671
  • Bergson, C., Mrzljak, L., Smiley, J.F., Pappy, M., Levenson, R., Goldman-Rakic, P.S., Regional cellular, and subcellular variations in the distribution of D1 and D5 dopamine receptors in primate brain (1995) J. Neurosci., 15, pp. 7821-7836
  • Muly, E.C., 3rd, Szigeti, K., Goldman-Rakic, P.S., D1 receptor in interneurons of macaque prefrontal cortex: Distribution and subcellular localization (1998) J. Neurosci., 18, pp. 10553-10565
  • Liu, F., Wan, Q., Pristupa, Z.B., Yu, X.M., Wang, Y.T., Niznik, H.B., Direct protein-protein coupling enables cross-talk between dopamine D5 and gamma-aminobutyric acid A receptors (2000) Nature, 403 (6767), pp. 274-280
  • Gao, W.J., Krimer, L.S., Goldman-Rakic, P.S., Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits (2001) Proc. Natl. Acad. Sci. U.S.A., 98, pp. 295-300
  • Seamans, J.K., Durstewitz, D., Christie, B.R., Stevens, C.F., Sejnowski, T.J., Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer v prefrontal cortex neurons (2001) Proc. Natl. Acad. Sci. U.S.A., 98, pp. 301-306
  • Mrzljak, L., Bergson, C., Pappy, M., Huff, R., Levenson, R., Goldman-Rakic, P.S., Localization of dopamine D4 receptors in GABAergic neurons of the primate brain (1996) Nature, 381, pp. 245-248
  • Yao, W.D., Spealman, R.D., Zhang, J., Dopaminergic signaling in dendritic spines (2008) Biochem. Pharmacol., 75 (11), pp. 2055-2069
  • Goldman-Rakic, P.S., Leranth, C., Williams, S.M., Mons, N., Geffard, M., Dopamine synaptic complex with pyramidal neurons in primate cerebral cortex (1989) Proc. Natl. Acad. Sci. U.S.A., 86 (22), pp. 9015-9019
  • Larkum, M.E., Zhu, J.J., Sakmann, B., A new cellular mechanism for coupling inputs arriving at different cortical layers (1999) Nature, 398 (6725), pp. 338-341
  • Seamans, J.K., Durstewitz, D., Christie, B.R., Stevens, C.F., Sejnowski, T.J., Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer v prefrontal cortex neurons (2001) Proc. Natl. Acad. Sci. U.S.A., 98, pp. 301-306
  • Gonzalez-Islas, C., Hablitz, J.J., Dopamine enhances EPSCs in layer II-III pyramidal neurons in rat prefrontal cortex (2003) J. Neurosci., 23, pp. 867-875
  • Sun, X., Zhao, Y., Wolf, M.E., Dopamine receptor stimulation modulates AMPA receptor synaptic insertion in prefrontal cortex neurons (2005) J. Neurosci., 25, pp. 7342-7351
  • Gao, C., Wolf, M.E., Dopamine receptors regulate NMDA receptor surface expression in prefrontal cortex neurons (2008) J. Neurochem., 106, pp. 2489-2501
  • Gurden, H., Takita, M., Jay, T.M., Essential role of D1 but not D2 receptors in the NMDA receptor-dependent long-term potentiation at hippocampal-prefrontal cortex synapses in vivo (2000) J. Neurosci., 20, p. RC106
  • Huang, Y.Y., Simpson, E., Kellendonk, C., Kandel, E.R., Genetic evidence for the bidirectional modulation of synaptic plasticity in the prefrontal cortex by D1 receptors (2004) Proc. Natl. Acad. Sci. U.S.A., 101, pp. 3236-3241
  • Cepeda, C., Levine, M.S., Where do you think you are going? the NMDA-D1 receptor trap (2006) Sci. STKE, (333). , pe. 20
  • Choi, D.W., Glutamate neurotoxicity and diseases of the nervous system (1988) Neuron, 1, pp. 623-634
  • Bozzi, Y., Borrelli, E., Dopamine in neurotoxicity and neuroprotection: What do D2 receptors have to do with it (2006) Trends Neurosci., 29, pp. 167-174
  • Llinás, R., Moreno, H., Local Ca2+ signaling in neurons (1998) Cell Calcium, 24 (5-6), pp. 359-366
  • Kawamoto, E.M., Vivar, C., Camandola, S., Physiology and pathology of calcium signaling in the brain (2012) Front. Pharmacol., 3, pp. 1-17
  • Young, C.E., Yang, C.R., Dopamine D1/D5 receptor modulates state-dependent switching of soma-dendritic Ca2+ potentials via differential protein kinase A and C activation in rat prefrontal cortical neurons (2004) J. Neurosci., 24 (1), pp. 8-23
  • Kisilevsky, A.E., Mulligan, S.J., Altier, C., Iftinca, M.C., Varela, D., Tai, C., Chen, L., Zamponi, G.W., D1 receptors physically interact with N-type calcium channels to regulate channel distribution and dendritic calcium entry (2008) Neuron, 58, pp. 557-570
  • Tedford, H.W., Zamponi, G.W., Direct G protein modulation of Cav2 calcium channels (2006) Pharmacol. Rev., 58 (4), pp. 837-862
  • Dolphin, A.C., G protein modulation of voltage-gated calcium channels (2003) Pharmacol. Rev., 55 (4), pp. 607-627
  • Chen, Y., Yu, F.H., Surmeier, D.J., Scheuer, T., Catterall, W.A., Neuromodulation of Na+ channel slow inactivation via cAMP-dependent protein kinase and protein kinase C (2006) Neuron, 49, pp. 409-420
  • Yang, C.R., Seamans, J.S., Dopamine D1 receptor actions in layer V-VI rat prefrontal cortex neurons in vitro: Modulation of dendritic-somatic signal integration (1996) J. Neurosci., 16, pp. 1922-1935
  • Kroener, S., Chandler, L.J., Phillips, P.E., Seamans, J.K., Dopamine modulates persistent synaptic activity and enhances the signal-to-noise ratio in the prefrontal cortex (2009) PLoS One, 4 (8), p. e6507
  • Vijayraghavan, S., Wang, M., Birnbaum, S.G., Williams, G.V., Arnsten, A.F., Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory (2007) Nat. Neurosci., 10 (3), pp. 376-384
  • He, C., Chen, F., Li, B., Hu, Z., Neurophysiology of HCN channels: From cellular functions to multiple regulations (2014) Prog. Neurobiol., 112, pp. 1-23
  • Wang, M., Ramos, B.P., Paspalas, C.D., Shu, Y., Simen, A., Duque, A., Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex (2007) Cell, 129, pp. 397-410
  • Chen, S., Wang, J., Siegelbaum, S.A., Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide (2001) J. Gen. Physiol., 117, pp. 491-504
  • Ulens, C., Tytgat, J., Functional heteromerization of HCN1 and HCN2 pacemaker channels (2001) J. Biol. Chem., 276, pp. 6069-6072
  • Notomi, T., Shigemoto, R., Immunohistochemical localization of Ih channel subunits HCN1-4, in the rat brain (2004) J. Comp. Neurol., 471, pp. 241-276
  • Santos-Vera, B., Vázquez-Torres, R., Marrero, H.G., Acevedo, J.M., Arencibia-Albite, F., Vélez-Hernández, M.E., Miranda, J.D., Jiménez-Rivera, C.A., Cocaine sensitization increases Ih current channel subunit 2 (HCN2) protein expression in structures of the mesocorticolimbic system (2013) J. Mol. Neurosci., 50, pp. 234-245
  • Santoro, B., Chen, S., Luthi, A., Pavlidis, P., Shumyatsky, G.P., Tibbs, G.R., Siegelbaum, S.A., Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS (2000) J. Neurosci., 20, pp. 5264-5275
  • Lörincz, A., Notomi, T., Tamás, G., Shigemoto, R., Nusser, Z., Polarized and compartment-dependent distribution of HCN1 in pyramidal cell dendrites (2002) Nat. Neurosci., 5, pp. 1185-1193
  • Berger, T., Senn, W., Lüscher, H.R., Hyperpolarization-activated current Ih disconnects somatic and dendritic spike initiation zones in layer v pyramidal neurons (2003) J. Neurophysiol., 90 (4), pp. 2428-2437
  • Wu, J., Hablitz, J.J., Cooperative activation of D1 and D2 dopamine receptors enhances a hyperpolarization-activated inward current in layer i interneurons (2005) J. Neurosci., 25 (27), pp. 6322-6328
  • Arnsten, A.F., Prefrontal cortical network connections: Key site of vulnerability in stress and schizophrenia (2011) Int. J. Dev. Neurosci., 29, pp. 215-223
  • Nolan, M.F., Malleret, G., Dudman, J.T., Buhl, D.L., Santoro, B., Gibbs, E., Vronskaya, S., Morozov, A., A behavioral role for dendritic integration: HCN1 channels constrain spatial memory and plasticity at inputs to distal dendrites of CA1 pyramidal neurons (2004) Cell, 119, pp. 719-732
  • Magee, J.C., Dendritic lh normalizes temporal summation in hippocampal CA1 neurons (1999) Nat. Neurosci., 2, pp. 508-514
  • Rotaru, D.C., Lewis, D.A., Gonzalez-Burgos, G., Dopamine D1 receptor activation regulates sodium channel-dependent EPSP amplification in rat prefrontal cortex pyramidal neurons (2007) J. Physiol., 581, pp. 981-1000
  • Gorelova, N., Seamans, J.K., Yang, C.R., Mechanisms of dopamine activation of fast-spiking interneurons that exert inhibition in rat prefrontal cortex (2002) J. Neurophysiol., 88 (6), pp. 3150-3166
  • Dong, Y., Cooper, D., Nasif, F., Hu, X.T., White, F.J., Dopamine modulates inwardly rectifying potassium currents in medial prefrontal cortex pyramidal neurons (2004) J. Neurosci., 24 (12), pp. 3077-3085
  • Witkowski, G., Szulczyk, B., Rola, R., Szulczyk, P., D(1) dopaminergic control of G protein-dependent inward rectifier K(+) (GIRK)-like channel current in pyramidal neurons of the medial prefrontal cortex (2008) Neuroscience, 155 (1), pp. 53-63
  • Maurice, N., Tkatch, T., Meisler, M., Sprunger, L.K., Surmeier, D.J., D1/D5 dopamine receptor activation differentially modulates rapidly inactivating and persistent sodium currents in prefrontal cortex pyramidal neurons (2001) J. Neurosci., 21 (7), pp. 2268-2277
  • Peterson, J.D., Wolf, M.E., White, F.J., Repeated amphetamine administration decreases D1 dopamine receptor-mediated inhibition of voltage-gated sodium currents in the prefrontal cortex (2006) J. Neurosci., 26, pp. 3164-3168
  • Franceschetti, S., Taverna, S., Sancini, G., Panzica, F., Lombardi, R., Avanzini, G., Protein kinase C-dependent modulation of Na+ currents increases the excitability of rat neocortical pyramidal neurones (2000) J. Physiol., 528, pp. 291-304
  • Goldman-Rakic, P.S., Muly, E.C., III, Williams, G.V., D(1) receptors in prefrontal cells and circuits (2000) Brain Res. Brain Res. Rev., 31 (2-3), pp. 295-301
  • Goldman-Rakic, P.S., Castner, S.A., Svensson, T.H., Siever, L.J., Williams, G.V., Targeting the dopamine D1 receptor in schizophrenia: Insights for cognitive dysfunction (2004) Psychopharmacology (Berlin), 174 (1), pp. 3-16
  • De Jongh, R., Bolt, I., Schermer, M., Oliver, B., Botox for the brain: Enhancement of cognition, mood and pro-social behavior and blunting of unwanted memories (2008) Neurosci. Biobehav. Rev., 32 (4), pp. 760-776
  • Lin, G.L., Borders, C.B., Lundewall, L.J., Wellman, C.L., D1 receptors regulate dendritic morphology in normal and stressed prelimbic cortex (2015) Psychoneuroendocrinology, 51, pp. 101-111
  • Mair, R.D., Kauer, J.A., Amphetamine depresses excitatory synaptic transmission at prefrontal cortical layer v synapses (2007) Neuropharmacology, 52, pp. 193-199
  • Berridge, C.W., Devilbiss, D.M., Andrzejewski, M.E., Arnsten, A.F., Kelley, A.E., Schmeichel, B., Hamilton, C., Spencer, R.C., Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function (2006) Biol. Psychiatry, 60 (10), pp. 1111-1120
  • Andrews, G.D., Lavin, A., Methylphenidate increases cortical excitability via activation of alpha-2 noradrenergic receptors (2006) Neuropsychopharmacology, 31 (3), pp. 594-601
  • Devilbiss, D.M., Berridge, C.W., Cognition-enhancing doses of methylphenidate preferentially increase prefrontal cortex neuronal responsiveness (2008) Biol. Psychiatry, 64 (7), pp. 626-635
  • Urban, K.R., Waterhouse, B.D., Gao, W.J., Distinct age-dependent effects of methylphenidate on developing and adult prefrontal neurons (2012) Biol. Psychiatry, 72 (10), pp. 880-888
  • Joo, E.Y., Tae, W.S., Jung, K.Y., Hong, S.B., Cerebral blood flow changes in man by wake-promoting drug, modafinil: A randomized double blind study (2008) J. Sleep Res., 17 (1), pp. 82-88
  • Saletu, M., Anderer, P., Semlitsch, H.V., Saletu-Zyhlarz, G.M., Mandl, M., Zeitlhofer, J., Saletu, B., Low-resolution brain electromagnetic tomography (LORETA) identifies brain regions linked to psychometric performance under modafinil in narcolepsy (2007) Psychiatry Res., 154 (1), pp. 69-84
  • Hunter, M.D., Ganesan, V., Wilkinson, I.D., Spence, S.A., Impact of modafinil on prefrontal executive function in schizophrenia (2006) Am. J. Psychiatry, 163 (12), pp. 2184-2186
  • Spence, S.A., Green, R.D., Wilkinson, I.D., Hunter, M.D., Modafinil modulates anterior cingulate function in chronic schizophrenia (2005) Br. J. Psychiatry, 187, pp. 55-61
  • Gozzi, A., Colavito, V., Seke Etet, P.F., Montanari, D., Fiorini, S., Tambalo, S., Bifone, A., Bentivoglio, M., Modulation of fronto-cortical activity by modafinil: A functional imaging and fos study in the rat (2012) Neuropsychopharmacology, 37 (3), pp. 822-837
  • Minzenberg, M.J., Carter, C.S., Modafinil: A review of neurochemical actions and effects on cognition (2008) Neuropsychopharmacology, 33 (7), pp. 1477-1502
  • Rowley, H.L., Kulkarni, R.S., Gosden, J., Brammer, R.J., Hackett, D., Heal, D.J., Differences in the neurochemical and behavioural profiles of lisdexamfetamine methylphenidate and modafinil revealed by simultaneous dual-probe microdialysis and locomotor activity measurements in freely-moving rats (2014) J. Psychopharmacol., 28 (3), pp. 254-269
  • Gonzalez, B., Raineri, M., Cadet, J.L., Garcia-Rill, E., Urbano, F.J., Bisagno, V., Modafinil improves methamphetamine-induced object recognition deficits and restores prefrontal cortex ERK signaling in mice (2014) Neuropharmacology, 87, pp. 188-197
  • Kamei, H., Nagai, T., Nakano, H., Togan, Y., Takayanagi, M., Takahashi, K., Kobayashi, K., Yamada, K., Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK1/2 activation in the prefrontal cortex of mice (2006) Biol. Psychiatry, 59, pp. 75-84
  • Nagai, T., Takuma, K., Dohniwa, M., Ibi, D., Mizoguchi, H., Kamei, H., Nabeshima, T., Yamada, K., Repeated methamphetamine treatment impairs spatial working memory in rats: Reversal by clozapine but not haloperidol (2007) Psychopharmacology (Berlin), 194 (1), pp. 21-32
  • Valjent, E., Corvol, J.C., Pages, C., Besson, M.J., Maldonado, R., Caboche, J., Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties (2000) J. Neurosci., 20 (23), pp. 8701-8709
  • Young, J.W., Geyer, M.A., Action of modafinil-increased motivation via the dopamine transporter inhibition and D1 receptors? (2010) Biol. Psychiatry, 67 (8), pp. 784-787
  • Cadet, J.L., Bisagno, V., Neuropsychological consequences of chronic drug use: Relevance to treatment approaches (2016) Front. Psychiatry, 6, p. 189
  • Tomasi, D., Goldstein, R.Z., Telang, F., Maloney, T., Alia-Klein, N., Caparelli, E.C., Volkow, N.D., Widespread disruption in brain activation patterns to a working memory task during cocaine abstinence (2007) Brain Res., 1171, pp. 83-92
  • Goldstein, R.Z., Leskovjan, A.C., Hoff, A.L., Hitzemann, R., Bashan, F., Khalsa, S.S., Wang, G.J., Volkow, N.D., Severity of neuropsychological impairment in cocaine and alcohol addiction: Association with metabolism in the prefrontal cortex (2004) Neuropsychologia, 42 (11), pp. 1447-1458
  • Camchong, J., MacDonald, A.W., 3rd, Nelson, B., Bell, C., Mueller, B.A., Specker, S., Lim, K.O., Frontal hyperconnectivity related to discounting and reversal learning in cocaine subjects (2011) Biol. Psychiatry, 69 (11), pp. 1117-1123
  • Barrós-Loscertales, A., Bustamante, J.C., Ventura-Campos, N., Llopis, J.J., Parcet, M.A., Avila, C., Lower activation in the right frontoparietal network during a counting Stroop task in a cocaine-dependent group (2011) Psychiatry Res., 194 (2), pp. 111-118
  • Bolla, K.I., Eldreth, D.A., London, E.D., Kiehl, K.A., Mouratidis, M., Contoreggi, C., Matochik, J.A., Ernst, M., Orbitofrontal cortex dysfunction in abstinent cocaine abusers performing a decision-making task (2003) Neuroimage, 19 (3), pp. 1085-1094
  • Bechara, A., The role of emotion in decision-making: Evidence from neurological patients with orbitofrontal damage (2004) Brain Cogn., 55 (1), pp. 30-40
  • Chen, B.T., Yau, H.J., Hatch, C., Kusumoto-Yoshida, I., Cho, S.L., Hopf, F.W., Bonci, A., Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking (2013) Nature, 496 (7445), pp. 359-362
  • Wayman, W.N., Chen, L., Napier, T.C., Hu, X.T., Cocaine self-administration enhances excitatory responses of pyramidal neurons in the rat medial prefrontal cortex to human immunodeficiency virus-1 Tat (2015) Eur. J. Neurosci., 41 (9), pp. 1195-1206
  • Paulus, M.P., Hozack, N.E., Zauscher, B.E., Frank, L., Brown, G.G., Braff, D.L., Behavioral and functional neuroimaging evidence for prefrontal dysfunction in methamphetamine-dependent subjects (2002) Neuropsychopharmacology, 26, pp. 53-63
  • Chang, L., Cloak, C., Patterson, K., Grob, C., Miller, E.N., Ernst, T., Enlarged striatum in abstinent methamphetamine abusers: A possible compensatory response (2005) Biol. Psychiatry, 57, pp. 967-974
  • London, E.D., Berman, S.M., Voytek, B., Simon, S.L., Mandelkern, M.A., Monterosso, J., Cerebral metabolic dysfunction and impaired vigilance in recently abstinent methamphetamine abusers (2005) Biol. Psychiatry, 58, pp. 770-778
  • Johanson, C.-E., Frey, K.A., Lundahl, L.H., Keenan, P., Lockhart, N., Roll, J., Cognitive function and nigrostriatal markers in abstinent methamphetamine abusers (2006) Psychopharmacology, 185, pp. 327-338
  • Monterosso, J.R., Ainslie, G., Xu, J., Cordova, X., Domier, C.P., London, E.D., Frontoparietal cortical activity of methamphetamine-dependent and comparison subjects performing a delay discounting task (2007) Hum. Brain Mapp., 28, pp. 383-393
  • Hoffman, W.F., Moore, M., Templin, R., McFarland, B., Hitzemann, R.J., Mitchell, S.H., Neuropsychological function and delay discounting in methamphetamine-dependent individuals (2006) Psychopharmacology, 188, pp. 162-170
  • Nestor, L.J., Ghahremani, D.G., Monterosso, J., London, E.D., Prefrontal hypoactivation during cognitive control in early abstinent methamphetamine-dependent subjects (2011) Psychiatry Res., 194, pp. 287-295
  • Parsegian, A., See, R.E., Dysregulation of dopamine and glutamate release in the prefrontal cortex and nucleus accumbens following methamphetamine self-administration and during reinstatement in rats (2014) Neuropsychopharmacology, 39, pp. 811-822
  • Salo, R., Ursu, S., Buonocore, M.H., Leamon, M.H., Carter, C., Impaired prefrontal cortical function and disrupted adaptive cognitive control in methamphetamine abusers: A functional magnetic resonance imaging study (2009) Biol. Psychiatry, 65, pp. 706-709
  • González, B., Rivero-Echeto, C., Muñiz, J.L., García-Rill, F.J., Bisagno, V., Methamphetamine blunts Ca2+ currents and excitatory synaptic transmission through D1 /5 receptor-mediated mechanisms in the mouse medial prefrontal cortex (2015) Addict. Biol., , (in press)
  • Zhou, W.L., Antic, S.D., Rapid dopaminergic and GABAergic modulation of calcium and voltage transients in dendrites of prefrontal cortex pyramidal neurons (2012) J. Physiol., 590, pp. 3891-3911
  • Dürsteler, K.M., Berger, E.M., Strasser, J., Caflisch, C., Mutschler, J., Herdener, M., Vogel, M., Clinical potential of methylphenidate in the treatment of cocaine addiction: A review of the current evidence (2016) Subst. Abuse Rehabil., , (in press)
  • Pérez-Mañá, C., Castells, X., Torrens, M., Capellà, D., Farre, M., Efficacy of psychostimulant drugs for amphetamine abuse or dependence (2013) Cochrane Database Syst. Rev., 9, p. CD009695
  • Castells, X., Casas, M., Pérez-Mañá, C., Roncero, C., Vidal, X., Capellà, D., Efficacy of psychostimulant drugs for cocaine dependence (2010) Cochrane Database Syst Rev., 2, p. CD007380


---------- APA ----------
Bisagno, V., González, B. & Urbano, F.J. (2016) . Cognitive enhancers versus addictive psychostimulants: The good and bad side of dopamine on prefrontal cortical circuits. Pharmacological Research, 109, 108-118.
---------- CHICAGO ----------
Bisagno, V., González, B., Urbano, F.J. "Cognitive enhancers versus addictive psychostimulants: The good and bad side of dopamine on prefrontal cortical circuits" . Pharmacological Research 109 (2016) : 108-118.
---------- MLA ----------
Bisagno, V., González, B., Urbano, F.J. "Cognitive enhancers versus addictive psychostimulants: The good and bad side of dopamine on prefrontal cortical circuits" . Pharmacological Research, vol. 109, 2016, pp. 108-118.
---------- VANCOUVER ----------
Bisagno, V., González, B., Urbano, F.J. Cognitive enhancers versus addictive psychostimulants: The good and bad side of dopamine on prefrontal cortical circuits. Pharmacol. Res. 2016;109:108-118.