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Effect of preexposure on methylphenidate-induced taste avoidance and related BDNF/TrkB activity in the insular cortex of the rat

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Abstract

Rationale

Exogenous brain-derived neurotrophic factor (BDNF) in the insular cortex (IC) is known to influence conditioned taste avoidance (CTA) learning, but little is known of its endogenous role in the phenomenon. Preexposure to many abusable compounds attenuates their ability to induce CTA, thus providing a possible platform from which to further elucidate the endogenous role of IC BDNF in CTA.

Objectives

The role of IC BDNF in CTA learning was examined by assessing the effect of preexposure to methylphenidate (MPH) on MPH-induced CTA, followed by expression between preexposure groups of BDNF in the IC, central nucleus of the amygdala (CeA), and the nucleus accumbens (NAc).

Methods

Following preexposure to MPH (18 mg/kg), CTAs induced by MPH (0, 10, 18, and 32 mg/kg) were assessed in adult male Sprague-Dawley rats (n = 64). In separate groups (n = 31), differences in BDNF and tropomyosin-related kinase receptor-B (TrkB) were assessed using Western blots following similar preexposure and conditioning procedures.

Results

Preexposure to MPH significantly blunted MPH-CTA compared to preexposure to vehicle. Unexpectedly, there were no significant effects of MPH on BDNF activity following CTA, but animals preexposed to MPH exhibited decreased activity in the CeA and enhanced activity in the IC and NAc.

Conclusions

Preexposure to MPH attenuates its aversive effects on subsequent presentations, and BDNF’s impact on CTA learning may be dependent upon its temporal relation to other CTA-related intracellular cascades.

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References

  • Barki-Harrington L, Belelovsky K, Doron G, Rosenblum K (2009) Molecular mechanisms of taste learning in the insular cortex and amygdala. In: Reilly S, Schachtman TR (eds) Conditioned Taste Aversion. Oxford University Press, New York, pp 341–363

    Google Scholar 

  • Bermúdez-Rattoni F (2014) The forgotten insular cortex: its role on recognition memory formation. Neurobiol Learn Mem 109:207–16. doi:10.1016/j.nlm.2014.01.001

    Article  PubMed  Google Scholar 

  • Bermúdez-Rattoni F, Ramírez-Lugo L, Gutiérrez R, Miranda MI (2004) Molecular signals into the insular cortex and amygdala during aversive gustatory memory formation. Cell Mol Neurobiol 24:25–36

    Article  PubMed  Google Scholar 

  • Bernstein IL, Koh MT (2007) Molecular signaling during taste aversion learning. Chem Senses 32:99–103. doi:10.1093/chemse/bjj032

    Article  CAS  PubMed  Google Scholar 

  • Bernstein IL, Wilkins EE, Barot SK (2009) Mapping conditioned taste aversion associations through patterns of c-Fos expression. In: Reilly S, Schachtman TR (eds) Conditioned Taste Aversion. Oxford University Press, New York, pp 328–340

    Google Scholar 

  • Brockwell N, Eikelboom R, Beninger R (1991) Caffeine-induced place and taste conditioning: production of dose-dependent preference and aversion. Pharmacol Biochem Behav 38:513–517. doi:10.1016/0091-3057(91)90006-N

    Article  CAS  PubMed  Google Scholar 

  • Bures J, Bermudez-Rattoni F, Yamamoto T (1998) Conditioned taste aversion: memory of a special kind. New York, Oxford

    Book  Google Scholar 

  • Canese R, Adriani W, Marco EM, De Pasquale F, Lorenzini P, De Luca N, Fabi F, Podo F, Laviola G (2009) Peculiar response to methylphenidate in adolescent compared to adult rats: a phMRI study. Psychopharmacology (Berl) 203:143–153

    Article  CAS  Google Scholar 

  • Cappell H, LeBlanc A (1977) Parametric investigations of the effects of prior exposure to amphetamine and morphine on conditioned gustatory aversion. Psychopharmacology (Berl) 51:265–271. doi:10.1007/BF00431634

    Article  CAS  Google Scholar 

  • Castillo DV, Escobar ML (2011) A role for MAPK and PI-3 K signaling pathways in brain-derived neurotrophic factor modification of conditioned taste aversion retention. Behav Brain Res 217:248–252

    Article  CAS  PubMed  Google Scholar 

  • Castillo DV, Figueroa-Guzmán Y, Escobar ML (2006) Brain-derived neurotrophic factor enhances conditioned taste aversion retention. Brain Res 1067:250–255

    Article  CAS  PubMed  Google Scholar 

  • Clark EW, Bernstein IL (2009) Boosting cholinergic activity in gustatory cortex enhances the salience of a familiar conditioned stimulus in taste aversion learning. Behav Neurosci 123:764

    Article  PubMed Central  PubMed  Google Scholar 

  • Contreras M, Ceric F, Torrealba F (2007) Inactivation of the interoceptive insula disrupts drug craving and malaise induced by lithium. Science 318:655–658

    Article  CAS  PubMed  Google Scholar 

  • Contreras M, Billeke P, Vicencio S, Madrid C, Perdomo G, González M, Torrealba F (2012) A role for the insular cortex in long-term memory for context-evoked drug craving in rats. Neuropsychopharmacology 37:2101–2108

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Domjan M, Best M (1980) Interference with ingestional aversion learning produced by preexposure to the unconditioned stimulus: associative and nonassociative aspects. Learn Motiv 11:522–537

    Article  Google Scholar 

  • Fayard B, Loeffler S, Weis J, Vögelin E, Krüttgen A (2005) The secreted brain‐derived neurotrophic factor precursor pro‐BDNF binds to TrkB and p75NTR but not to TrkA or TrkC. J Neurosci Res 80:18–28

    Article  CAS  PubMed  Google Scholar 

  • Fischer GJ, Vail BJ (1980) Preexposure to delta-9-THC blocks THC-induced conditioned taste aversion in rats. Behav Neural Biol 30:191–196

    Article  CAS  PubMed  Google Scholar 

  • Freeman KB, Riley AL (2009) The origins of conditioned taste aversion learning: An historical analysis. In: Reilly S, Schachtman TR (eds) Conditioned taste aversion: Behavioral and neural processes. Oxford University Press, New York, pp 9–33

    Google Scholar 

  • Goudie A, Taylor M, Atherton H (1975) Effects of prior drug experience on the establishment of taste aversions in rats. Pharmacol Biochem Behav 3:947–952

    Article  CAS  PubMed  Google Scholar 

  • Goudie A, Thornton E, Wheller T (1976) Drug pretreatment effects in drug induced taste aversions: effects of dose and duration of pretreatment. Pharmacol Biochem Behav 4:629–633

    Article  CAS  PubMed  Google Scholar 

  • Gutiérrez R, Rodriguez-Ortiz CJ, De La Cruz V, Núñez-Jaramillo L, Bermúdez-Rattoni F (2003) Cholinergic dependence of taste memory formation: evidence of two distinct processes. Neurobiol Learn Mem 80:323–331

    Article  PubMed  Google Scholar 

  • Hunt T, Amit Z (1987) Conditioned taste aversion induced by self-administered drugs: paradox revisited. Neurosci Biobehav Rev 11:107–130

    Article  CAS  PubMed  Google Scholar 

  • Iwamoto ET, Williamson EC (1984) Nicotine-induced taste aversion: characterization and preexposure effects in rats. Pharmacol Biochem Behav 21:527–532

    Article  CAS  PubMed  Google Scholar 

  • King H, Riley A (2013) A history of morphine-induced taste aversion learning fails to affect morphine-induced place preference conditioning in rats. Learn Behav 41:433–442. doi:10.3758/s13420-013-0118-6

    Article  PubMed  Google Scholar 

  • Kolbeck R, Jungbluth S, Barde YA (1994) Characterisation of neurotrophin dimers and monomers. Eur J Biochem 225:995–1003

    Article  CAS  PubMed  Google Scholar 

  • Li X, Wolf ME (2014) Multiple faces of BDNF in cocaine addiction. Behav Brain Res. doi:10.1016/j.bbr.2014.11.018

    PubMed Central  Google Scholar 

  • Ma L, Wang DD, Zhang TY, Yu H, Wang Y, Huang SH, Lee FS, Chen ZY (2011) Region-Specific Involvement of BDNF Secretion and Synthesis in Conditioned Taste Aversion Memory Formation. J Neurosci 31:2079–2090

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Marco EM, Adriani W, Ruocco LA, Canese R, Sadile AG, Laviola G (2011) Neurobehavioral adaptations to methylphenidate: the issue of early adolescent exposure. Neurosci Biobehav Rev 35:1722–1739

    Article  CAS  PubMed  Google Scholar 

  • McClung CA, Nestler EJ (2008) Neuroplasticity mediated by altered gene expression. Neuropsychopharmacology 33:3–17. doi:10.1038/sj.npp.1301544

    Article  CAS  PubMed  Google Scholar 

  • Meririnne E, Kankaanpää A, Seppälä T (2001) Rewarding properties of methylphenidate: sensitization by prior exposure to the drug and effects of dopamine D1-and D2-receptor antagonists. J Pharmacol Exp Ther 298:539–550

    CAS  PubMed  Google Scholar 

  • Minichiello L (2009) TrkB signalling pathways in LTP and learning. Nat Rev Neurosci 10:850–860

    Article  CAS  PubMed  Google Scholar 

  • Moguel-González M, Gómez-Palacio-Schjetnan A, Escobar ML (2008) BDNF reverses the CTA memory deficits produced by inhibition of protein synthesis. Neurobiol Learn Mem 90:584–587

    Article  PubMed  Google Scholar 

  • Musumeci G, Sciarretta C, Rodríguez-Moreno A, Al Banchaabouchi M, Negrete-Díaz V, Costanzi M, Berno V, Egorov AV, Und Halbach OB, Cestari V (2009) TrkB modulates fear learning and amygdalar synaptic plasticity by specific docking sites. J Neurosci 29:10131–10143

    Article  CAS  PubMed  Google Scholar 

  • Naqvi NH, Rudrauf D, Damasio H, Bechara A (2007) Damage to the insula disrupts addiction to cigarette smoking. Science 315:531–534

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • National Research Council (2003) Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research. National Academy Press, Washington

    Google Scholar 

  • National Research Council (2011) Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington

    Google Scholar 

  • Nestler EJ (2001) Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2:119–128. doi:10.1038/35053570

    Article  CAS  PubMed  Google Scholar 

  • Nestler EJ (2005) Is there a common molecular pathway for addiction? Nat Neurosci 8:1445–1449. doi:10.1038/nn1578

    Article  CAS  PubMed  Google Scholar 

  • Ohira K, Hayashi M (2009) A new aspect of the TrkB signaling pathway in neural plasticity. Curr Neuropharmacol 7:276–285

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Palkovits M, Brownstein MJ (1988) Maps and guide to microdissection of the rat brain. Elsevier, New York

    Google Scholar 

  • Paxinos G, Watson C (2005) The Rat Brain in Stereotaxic Coordinates, 5th edn. Academic Press, San Diego

    Google Scholar 

  • Pierce RC, Kalivas PW (1997) A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Rev 25:192–216

    Article  CAS  PubMed  Google Scholar 

  • Randich A, LoLordo VM (1979) Associative and nonassociative theories of the UCS preexposure phenomenon: implications for Pavlovian conditioning. Psychol Bull 86:523–548. doi:10.1037//0033-2909.86.3.523

    Article  CAS  PubMed  Google Scholar 

  • Reilly S (2009) Central gustatory system lesions and conditioned taste aversion. In: Reilly S, Schachtman TR (eds) Conditioned Taste Aversion. Oxford University Press, New York, pp 309–327

    Google Scholar 

  • Riley AL (2011) The paradox of drug taking: The role of the aversive effects of drugs. Physiol Behav 103:69–78. doi:10.1016/j.physbeh.2010.11.021

    Article  CAS  PubMed  Google Scholar 

  • Riley AL, Diamond H (1998) The effects of cocaine preexposure on the acquisition of cocaine-induced taste aversions. Pharmacol Biochem Behav 60:739–745. doi:10.1016/S0091-3057(98)00052-5

    Article  CAS  PubMed  Google Scholar 

  • Riley AL, Simpson G (2001) The attenuating effects of drug preexposure on taste aversion conditioning: generality, experimental parameters, underlying mechanisms, and implications for drug use and abuse. In: Mowrer RR, Klein SB (eds) Handbook of contemporary learning theories. Earlbaum Associates, Hillsdale, New Jersey, pp 505–559

    Google Scholar 

  • Riley AL, Tuck D (1985) Conditioned taste aversions: a behavioral index of toxicity. Ann N Y Acad Sci 443:272–292. doi:10.1111/j.1749-6632.1985.tb27079.x

    Article  CAS  PubMed  Google Scholar 

  • Riley AL, Zellner D (1978) Methylphenidate-induced conditioned taste aversion: An index of toxicity. Physiol Psychol 6:354–358

    Article  CAS  Google Scholar 

  • Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18:247–291

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez-Serrano LM, Ramirez-Leon B, Rodriguez-Duran LF, Escobar ML (2014) Acute infusion of brain-derived neurotrophic factor in the insular cortex promotes conditioned taste aversion extinction. Neurobiol Learn Mem 116:139–144

    Article  CAS  PubMed  Google Scholar 

  • Rosenblum K, Berman DE, Hazvi S, Dudai Y (1996) Carbachol mimics effects of sensory input on tyrosine phosphorylation in cortex. Neuroreport 7:1401–1404

    Article  CAS  PubMed  Google Scholar 

  • Rosenblum K, Berman DE, Hazvi S, Lamprecht R, Dudai Y (1997) NMDA receptor and the tyrosine phosphorylation of its 2B subunit in taste learning in the rat insular cortex. J Neurosci 17:5129–5135

    CAS  PubMed  Google Scholar 

  • Rutherford LC, Nelson SB, Turrigiano GG (1998) BDNF has opposite effects on the quantal amplitude of pyramidal neuron and interneuron excitatory synapses. Neuron 21:521–530

    Article  CAS  PubMed  Google Scholar 

  • Schoffelmeer AN, De Vries TJ, Wardeh G, van de Ven HW, Vanderschuren LJ (2002) Psychostimulant-induced behavioral sensitization depends on nicotinic receptor activation. J Neurosci 22:3269–3276

    CAS  PubMed  Google Scholar 

  • Serafine K, Riley A (2010) Preexposure to cocaine attenuates aversions induced by both cocaine and fluoxetine: Implications for the basis of cocaine-induced conditioned taste aversions. Pharmacol Biochem Behav 95:230–234

    Article  CAS  PubMed  Google Scholar 

  • Tirelli E, Laviola G, Adriani W (2003) Ontogenesis of behavioral sensitization and conditioned place preference induced by psychostimulants in laboratory rodents. Neurosci Biobehav Rev 27:163–178

    Article  PubMed  Google Scholar 

  • Turrigiano G (2012) Homeostatic synaptic plasticity: local and global mechanisms for stabilizing neuronal function. Cold Spring Harb Perspect Biol 4:a005736

    Article  PubMed Central  PubMed  Google Scholar 

  • Uhl GR, Drgonova J, Hall FS (2014) Curious cases: Altered dose–response relationships in addiction genetics. Pharmacol Ther 141:335–346

    Article  CAS  PubMed  Google Scholar 

  • van der Marel K, Klomp A, Meerhoff GF, Schipper P, Lucassen PJ, Homberg JR, Dijkhuizen RM, Reneman L (2013) Long-term oral methylphenidate treatment in adolescent and adult rats: differential effects on brain morphology and function. Neuropsychopharmacology 39:263–273

    Article  PubMed Central  PubMed  Google Scholar 

  • Volkow ND, Ding Y-S, Fowler JS, Wang G-J, Logan J, Gatley JS, Dewey S, Ashby C, Liebermann J, Hitzemann R (1995) Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. Arch Gen Psychiatry 52:456–463

    Article  CAS  PubMed  Google Scholar 

  • Wang G-J, Volkow ND, Fowler JS, Cervany P, Hitzemann RJ, Pappas NR, Wong CT, Felder C (1999) Regional brain metabolic activation during craving elicited by recall of previous drug experiences. Life Sci 64:775–784

    Article  CAS  PubMed  Google Scholar 

  • Waterhouse EG, Xu B (2009) New insights into the role of brain-derived neurotrophic factor in synaptic plasticity. Mol Cell Neurosci 42:81–89

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wetzell B, Riley A (2012) Adolescent exposure to methylphenidate has no effect on the aversive properties of cocaine in adulthood. Pharmacol Biochem Behav 101:394–402. doi:10.1016/j.pbb.2012.02.002

    Article  CAS  PubMed  Google Scholar 

  • Wetzell B, Muller M, Cobuzzi J, Hurwitz Z, DeCicco-Skinner K, Riley A (2014) Effect of age on methylphenidate-induced conditioned taste avoidance and related BDNF/TrkB signaling in the insular cortex of the rat. Psychopharmacology (Berl) 231:1493–1501. doi:10.1007/s00213-014-3500-y

    Article  CAS  Google Scholar 

  • Wise R, Yokel R, DeWitt H (1976) Both positive reinforcement and conditioned aversion from amphetamine and from apomorphine in rats. Science 191:1273–1275. doi:10.1126/science.1257748

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto T, Ueji K (2011) Brain mechanisms of flavor learning. Front Syst Neurosci 5:75–82

    Article  Google Scholar 

  • Yang PB, Cuellar DO III, Swann AC, Dafny N (2011) Age and genetic strain differences in response to chronic methylphenidate administration. Behav Brain Res 218:206–217

    Article  CAS  PubMed  Google Scholar 

  • Yetnikoff L, Arvanitogiannis A (2013) Differential sensitivity to the acute and sensitizing behavioral effects of methylphenidate as a function of strain in adolescent and young adult rats. Behav Brain Funct 9:38

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Anand Adhikari and Ben Taylor from the Department of Biology, American University for their technical assistance with the Western blot and densitometry analyses. This work was supported by a grant from the Mellon Foundation to ALR, a Dean’s Graduate Research Grant to BBW and a Dean’s Undergraduate Research Grant to MMM.

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Wetzell, B.B., Muller, M.M., Flax, S.M. et al. Effect of preexposure on methylphenidate-induced taste avoidance and related BDNF/TrkB activity in the insular cortex of the rat. Psychopharmacology 232, 2837–2847 (2015). https://doi.org/10.1007/s00213-015-3924-z

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