, Volume 234, Issue 19, pp 2897–2909 | Cite as

Blockade of α2-adrenergic receptors in prelimbic cortex: impact on cocaine self-administration in adult spontaneously hypertensive rats following adolescent atomoxetine treatment

  • Britahny M. Baskin
  • Bríd Á. Nic Dhonnchadha
  • Linda P. Dwoskin
  • Kathleen M. KantakEmail author
Original Investigation



Research with the spontaneously hypertensive rat (SHR) model of attention deficit/hyperactivity disorder demonstrated that chronic methylphenidate treatment during adolescence increased cocaine self-administration established during adulthood under a progressive ratio (PR) schedule. Compared to vehicle, chronic atomoxetine treatment during adolescence failed to increase cocaine self-administration under a PR schedule in adult SHR.


We determined if enhanced noradrenergic transmission at α2-adrenergic receptors within prefrontal cortex contributes to this neutral effect of adolescent atomoxetine treatment in adult SHR.


Following treatment from postnatal days 28–55 with atomoxetine (0.3 mg/kg) or vehicle, adult male SHR and control rats from Wistar-Kyoto (WKY) and Wistar (WIS) strains were trained to self-administer 0.3 mg/kg cocaine. Self-administration performance was evaluated under a PR schedule of cocaine delivery following infusion of the α2-adrenergic receptor antagonist idazoxan (0 and 10–56 μg/side) directly into prelimbic cortex.


Adult SHR attained higher PR break points and had greater numbers of active lever responses and infusions than WKY and WIS. Idazoxan dose-dependently increased PR break points and active lever responses in SHR following adolescent atomoxetine vs. vehicle treatment. Behavioral changes were negligible after idazoxan pretreatment in SHR following adolescent vehicle or in WKY and WIS following adolescent atomoxetine or vehicle.


α2-Adrenergic receptor blockade in prelimbic cortex of SHR masked the expected neutral effect of adolescent atomoxetine on adult cocaine self-administration behavior. Moreover, greater efficacy of acute idazoxan challenge in adult SHR after adolescent atomoxetine relative to vehicle is consistent with the idea that chronic atomoxetine may downregulate presynaptic α2A-adrenergic autoreceptors in SHR.


Atomoxetine Attention deficit/hyperactivity disorder Cocaine Idazoxan Norepinephrine Prelimbic cortex Self-administration 



The authors thank Brian Coughlin, Robert Pulido, and Audrey-Jo Santo for the technical assistance.

Compliance with ethical standards

Research involving animals

All procedures were approved by the Boston University Institutional Animal Care and Use Committee and were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (8th Edition).


National Institutes of Health grant DA011716.

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. Ago Y, Umehara M, Higashino K, Hasebe S, Fujita K, Takuma K, Matsuda T (2014) Atomoxetine-induced increases in monoamine release in the prefrontal cortex are similar in spontaneously hypertensive rats and Wistar-Kyoto rats. Neurochem Res 39:825–832. doi: 10.1007/s11064-014-1275-5 CrossRefPubMedGoogle Scholar
  2. Aoki C, Go CG, Venkatesan C, Kurose H (1994) Perikaryal and synaptic localization of alpha 2A-adrenergic receptor-like immunoreactivity. Brain Res 650:181–204CrossRefPubMedGoogle Scholar
  3. Aoki C, Venkatesan C, Go CG, Forman R, Kurose H (1998) Cellular and subcellular sites for noradrenergic action in the monkey dorsolateral prefrontal cortex as revealed by the immunocytochemical localization of noradrenergic receptors and axons. Cereb Cortex 8:269–277CrossRefPubMedGoogle Scholar
  4. Arnsten AF (2009) Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. CNS drugs 23(Suppl 1):33–41. doi: 10.2165/00023210-200923000-00005 CrossRefPubMedGoogle Scholar
  5. Bari A, Mar AC, Theobald DE, Elands SA, Oganya KC, Eagle DM, Robbins TW (2011) Prefrontal and monoaminergic contributions to stop-signal task performance in rats. J Neurosci 31:9254–9263. doi: 10.1523/JNEUROSCI.1543-11.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Baskin BM, Dwoskin LP, Kantak KM (2015) Methylphenidate treatment beyond adolescence maintains increased cocaine self-administration in the spontaneously hypertensive rat model of attention deficit/hyperactivity disorder. Pharmacol Biochem Behav 131:51–56. doi: 10.1016/j.pbb.2015.01.019 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Berridge CW et al (2006) Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry 60:1111–1120. doi: 10.1016/j.biopsych.2006.04.022 CrossRefPubMedGoogle Scholar
  8. Berridge CW, Stalnaker TA (2002) Relationship between low-dose amphetamine-induced arousal and extracellular norepinephrine and dopamine levels within prefrontal cortex. Synapse 46:140–149. doi: 10.1002/syn.10131 CrossRefPubMedGoogle Scholar
  9. Bolden-Watson C, Richelson E (1993) Blockade by newly-developed antidepressants of biogenic amine uptake into rat brain synaptosomes. Life Sci 52:1023–1029CrossRefPubMedGoogle Scholar
  10. Boyle AE, Gill K, Smith BR, Amit Z (1991) Differential effects of an early housing manipulation on cocaine-induced activity and self-administration in laboratory rats. Pharmacol Biochem Behav 39:269–274CrossRefPubMedGoogle Scholar
  11. Bradshaw SE, Agster KL, Waterhouse BD, McGaughy JA (2016) Age-related changes in prefrontal norepinephrine transporter density: the basis for improved cognitive flexibility after low doses of atomoxetine in adolescent rats. Brain Res 1641:245–257. doi: 10.1016/j.brainres.2016.01.001 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Broos N, Loonstra R, van Mourik Y, Schetters D, Schoffelmeer AN, Pattij T, De Vries TJ (2015) Subchronic administration of atomoxetine causes an enduring reduction in context-induced relapse to cocaine seeking without affecting impulsive decision making. Addict Biol 20:714–723. doi: 10.1111/adb.12168 CrossRefPubMedGoogle Scholar
  13. Bymaster FP et al (2002) Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27:699–711. doi: 10.1016/S0893-133X(02)00346-9 CrossRefPubMedGoogle Scholar
  14. Capdevila S, Giral M, Ruiz de la Torre JL, Russell RJ, Kramer K (2007) Acclimatization of rats after ground transportation to a new animal facility. Lab Anim 41:255–261. doi: 10.1258/002367707780378096 CrossRefPubMedGoogle Scholar
  15. Chauvet C, Lardeux V, Goldberg SR, Jaber M, Solinas M (2009) Environmental enrichment reduces cocaine seeking and reinstatement induced by cues and stress but not by cocaine. Neuropsychopharmacology 34:2767–2778. doi: 10.1038/npp.2009.127 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Cohen J (1988) Statistical power analysis for the behavioral sciences. Erlbaum, HillsdaleGoogle Scholar
  17. Cottingham C, Chen Y, Jiao K, Wang Q (2011) The antidepressant desipramine is an arrestin-biased ligand at the alpha(2A)-adrenergic receptor driving receptor down-regulation in vitro and in vivo. J Biol Chem 286:36063–36075. doi: 10.1074/jbc.M111.261578 CrossRefPubMedPubMedCentralGoogle Scholar
  18. De Bruin NM, Kiliaan AJ, De Wilde MC, Broersen LM (2003) Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats. Neurobiol Learn Mem 80:63–79CrossRefPubMedGoogle Scholar
  19. Delaville C, Zapata J, Cardoit L, Benazzouz A (2012) Activation of subthalamic alpha 2 noradrenergic receptors induces motor deficits as a consequence of neuronal burst firing. Neurobiol Dis 47:322–330. doi: 10.1016/j.nbd.2012.05.019 CrossRefPubMedGoogle Scholar
  20. Di Pietro NC, Black YD, Kantak KM (2006) Context-dependent prefrontal cortex regulation of cocaine self-administration and reinstatement behaviors in rats. Eur J Neurosci 24:3285–3298. doi: 10.1111/j.1460-9568.2006.05193.x CrossRefPubMedGoogle Scholar
  21. Easton N, Steward C, Marshall F, Fone K, Marsden C (2007) Effects of amphetamine isomers, methylphenidate and atomoxetine on synaptosomal and synaptic vesicle accumulation and release of dopamine and noradrenaline in vitro in the rat brain. Neuropharmacology 52:405–414. doi: 10.1016/j.neuropharm.2006.07.035 CrossRefPubMedGoogle Scholar
  22. Economidou D, Pelloux Y, Robbins TW, Dalley JW, Everitt BJ (2009) High impulsivity predicts relapse to cocaine-seeking after punishment-induced abstinence. Biol Psychiatry 65:851–856. doi: 10.1016/j.biopsych.2008.12.008 CrossRefPubMedGoogle Scholar
  23. Efron D, Jarman F, Barker M (1997) Side effects of methylphenidate and dexamphetamine in children with attention deficit hyperactivity disorder: a double-blind, crossover trial. Pediatrics 100:662–666CrossRefPubMedGoogle Scholar
  24. Gamo NJ, Wang M, Arnsten AF (2010) Methylphenidate and atomoxetine enhance prefrontal function through alpha2-adrenergic and dopamine D1 receptors. J Am Acad Child Adolesc Psychiatry 49:1011–1023. doi: 10.1016/j.jaac.2010.06.015 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Garcia AS, Barrera G, Burke TF, Ma S, Hensler JG, Morilak DA (2004) Autoreceptor-mediated inhibition of norepinephrine release in rat medial prefrontal cortex is maintained after chronic desipramine treatment. J Neurochem 91:683–693. doi: 10.1111/j.1471-4159.2004.02748.x CrossRefPubMedGoogle Scholar
  26. Garnier LM, Arria AM, Caldeira KM, Vincent KB, O’Grady KE, Wish ED (2010) Sharing and selling of prescription medications in a college student sample. J Clin Psychiatry 71:262–269. doi: 10.4088/JCP.09m05189ecr CrossRefPubMedPubMedCentralGoogle Scholar
  27. Gattu M, Terry AV Jr, Pauly JR, Buccafusco JJ (1997) Cognitive impairment in spontaneously hypertensive rats: role of central nicotinic receptors. Part II Brain Res 771:104–114CrossRefPubMedGoogle Scholar
  28. Gauthier JM, Tassin DH, Dwoskin LP, Kantak KM (2014) Effects of dopamine D1 receptor blockade in the prelimbic prefrontal cortex or lateral dorsal striatum on frontostriatal function in Wistar and spontaneously hypertensive rats. Behav Brain Res 268:229–238. doi: 10.1016/j.bbr.2014.04.018 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Hains AB, Yabe Y, Arnsten AF (2015) Chronic stimulation of alpha-2A-adrenoceptors with guanfacine protects rodent prefrontal cortex dendritic spines and cognition from the effects of chronic stress. Neurobiol Stress 2:1–9. doi: 10.1016/j.ynstr.2015.01.001 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Hand DJ, Fox AT, Reilly MP (2009) Differential effects of d-amphetamine on impulsive choice in spontaneously hypertensive and Wistar-Kyoto rats. Behav Pharmacol 20:549–553. doi: 10.1097/FBP.0b013e3283305ee1 CrossRefPubMedGoogle Scholar
  31. Harvey RC, Jordan CJ, Tassin DH, Moody KR, Dwoskin LP, Kantak KM (2013) Performance on a strategy set shifting task during adolescence in a genetic model of attention deficit/hyperactivity disorder: methylphenidate vs. atomoxetine treatments. Behav Brain Res 244:38–47. doi: 10.1016/j.bbr.2013.01.027 CrossRefPubMedGoogle Scholar
  32. Harvey RC, Sen S, Deaciuc A, Dwoskin LP, Kantak KM (2011) Methylphenidate treatment in adolescent rats with an attention deficit/hyperactivity disorder phenotype: cocaine addiction vulnerability and dopamine transporter function. Neuropsychopharmacology 36:837–847. doi: 10.1038/npp.2010.223 CrossRefPubMedGoogle Scholar
  33. Invernizzi RW, Garattini S (2004) Role of presynaptic alpha2-adrenoceptors in antidepressant action: recent findings from microdialysis studies. Prog Neuropsychopharmacol Biol Psychiatry 28:819–827. doi: 10.1016/j.pnpbp.2004.05.026 CrossRefPubMedGoogle Scholar
  34. Jentsch JD (2005) Impaired visuospatial divided attention in the spontaneously hypertensive rat. Behav Brain Res 157:323–330. doi: 10.1016/j.bbr.2004.07.011 CrossRefPubMedGoogle Scholar
  35. Jordan CJ, Harvey RC, Baskin BB, Dwoskin LP, Kantak KM (2014) Cocaine-seeking behavior in a genetic model of attention-deficit/hyperactivity disorder following adolescent methylphenidate or atomoxetine treatments. Drug Alcohol Depend 140:25–32. doi: 10.1016/j.drugalcdep.2014.04.020 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Jordan CJ, Lemay C, Dwoskin LP, Kantak KM (2016a) Adolescent d-amphetamine treatment in a rodent model of attention deficit/hyperactivity disorder: impact on cocaine abuse vulnerability in adulthood. Psychopharmacology (Berl) 233:3891–3903. doi: 10.1007/s00213-016-4419-2 CrossRefGoogle Scholar
  37. Jordan CJ, Taylor DM, Dwoskin LP, Kantak KM (2016b) Adolescent D-amphetamine treatment in a rodent model of ADHD: pro-cognitive effects in adolescence without an impact on cocaine cue reactivity in adulthood. Behav Brain Res 297:165–179. doi: 10.1016/j.bbr.2015.10.017 CrossRefPubMedGoogle Scholar
  38. Kantak KM et al (2008) Advancing the spontaneous hypertensive rat model of attention deficit/hyperactivity disorder. Behav Neurosci 122:340–357. doi: 10.1037/0735-7044.122.2.340 CrossRefPubMedGoogle Scholar
  39. Kirkpatrick K, Marshall AT, Smith AP, Koci J, Park Y (2014) Individual differences in impulsive and risky choice: effects of environmental rearing conditions. Behav Brain Res 269:115–127. doi: 10.1016/j.bbr.2014.04.024 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Klein-Schwartz W, McGrath J (2003) Poison centers’ experience with methylphenidate abuse in pre-teens and adolescents. J Am Acad Child Adolesc Psychiatry 42:288–294. doi: 10.1097/00004583-200303000-00008 CrossRefPubMedGoogle Scholar
  41. Koob GF, Bloom FE (1988) Cellular and molecular mechanisms of drug dependence. Science 242:715–723CrossRefPubMedGoogle Scholar
  42. Kuczenski R, Segal DS (2002) Exposure of adolescent rats to oral methylphenidate: preferential effects on extracellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine. J Neurosci 22:7264–7271 doi:20026690PubMedGoogle Scholar
  43. Lee B, Tiefenbacher S, Platt DM, Spealman RD (2004) Pharmacological blockade of alpha2-adrenoceptors induces reinstatement of cocaine-seeking behavior in squirrel monkeys. Neuropsychopharmacology 29:686–693. doi: 10.1038/sj.npp.1300391 CrossRefPubMedGoogle Scholar
  44. Loh EA, Roberts DC (1990) Break-points on a progressive ratio schedule reinforced by intravenous cocaine increase following depletion of forebrain serotonin. Psychopharmacology (Berl) 101:262–266CrossRefGoogle Scholar
  45. MacDonald E, Scheinin M (1995) Distribution and pharmacology of alpha 2-adrenoceptors in the central nervous system. J Physiol Pharmacol 46:241–258PubMedGoogle Scholar
  46. Mallard NJ, Hudson AL, Nutt DJ (1992) Characterization and autoradiographical localization of non-adrenoceptor idazoxan binding sites in the rat brain. Br J Pharmacol 106:1019–1027CrossRefPubMedPubMedCentralGoogle Scholar
  47. Mantsch JR, Vranjkovic O, Twining RC, Gasser PJ, McReynolds JR, Blacktop JM (2014) Neurobiological mechanisms that contribute to stress-related cocaine use. Neuropharmacology 76(Pt B):383–394. doi: 10.1016/j.neuropharm.2013.07.021 CrossRefPubMedGoogle Scholar
  48. Martins S, Tramontina S, Polanczyk G, Eizirik M, Swanson JM, Rohde LA (2004) Weekend holidays during methylphenidate use in ADHD children: a randomized clinical trial. J Child Adolesc Psychopharmacol 14:195–206. doi: 10.1089/1044546041649066 CrossRefPubMedGoogle Scholar
  49. Masana M, Bortolozzi A, Artigas F (2011) Selective enhancement of mesocortical dopaminergic transmission by noradrenergic drugs: therapeutic opportunities in schizophrenia. Int J Neuropsychopharmacol 14:53–68. doi: 10.1017/S1461145710000908 CrossRefPubMedGoogle Scholar
  50. Mashhoon Y, Wells AM, Kantak KM (2010) Interaction of the rostral basolateral amygdala and prelimbic prefrontal cortex in regulating reinstatement of cocaine-seeking behavior. Pharmacol Biochem Behav 96:347–353. doi: 10.1016/j.pbb.2010.06.005 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Moron JA, Brockington A, Wise RA, Rocha BA, Hope BT (2002) Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J Neurosci 22:389–395PubMedGoogle Scholar
  52. Myers MM, Whittemore SR, Hendley ED (1981) Changes in catecholamine neuronal uptake and receptor binding in the brains of spontaneously hypertensive rats (SHR). Brain Res 220:325–338CrossRefPubMedGoogle Scholar
  53. Nakamura-Palacios EM, Caldas CK, Fiorini A, Chagas KD, Chagas KN, Vasquez EC (1996) Deficits of spatial learning and working memory in spontaneously hypertensive rats. Behav Brain Res 74:217–227CrossRefPubMedGoogle Scholar
  54. Nam H, Clinton SM, Jackson NL, Kerman IA (2014) Learned helplessness and social avoidance in the Wistar-Kyoto rat. Front Behav Neurosci 8:109. doi: 10.3389/fnbeh.2014.00109 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Nikolas MA, Nigg JT (2013) Neuropsychological performance and attention-deficit hyperactivity disorder subtypes and symptom dimensions. Neuropsychology 27:107–120. doi: 10.1037/a0030685 CrossRefPubMedGoogle Scholar
  56. Pamplona FA, Pandolfo P, Savoldi R, Prediger RD, Takahashi RN (2009) Environmental enrichment improves cognitive deficits in spontaneously hypertensive rats (SHR): relevance for attention deficit/hyperactivity disorder (ADHD). Prog Neuropsychopharmacol Biol Psychiatry 33:1153–1160. doi: 10.1016/j.pnpbp.2009.06.012 CrossRefPubMedGoogle Scholar
  57. Prasad S, Steer C (2008) Switching from neurostimulant therapy to atomoxetine in children and adolescents with attention-deficit hyperactivity disorder: clinical approaches and review of current available evidence. Paediatr Drugs 10:39–47CrossRefPubMedGoogle Scholar
  58. Puhl MD, Blum JS, Acosta-Torres S, Grigson PS (2012) Environmental enrichment protects against the acquisition of cocaine self-administration in adult male rats, but does not eliminate avoidance of a drug-associated saccharin cue. Behav Pharmacol 23:43–53. doi: 10.1097/FBP.0b013e32834eb060 CrossRefPubMedPubMedCentralGoogle Scholar
  59. Richardson NR, Roberts DC (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11CrossRefPubMedGoogle Scholar
  60. Richelson E, Pfenning M (1984) Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake. Eur J Pharmacol 104:277–286CrossRefPubMedGoogle Scholar
  61. Roessner V et al (2010) Methylphenidate normalizes elevated dopamine transporter densities in an animal model of the attention-deficit/hyperactivity disorder combined type, but not to the same extent in one of the attention-deficit/hyperactivity disorder inattentive type. Neuroscience 167:1183–1191. doi: 10.1016/j.neuroscience.2010.02.073 CrossRefPubMedGoogle Scholar
  62. Roman O, Seres J, Pometlova M, Jurcovicova J (2004) Neuroendocrine or behavioral effects of acute or chronic emotional stress in Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Endocr Regul 38:151–155PubMedGoogle Scholar
  63. Russell V, Allie S, Wiggins T (2000) Increased noradrenergic activity in prefrontal cortex slices of an animal model for attention-deficit hyperactivity disorder—the spontaneously hypertensive rat. Behav Brain Res 117:69–74CrossRefPubMedGoogle Scholar
  64. Russell VA (2011) Overview of animal models of attention deficit hyperactivity disorder (ADHD). Curr Protoc Neurosci 9(Unit9):35. doi: 10.1002/0471142301.ns0935s54 PubMedGoogle Scholar
  65. Sagvolden T, Metzger MA, Schiorbeck HK, Rugland AL, Spinnangr I, Sagvolden G (1992) The spontaneously hypertensive rat (SHR) as an animal model of childhood hyperactivity (ADHD): changed reactivity to reinforcers and to psychomotor stimulants. Behav Neural Biol 58:103–112CrossRefPubMedGoogle Scholar
  66. Scheffler RM, Hinshaw SP, Modrek S, Levine P (2007) The global market for ADHD medications. Health Aff (Millwood) 26:450–457. doi: 10.1377/hlthaff.26.2.450 CrossRefGoogle Scholar
  67. Schneider M (2013) Adolescence as a vulnerable period to alter rodent behavior. Cell Tissue Res 354:99–106. doi: 10.1007/s00441-013-1581-2 CrossRefPubMedGoogle Scholar
  68. Silva N Jr et al (2014) Searching for a neurobiological basis for self-medication theory in ADHD comorbid with substance use disorders: an in vivo study of dopamine transporters using (99m)Tc-TRODAT-1 SPECT. Clin Nucl Med 39:e129–e134. doi: 10.1097/RLU.0b013e31829f9119 PubMedGoogle Scholar
  69. Smith CD, Holschbach MA, Olsewicz J, Lonstein JS (2012) Effects of noradrenergic alpha-2 receptor antagonism or noradrenergic lesions in the ventral bed nucleus of the stria terminalis and medial preoptic area on maternal care in female rats. Psychopharmacology (Berl) 224:263–276. doi: 10.1007/s00213-012-2749-2 CrossRefGoogle Scholar
  70. Smith CD, Piasecki CC, Weera M, Olszewicz J, Lonstein JS (2013) Noradrenergic alpha-2 receptor modulators in the ventral bed nucleus of the stria terminalis: effects on anxiety behavior in postpartum and virgin female rats. Behav Neurosci 127:582–597. doi: 10.1037/a0032776 CrossRefPubMedPubMedCentralGoogle Scholar
  71. Somkuwar SS, Darna M, Kantak KM, Dwoskin LP (2013b) Adolescence methylphenidate treatment in a rodent model of attention deficit/hyperactivity disorder: dopamine transporter function and cellular distribution in adulthood. Biochem Pharmacol 86:309–316. doi: 10.1016/j.bcp.2013.04.013 CrossRefPubMedPubMedCentralGoogle Scholar
  72. Somkuwar SS, Jordan CJ, Kantak KM, Dwoskin LP (2013a) Adolescent atomoxetine treatment in a rodent model of ADHD: effects on cocaine self-administration and dopamine transporters in frontostriatal regions. Neuropsychopharmacology 38:2588–2597. doi: 10.1038/npp.2013.163 CrossRefPubMedPubMedCentralGoogle Scholar
  73. Somkuwar SS, Kantak KM, Bardo MT, Dwoskin LP (2016) Adolescent methylphenidate treatment differentially alters adult impulsivity and hyperactivity in the spontaneously hypertensive rat model of ADHD. Pharmacol Biochem Behav 141:66–77. doi: 10.1016/j.pbb.2015.12.002 CrossRefPubMedGoogle Scholar
  74. Somkuwar SS, Kantak KM, Dwoskin LP (2015) Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder. J Neurosci Methods 252:55–63. doi: 10.1016/j.jneumeth.2015.02.002 CrossRefPubMedPubMedCentralGoogle Scholar
  75. Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417–463CrossRefPubMedGoogle Scholar
  76. Stamp JA, Mashoodh R, van Kampen JM, Robertson HA (2008) Food restriction enhances peak corticosterone levels, cocaine-induced locomotor activity, and DeltaFosB expression in the nucleus accumbens of the rat. Brain Res 1204:94–101. doi: 10.1016/j.brainres.2008.02.019 CrossRefPubMedGoogle Scholar
  77. Stefanik MT et al (2013) Optogenetic inhibition of cocaine seeking in rats. Addict Biol 18:50–53. doi: 10.1111/j.1369-1600.2012.00479.x CrossRefPubMedGoogle Scholar
  78. Stein MA et al (2003) A dose-response study of OROS methylphenidate in children with attention-deficit/hyperactivity disorder. Pediatrics 112:e404CrossRefPubMedGoogle Scholar
  79. Sterley TL, Howells FM, Russell VA (2011) Effects of early life trauma are dependent on genetic predisposition: a rat study. Behav Brain Funct 7:11. doi: 10.1186/1744-9081-7-11 CrossRefPubMedPubMedCentralGoogle Scholar
  80. Swanson L (1992) Brain maps: structure of the rat brain. Elsevier, AmsterdamGoogle Scholar
  81. Tella SR (1995) Effects of monoamine reuptake inhibitors on cocaine self-administration in rats. Pharmacol Biochem Behav 51:687–692CrossRefPubMedGoogle Scholar
  82. Thiel KJ, Pentkowski NS, Peartree NA, Painter MR, Neisewander JL (2010) Environmental living conditions introduced during forced abstinence alter cocaine-seeking behavior and Fos protein expression. Neuroscience 171:1187–1196. doi: 10.1016/j.neuroscience.2010.10.001 CrossRefPubMedPubMedCentralGoogle Scholar
  83. Turner M, Wilding E, Cassidy E, Dommett EJ (2013) Effects of atomoxetine on locomotor activity and impulsivity in the spontaneously hypertensive rat. Behav Brain Res 243:28–37. doi: 10.1016/j.bbr.2012.12.025 CrossRefPubMedGoogle Scholar
  84. Valentini V, Cacciapaglia F, Frau R, Di Chiara G (2006) Differential alpha-mediated inhibition of dopamine and noradrenaline release in the parietal and occipital cortex following noradrenaline transporter blockade. J Neurochem 98:113–121. doi: 10.1111/j.1471-4159.2006.03851.x CrossRefPubMedGoogle Scholar
  85. van Ruiven R, Meijer GW, Wiersma A, Baumans V, van Zutphen LF, Ritskes-Hoitinga J (1998) The influence of transportation stress on selected nutritional parameters to establish the necessary minimum period for adaptation in rat feeding studies. Lab Anim 32:446–456. doi: 10.1258/002367798780599893 CrossRefPubMedGoogle Scholar
  86. van Veldhuizen MJ, Feenstra MG, Boer GJ (1994) Regional differences in the in vivo regulation of the extracellular levels of noradrenaline and its metabolites in rat brain. Brain Res 635:238–248CrossRefPubMedGoogle Scholar
  87. van Veldhuizen MJ, Feenstra MG, Heinsbroek RP, Boer GJ (1993) In vivo microdialysis of noradrenaline overflow: effects of alpha-adrenoceptor agonists and antagonists measured by cumulative concentration-response curves. Br J Pharmacol 109:655–660CrossRefPubMedPubMedCentralGoogle Scholar
  88. Wang M et al (2007) Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129:397–410. doi: 10.1016/j.cell.2007.03.015 CrossRefPubMedGoogle Scholar
  89. Wang Y et al (2011) alpha2-adrenoceptor regulates the spontaneous and the GABA/glutamate modulated firing activity of the rat medial prefrontal cortex pyramidal neurons. Neuroscience 182:193–202. doi: 10.1016/j.neuroscience.2011.03.016 CrossRefPubMedGoogle Scholar
  90. Wells AM, Janes AC, Liu X, Deschepper CF, Kaufman MJ, Kantak KM (2010) Medial temporal lobe functioning and structure in the spontaneously hypertensive rat: comparison with Wistar-Kyoto normotensive and Wistar-Kyoto hypertensive strains. Hippocampus 20:787–797. doi: 10.1002/hipo.20681 PubMedPubMedCentralGoogle Scholar
  91. Westenbroek C, Perry AN, Becker JB (2013) Pair housing differentially affects motivation to self-administer cocaine in male and female rats. Behav Brain Res 252:68–71. doi: 10.1016/j.bbr.2013.05.040 CrossRefPubMedPubMedCentralGoogle Scholar
  92. Winer BJ (1971) Statistical principles in experimental design, 2nd edn. McGraw-Hill, New York, p 201Google Scholar
  93. Zlebnik NE, Carroll ME (2015) Effects of the combination of wheel running and atomoxetine on cue- and cocaine-primed reinstatement in rats selected for high or low impulsivity. Psychopharmacology (Berl) 232:1049–1059. doi: 10.1007/s00213-014-3744-6 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Britahny M. Baskin
    • 1
  • Bríd Á. Nic Dhonnchadha
    • 1
  • Linda P. Dwoskin
    • 2
  • Kathleen M. Kantak
    • 1
    Email author
  1. 1.Department of Psychological and Brain SciencesBoston UniversityBostonUSA
  2. 2.Department of Pharmaceutical Sciences, College of PharmacyUniversity of KentuckyLexingtonUSA

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