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Repeated amphetamine administration induces Fos in prefrontal cortical neurons that project to the lateral hypothalamus but not the nucleus accumbens or basolateral amygdala

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Abstract

Rationale

The development of sensitization to amphetamine (AMPH) is dependent on increases in excitatory outflow from the medial prefrontal cortex (mPFC) to subcortical centers. These projections are clearly important for the progressive enhancement of the behavioral response during drug administration that persists through withdrawal.

Objectives

The objective of this study was to identify the mPFC subcortical pathway(s) activated by a sensitizing regimen of AMPH.

Materials and methods

Using retrograde labeling techniques, Fos activation was evaluated in the predominant projection pathways of the mPFC of sensitized rats after a challenge injection of AMPH.

Results

There was a significant increase in Fos-immunoreactive cells in the mPFC, nucleus accumbens (NAc), basolateral amygdala (BLA), and lateral hypothalamus (LH) of rats treated repeatedly with AMPH when compared to vehicle-treated controls. The mPFC pyramidal neurons that project to the LH but not the NAc or BLA show a significant induction of Fos after repeated AMPH treatment. In addition, we found a dramatic increase in Fos-activated orexin neurons.

Conclusions

The LH, a region implicated in natural and drug reward processes, may play a role in the development and persistence of sensitization to repeated AMPH through its connections with the mPFC and possibly through its orexin neurons.

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References

  • Ahmed SH, Lutjens R, van der Stap LD, Lekic D, Romano-Spica V, Morales M, Koob GF, Repunte-Canonigo V, Sanna PP (2005) Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction. Proc Natl Acad Sci USA 102:11533–8

    Article  PubMed  CAS  Google Scholar 

  • Berod AM, Colussi-Mas J (2005) Afferent projections to the rat ventral tegmental area activated by a single exposure to amphetamine. Society for Neuroscience, Abstract Viewer/Itinerary Planner, Washington, DC

    Google Scholar 

  • Borgland SL, Taha SA, Sarti F, Fields HL, Bonci A (2006) Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 49:589–601

    Article  PubMed  CAS  Google Scholar 

  • Brady AM, O’Donnell P (2004) Dopaminergic modulation of prefrontal cortical input to nucleus accumbens neurons in vivo. J Neurosci 24:1040–1049

    Article  PubMed  CAS  Google Scholar 

  • Brown EE, Fibiger HC (1993) Differential effects of excitotoxic lesions of the amygdala on cocaine-induced conditioned locomotion and conditioned place preference. Psychopharmacology (Berl) 113:123–130

    Article  CAS  Google Scholar 

  • Cadoni C, Solinas M, Di Chiara G (2000) Psychostimulant sensitization: differential changes in accumbal shell and core dopamine. Eur J Pharmacol 388:69–76

    Article  PubMed  CAS  Google Scholar 

  • Ciccocioppo R, Sanna PP, Weiss F (2001) Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence: reversal by D(1) antagonists. Proc Natl Acad Sci USA 98:1976–1981

    Article  PubMed  CAS  Google Scholar 

  • Dado RJ, Burstein R, Cliffer KD, Giesler GJ Jr (1990) Evidence that Fluoro-Gold can be transported avidly through fibers of passage. Brain Res 533:329–333

    Article  PubMed  CAS  Google Scholar 

  • de Lecea L, Jones BE, Boutrel B, Borgland SL, Nishino S, Bubser M, DiLeone R (2006) Addiction and arousal: alternative roles of hypothalamic peptides. J Neurosci 26:10372–10375

    Article  PubMed  Google Scholar 

  • de Souza IE, Meredith GE (1999) NMDA receptor blockade attenuates the haloperidol induction of Fos protein in the dorsal but not the ventral striatum. Synapse 32:243–253

    Article  PubMed  Google Scholar 

  • De Vries TJ, Schoffelmeer AN, Binnekade R, Mulder AH, Vanderschuren LJ (1998) Drug-induced reinstatement of heroin- and cocaine-seeking behaviour following long-term extinction is associated with expression of behavioural sensitization. Eur J Neurosci 10:3565–3571

    Article  PubMed  Google Scholar 

  • Di Chiara G (2002) Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav Brain Res 137:75–114

    Article  PubMed  Google Scholar 

  • Dragunow M, Robertson HA (1987) Kindling stimulation induces c-fos protein(s) in granule cells of the rat dentate gyrus. Nature 329:441–442

    Article  PubMed  CAS  Google Scholar 

  • Everitt BJ, Wolf ME (2002) Psychomotor stimulant addiction: a neural systems perspective. J Neurosci 22:3312–3320

    PubMed  CAS  Google Scholar 

  • Fadel J, Deutch AY (2002) Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience 111:379–387

    Article  PubMed  CAS  Google Scholar 

  • Fadel J, Bubser M, Deutch AY (2002) Differential activation of orexin neurons by antipsychotic drugs associated with weight gain. J Neurosci 22:6742–6746

    PubMed  CAS  Google Scholar 

  • Feldpausch DL, Needham LM, Stone MP, Althaus JS, Yamamoto BK, Svensson KA, Merchant KM (1998) The role of dopamine D4 receptor in the induction of behavioral sensitization to amphetamine and accompanying biochemical and molecular adaptations. J Pharmacol Exp Ther 286:497–508

    PubMed  CAS  Google Scholar 

  • Franklin TR, Druhan JP (2000) The retrograde tracer fluoro-gold interferes with the expression of fos-related antigens. J Neurosci Methods 98:1–8

    Article  PubMed  CAS  Google Scholar 

  • Fuchs RA, See RE (2002) Basolateral amygdala inactivation abolishes conditioned stimulus- and heroin-induced reinstatement of extinguished heroin-seeking behavior in rats. Psychopharmacology (Berl) 160:425–433

    Article  CAS  Google Scholar 

  • Fuchs RA, Evans KA, Ledford CC, Parker MP, Case JM, Mehta RH, See RE (2005) The role of the dorsomedial prefrontal cortex, basolateral amygdala, and dorsal hippocampus in contextual reinstatement of cocaine seeking in rats. Neuropsychopharmacology 30:296–309

    Article  PubMed  CAS  Google Scholar 

  • Gabbott PL, Warner TA, Jays PR, Salway P, Busby SJ (2005) Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers. J Comp Neurol 492:145–177

    Article  PubMed  Google Scholar 

  • Giorgi O, Piras G, Lecca D, Corda MG (2005) Differential activation of dopamine release in the nucleus accumbens core and shell after acute or repeated amphetamine injections: a comparative study in the Roman high- and low-avoidance rat lines. Neuroscience 135:987–998

    Article  PubMed  CAS  Google Scholar 

  • Hagan JJ, Leslie RA, Patel S, Evans ML, Wattam TA, Holmes S, Benham CD, Taylor SG, Routledge C, Hemmati P, Munton RP, Ashmeade TE, Shah AS, Hatcher JP, Hatcher PD, Jones DN, Smith MI, Piper DC, Hunter AJ, Porter RA, Upton N (1999) Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci USA 96:10911–10916

    Article  PubMed  CAS  Google Scholar 

  • Harris GC, Wimmer M, Aston-Jones G (2005) A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437:556–559

    Article  PubMed  CAS  Google Scholar 

  • Hedou G, Feldon J, Heidbreder CA (1999) Effects of cocaine on dopamine in subregions of the rat prefrontal cortex and their efferents to subterritories of the nucleus accumbens. Eur J Pharmacol 372:143–155

    Article  PubMed  CAS  Google Scholar 

  • Hedou G, Jongen-Relo AL, Murphy CA, Heidbreder CA, Feldon J (2002) Sensitized Fos expression in subterritories of the rat medial prefrontal cortex and nucleus accumbens following amphetamine sensitization as revealed by stereology. Brain Res 950:165–179

    Article  PubMed  CAS  Google Scholar 

  • Heimer L, Zahm DS, Churchill L, Kalivas PW, Wohltmann C (1991) Specificity in the projection patterns of accumbal core and shell in the rat. Neuroscience 41:89–125

    Article  PubMed  CAS  Google Scholar 

  • Henry DJ, White FJ (1995) The persistence of behavioral sensitization to cocaine parallels enhanced inhibition of nucleus accumbens neurons. J Neurosci 15:6287–6299

    PubMed  CAS  Google Scholar 

  • Ito R, Robbins TW, Everitt BJ (2004) Differential control over cocaine-seeking behavior by nucleus accumbens core and shell. Nat Neurosci 7:389–397

    Article  PubMed  CAS  Google Scholar 

  • Korotkova TM, Sergeeva OA, Eriksson KS, Haas HL, Brown RE (2003) Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J Neurosci 23:7–11

    PubMed  CAS  Google Scholar 

  • Labiner DM, Butler LS, Cao Z, Hosford DA, Shin C, McNamara JO (1993) Induction of c-fos mRNA by kindled seizures: complex relationship with neuronal burst firing. J Neurosci 13:744–751

    PubMed  CAS  Google Scholar 

  • Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435:6–25

    Article  PubMed  CAS  Google Scholar 

  • McFarland K, Kalivas PW (2001) The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 21:8655–8663

    PubMed  CAS  Google Scholar 

  • McLaughlin J, See RE (2003) Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned-cued reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacology (Berl) 168:57–65

    Article  CAS  Google Scholar 

  • Miller CA, Marshall JF (2004) Altered prelimbic cortex output during cue-elicited drug seeking. J Neurosci 24:6889–6897

    Article  PubMed  CAS  Google Scholar 

  • Miller CA, Marshall JF (2005) Altered Fos expression in neural pathways underlying cue-elicited drug seeking in the rat. Eur J Neurosci 21:1385–1393

    Article  PubMed  Google Scholar 

  • Morshedi MM, Meredith GE (2007) Differential laminar effects of amphetamine on prefrontal parvalbumin interneurons. Neuroscience 149:617–624

    Article  PubMed  CAS  Google Scholar 

  • Nakamura T, Uramura K, Nambu T, Yada T, Goto K, Yanagisawa M, Sakurai T (2000) Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system. Brain Res 873:181–187

    Article  PubMed  CAS  Google Scholar 

  • Nasif FJ, Hu XT, White FJ (2005) Repeated cocaine administration increases voltage-sensitive calcium currents in response to membrane depolarization in medial prefrontal cortex pyramidal neurons. J Neurosci 25:3674–3679

    Article  PubMed  CAS  Google Scholar 

  • Nikulina EM, Covington HE 3rd, Ganschow L, Hammer RP Jr., Miczek KA (2004) Long-term behavioral and neuronal cross-sensitization to amphetamine induced by repeated brief social defeat stress: Fos in the ventral tegmental area and amygdala. Neuroscience 123:857–865

    Article  PubMed  CAS  Google Scholar 

  • Nogueira L, Kalivas PW, Lavin A (2006) Long-term neuroadaptations produced by withdrawal from repeated cocaine treatment: role of dopaminergic receptors in modulating cortical excitability. J Neurosci 26:12308–12313

    Article  PubMed  CAS  Google Scholar 

  • Onn SP, Grace AA (2000) Amphetamine withdrawal alters bistable states and cellular coupling in rat prefrontal cortex and nucleus accumbens neurons recorded in vivo. J Neurosci 20:2332–2345

    PubMed  CAS  Google Scholar 

  • Ostrander MM, Richtand NM, Herman JP (2003) Stress and amphetamine induce Fos expression in medial prefrontal cortex neurons containing glucocorticoid receptors. Brain Res 990:209–214

    Article  PubMed  CAS  Google Scholar 

  • Paulson PE, Camp DM, Robinson TE (1991) Time course of transient behavioral depression and persistent behavioral sensitization in relation to regional brain monoamine concentrations during amphetamine withdrawal in rats. Psychopharmacology (Berl) 103:480–492

    Article  CAS  Google Scholar 

  • Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 5th edn. Academic, New York

    Google Scholar 

  • Peterson JD, Wolf ME, White FJ (2000) Altered responsiveness of medial prefrontal cortex neurons to glutamate and dopamine after withdrawal from repeated amphetamine treatment. Synapse 36:342–344

    Article  PubMed  CAS  Google Scholar 

  • Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18:9996–10015

    PubMed  CAS  Google Scholar 

  • Pierce RC, Kalivas PW (1995) Amphetamine produces sensitized increases in locomotion and extracellular dopamine preferentially in the nucleus accumbens shell of rats administered repeated cocaine. J Pharmacol Exp Ther 275:1019–1029

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Pierce RC, Bell K, Duffy P, Kalivas PW (1996) Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization. J Neurosci 16:1550–1560

    PubMed  CAS  Google Scholar 

  • Pierce RC, Reeder DC, Hicks J, Morgan ZR, Kalivas PW (1998) Ibotenic acid lesions of the dorsal prefrontal cortex disrupt the expression of behavioral sensitization to cocaine. Neuroscience 82:1103–1114

    Article  PubMed  CAS  Google Scholar 

  • Pieribone VA, Aston-Jones G (1988) The iontophoretic application of Fluoro-Gold for the study of afferents to deep brain nuclei. Brain Res 475:259–271

    Article  PubMed  CAS  Google Scholar 

  • Pinto A, Sesack SR (2000) Limited collateralization of neurons in the rat prefrontal cortex that project to the nucleus accumbens. Neuroscience 97:635–642

    Article  PubMed  CAS  Google Scholar 

  • Rademacher DJ, Kovacs B, Shen F, Napier TC, Meredith GE (2006) The neural substrates of amphetamine conditioned place preference: implications for the formation of conditioned stimulus-reward associations. Eur J Neurosci 24:2089–2097

    Article  PubMed  Google Scholar 

  • Robinson TE, Camp DM (1987) Long-lasting effects of escalating doses of d-amphetamine on brain monoamines, amphetamine-induced stereotyped behavior and spontaneous nocturnal locomotion. Pharmacol Biochem Behav 26:821–827

    Article  PubMed  CAS  Google Scholar 

  • Robinson TE, Kolb B (1997) Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. J Neurosci 17:8491–8497

    PubMed  CAS  Google Scholar 

  • Robinson TE, Kolb B (1999) Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine. Eur J Neurosci 11:1598–1604

    Article  PubMed  CAS  Google Scholar 

  • Robinson TE, Berridge KC (2000) The psychology and neurobiology of addiction: an incentive-sensitization view. Addiction 95(Suppl 2):S91–S117

    Article  PubMed  Google Scholar 

  • Rosenkranz JA, Grace AA (2001) Dopamine attenuates prefrontal cortical suppression of sensory inputs to the basolateral amygdala of rats. J Neurosci 21:4090–4103

    PubMed  CAS  Google Scholar 

  • Saito Y, Cheng M, Leslie FM, Civelli O (2001) Expression of the melanin-concentrating hormone (MCH) receptor mRNA in the rat brain. J Comp Neurol 435:26–40

    Article  PubMed  CAS  Google Scholar 

  • Schmued LC, Fallon JH (1986) Fluoro-Gold: a new fluorescent retrograde axonal tracer with numerous unique properties. Brain Res 377:147–154

    Article  PubMed  CAS  Google Scholar 

  • Schultz W, Tremblay L, Hollerman JR (2000) Reward processing in primate orbitofrontal cortex and basal ganglia. Cereb Cortex 10:272–284

    Article  PubMed  CAS  Google Scholar 

  • Self DW, Nestler EJ (1998) Relapse to drug-seeking: neural and molecular mechanisms. Drug Alcohol Depend 51:49–60

    Article  PubMed  CAS  Google Scholar 

  • Sesack SR, Deutch AY, Roth RH, Bunney BS (1989) Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin. J Comp Neurol 290:213–242

    Article  PubMed  CAS  Google Scholar 

  • Simpson JN, Wang JQ, McGinty JF (1995) Repeated amphetamine administration induces a prolonged augmentation of phosphorylated cyclase response element-binding protein and Fos-related antigen immunoreactivity in rat striatum. Neuroscience 69:441–457

    Article  PubMed  CAS  Google Scholar 

  • Smith DG, Tzavara ET, Shaw J, Luecke S, Wade M, Davis R, Salhoff C, Nomikos GG, Gehlert DR (2005) Mesolimbic dopamine super-sensitivity in melanin-concentrating hormone-1 receptor-deficient mice. J Neurosci 25:914–922

    Article  PubMed  CAS  Google Scholar 

  • Sutcliffe JG, de Lecea L (2002) The hypocretins: setting the arousal threshold. Nat Rev Neurosci 3:339–349

    Article  PubMed  CAS  Google Scholar 

  • Thomas KL, Everitt BJ (2001) Limbic–cortical–ventral striatal activation during retrieval of a discrete cocaine-associated stimulus: a cellular imaging study with gamma protein kinase C expression. J Neurosci 21:2526–2535

    PubMed  CAS  Google Scholar 

  • Trantham H, Szumlinski KK, McFarland K, Kalivas PW, Lavin A (2002) Repeated cocaine administration alters the electrophysiological properties of prefrontal cortical neurons. Neuroscience 113:749–753

    Article  PubMed  CAS  Google Scholar 

  • Uslaner J, Badiani A, Day HE, Watson SJ, Akil H, Robinson TE (2001) Environmental context modulates the ability of cocaine and amphetamine to induce c-fos mRNA expression in the neocortex, caudate nucleus, and nucleus accumbens. Brain Res 920:106–116

    Article  PubMed  CAS  Google Scholar 

  • Vertes RP (2004) Differential projections of the infralimbic and prelimbic cortex in the rat. Synapse 51:32–58

    Article  PubMed  CAS  Google Scholar 

  • White FJ, Hu XT, Henry DJ (1993) Electrophysiological effects of cocaine in the rat nucleus accumbens: microiontophoretic studies. J Pharmacol Exp Ther 266:1075–1084

    PubMed  CAS  Google Scholar 

  • White FJ, Hu XT, Zhang XF, Wolf ME (1995) Repeated administration of cocaine or amphetamine alters neuronal responses to glutamate in the mesoaccumbens dopamine system. J Pharmacol Exp Ther 273:445–454

    PubMed  CAS  Google Scholar 

  • Wolf ME (1998) The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol 54:679–720

    Article  PubMed  CAS  Google Scholar 

  • Wolf ME (2002) Addiction: making the connection between behavioral changes and neuronal plasticity in specific pathways. Mol Interv 2:146–157

    Article  PubMed  CAS  Google Scholar 

  • Yoshida K, McCormack S, Espana RA, Crocker A, Scammell TE (2006) Afferents to the orexin neurons of the rat brain. J Comp Neurol 494:845–861

    Article  PubMed  Google Scholar 

  • Zhang XF, Hu XT, White FJ (1998) Whole-cell plasticity in cocaine withdrawal: reduced sodium currents in nucleus accumbens neurons. J Neurosci 18:488–498

    PubMed  Google Scholar 

  • Zhang XF, Cooper DC, White FJ (2002) Repeated cocaine treatment decreases whole-cell calcium current in rat nucleus accumbens neurons. J Pharmacol Exp Ther 301:1119–1125

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The work was supported by a USPHS grant from the NIH, DA16662. We thank Drs. Anthony West and David Rademacher for their critical reading of the manuscript and Mrs. Jennifer Jackolin for her technical assistance. All experiments were conducted in accordance with the current laws of the USA.

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  1. Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA

    Maud M. Morshedi & Gloria E. Meredith

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  1. Maud M. Morshedi
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  2. Gloria E. Meredith
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Correspondence to Maud M. Morshedi.

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Morshedi, M.M., Meredith, G.E. Repeated amphetamine administration induces Fos in prefrontal cortical neurons that project to the lateral hypothalamus but not the nucleus accumbens or basolateral amygdala. Psychopharmacology 197, 179–189 (2008). https://doi.org/10.1007/s00213-007-1021-7

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