Sensitization to the effects of drugs of abuse and associated stimuli contributes to drug craving, compulsive drug use, and relapse in addiction. Repeated opiate exposure produces behavioral sensitization that is hypothesized to result from neural plasticity in specific limbic, striatal and cortical systems. ΔFosB and FosB are members of the Fos family of transcription factors that are implicated in neural plasticity in addiction. This study examined the effects of intermittent morphine treatment, associated with motor sensitization, on FosB/ΔFosB levels using quantitative immunohistochemistry. Motor sensitization was tested in C57BL/6 mice that received six intermittent pre-treatments (on days 1, 3, 5, 8, 10, 12) with either subcutaneous morphine (10 mg/kg) or saline followed by a challenge injection of morphine or saline on day 16. Mice receiving repeated morphine injections demonstrated significant increases in locomotor activity on days 8, 10, and 12 of treatment (vs. day 1), consistent with development of locomotor sensitization. A morphine challenge on day 16 significantly increased locomotor activity of saline pre-treated mice and produced even larger increases in motor activity in the morphine pre-treated mice, consistent with the expression of opiate sensitization. Intermittent morphine pre-treatment on these six pre-treatment days produced a significant induction of FosB/ΔFosB, measured on day 16, in multiple brain regions including prelimbic (PL) and infralimbic (IL) cortex, nucleus accumbens (NAc) core, dorsomedial caudate-putamen (CPU), basolateral amygdala (BLA) and central nucleus of the amygdala (CNA) but not in a motor cortex control region. Opiate induced sensitization may develop via Fos/ΔFosB plasticity in motivational pathways (NAc), motor outputs (CPU), and associative learning (PL, IL, BLA) and stress pathways (CNA).
References
[1]
Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18: 247–291.
[2]
Kalivas PW, Duffy P (1987) Sensitization to repeated morphine injection in the rat: possible involvement of A10 dopamine neurons. J Pharmacol Exper Ther 241: 204–212.
[3]
Vanderschuren LJ, Kalivas PW (2000) Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharm (Berl) 151: 99–120.
[4]
Powell KR, Holtzman SG (2001) Parametric evaluation of the development of sensitization to the effects of morphine on locomotor activity. Drug Alcohol Depend 62(1): 83–90.
[5]
Babbini M, Davis WM (1972) Time-dose relationships for locomotor activity effects of morphine after acute or repeated treatment. Br J Pharmacol 46: 213–24.
[6]
Lett BT (1989) Repeated exposures intensify rather than diminish the rewarding effects of amphetamine, morphine, and cocaine. Psychopharm (Berl) 98: 357–62.
[7]
Shippenberg TS, Heidbreder C, Lefevour A (1996) Sensitization to the conditioned rewarding effects of morphine: pharmacology and temporal characteristics. Eur J Pharmacol 299: 33–9.
[8]
Koob GF, Ahmed SH, Boutrel B, Chen SA, Kenny PJ, et al. (2004) Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev 27: 739–49.
[9]
Nestler EJ, Barrot M, Self DW (2001) DeltaFosB: a sustained molecular switch for addiction. Proc Natl Acad Sci USA 98: 11042–11046.
[10]
Berke JD, Hyman SE (2000) Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25: 515–532.
[11]
Everitt BJ, Wolf ME (2002) Psychomotor stimulant addiction: a neural systems perspective. J Neurosci 22: 3312–20.
[12]
Gerdeman GL, Partridge JG, Lupica CR, Lovinger DM (2003) It could be habit forming: drugs of abuse and striatal synaptic plasticity. Trends Neurosci 26: 184–192.
[13]
Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85: 5274–5278.
[14]
Bjijou Y, De Deurwaerdere P, Spampinato U, Stinus L, Cador M (2002) D-amphetamine-induced behavioral sensitization: effect of lesioning dopaminergic terminals in the medial prefrontal cortex, the amygdala and the entorhinal cortex. Neuroscience 109: 499–516.
[15]
Steketee JD (2003) Neurotransmitter systems of the medial prefrontal cortex: potential role in sensitization to psychostimulants. Brain Res 41: 203–228.
[16]
Nye HE, Hope BT, Kelz MB, Iadarola M, Nestler EJ (1995) Pharmacological studies of the regulation of chronic FOS-related antigen induction by cocaine in the striatum and nucleus accumbens. J Pharmacol Exp Ther 275: 1671–1680.
[17]
Nye HE, Nestler EJ (1996) Induction of chronic Fos-related antigens in rat brain by chronic morphine administration. Mol Pharmacol 49: 636–645.
[18]
Chen J, Kelz MB, Hope BT, Nakabeppu Y, Nestler EJ (1997) Chronic Fos-related antigens: stable variants of FosB induced in brain by chronic treatments. J Neurosci 17: 4933–4941.
[19]
Brenhouse HC, Stellar JR (2006) c-Fos and deltaFosB expression are differentially altered in distinct subregions of the nucleus accumbens shell in cocaine-sensitized rats. Neurosci 137: 773–80.
[20]
Perrotti LI, Weaver RR, Robinson B, Renthal W, Maze I, et al. (2008) Distinct patterns of DeltaFosB induction in brain by drugs of abuse. Synapse 62: 358–369.
[21]
Marttila K, Raattamaa H, Ahtee L (2006) Effects of chronic nicotine administration and its withdrawal on striatal FosB/DeltaFosB and c-Fos expression in rats and mice. Neuropharm 51: 44–51.
[22]
Kelz MB, Chen J, Carlezon WA, Whisler K, Gilden L, et al. (1999) Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine. Nature 401: 272–276.
Perrotti LI, Hadeishi Y, Ulery PG, Barrot M, Monteggia L, Duman RS, et al. (2004) Induction of deltaFosB in reward-related brain structures after chronic stress. J Neurosci 24(47): 10594–602.
[25]
Perrotti LI, Bola?os CA, Choi KH, Russo SJ, Edwards S, et al. (2005) DeltaFosB accumulates in a GABAergic cell population in the posterior tail of the ventral tegmental area after psychostimulant treatment. Eur J Neurosci 21(10): 2817–2824.
[26]
Zachariou V, Bolanos CA, Selley DE, Theobald D, Cassidy MP, et al. (2006) An essential role for DeltaFosB in the nucleus accumbens in morphine action. Nat Neurosci 9(2): 205–211.
[27]
Hiroi N, Brown JR, Haile CN, Ye H, Greenberg ME, et al. (1997) FosB mutant mice: loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine's psychomotor and rewarding effects. Proc Natl Acad Sci U S A 94(19): 10397–402.
[28]
Muller DL, Unterwald EM (2005) D1 dopamine receptors modulate deltaFosB induction in rat striatum after intermittent morphine administration. J Pharmacol Exp Ther 314(1): 148–154.
[29]
Kaste K, Kivinummi T, Piepponen TP, Kiianmaa K, Ahtee L (2009) Differences in basal and morphine-induced FosB/DeltaFosB and pCREB immunoreactivities in dopaminergic brain regions of alcohol-preferring AA and alcohol-avoiding ANA rats. Pharmacol Biochem Behav 92(4): 655–62.
[30]
McDaid J, Dallimore JE, Mackie AR, Napier TC (2006) Changes in accumbal and pallidal pCREB and deltaFosB in morphine-sensitized rats: correlations with receptor-evoked electrophysiological measures in the ventral pallidum. Neuropsychopharm 31(6): 1212–1226.
[31]
Leite-Morris KA, Fukudome EY, Shoeb MH, Kaplan GB (2004) GABA(B) receptor activation in the ventral tegmental area inhibits the acquisition and expression of opiate-induced motor sensitization. J Pharmacol Exp Ther 308(2): 667–678.
[32]
Zar JU (1984) Biostatistical Analysis: Second Edition. Prentice-Hall Inc, Englewood Cliffs, NJ. pp. 83–88.
[33]
Eitan S, Bryant CD, Saliminejad N, Yang YC, Vojdani E, et al. (2003) Brain region-specific mechanisms for acute morphine-induced mitogen-activated protein kinase modulation and distinct patterns of activation during analgesic tolerance and locomotor sensitization. J Neurosci 23(23): 8360–9.
[34]
Narita M, Shibasaki M, Nagumo Y, Narita M, Yajima Y, et al. (2005) Implication of cyclin-dependent kinase 5 in the development of psychological dependence on an behavioral sensitization to morphine. J Neruochem 93(6): 1463–8.
[35]
Mickiewicz AL, Dallimore JE, Napier TC (2009) The ventral pallidum is critically involved in the development and expression of morphine-induced sensitization. Neuropsychopharm 34(4): 874–886.
[36]
Ulery PG, Rudenko G, Nestler EJ (2006) Regulation of DeltaFosB stability by phosphorylation. Neurosci 26(19): 5131–5142.
[37]
Carle TL, Ohnishi YN, Ohnishi YH, Alibhai IN, Wilkinson MB, et al. (2007) Proteasome-dependent and -independent mechanisms for FosB destabilization: identification of FosB degron domains and implications for DeltaFosB stability. Eur J Neurosci 25(10): 3009–3019.
[38]
Hope BT, Nye HE, Kelz MB, Self DW, Iadarola MJ, et al. (1994) Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron 13(5): 1235–1244.
[39]
Ehrlich ME, Sommer J, Canas E, Unterwald EM (2002) Periadolescent mice show enhanced DeltaFosB upregulation in response to cocaine and amphetamine. J Neurosci 22(21): 9155–9.
[40]
McClung CA, Nestler EJ (2003) Regulation of gene expression and cocaine reward by CREB and DeltaFosB. Nat Neurosci 6(11): 1208–1215.
[41]
LaLumiere Rt, Kalivas PW (2008) Glutamate release in the nucleus accumbens core is necessary for heroin seeking. J Neurosci 28(12): 3170–7.
[42]
Peters J, LaLumiere RT, Kalivas PW (2008) Infralimbic prefrontal cortex is responsible for inhibiting cocaine seeking in extinguished rats. J Neurosci 28(23): 6046–6053.
[43]
Sesack SR, Carr DB, Omelchenko N, Pinto A, et al. (2003) Anatomical substrates for glutamate-dopamine interactions: evidence for specificity of connections and extrasynaptic actions. Ann N Y Acad Sci 1003: 36–52.
[44]
Pontieri FE, Tanda G, Di Chiara G (1995) Intravenous cocaine, morphine and amphetamine preferentially increase extracellular dopamine in the “shell” as compare with the “core” of the rat nucleus accumbens. Proc Natl Acad Sci U S A 92(26): 12304–8.
[45]
Murphy NP, Lam HA, Maidment NT (2001) A comparison of morphine-induced locomotor activity and mesolimbic dopamine release in C57BL6, 129Sv and DBA2 mice. J Neurochem 79(3): 626–35.
[46]
Ghasemzadeh MB, Nelson LC, Lu XY, Kalivas PW, et al. (1999) Neuroadaptations in ionotropic and metabotropic glutamate receptor mRNA produced by cocaine treatment. J Neurochem 72(1): 157–165.
[47]
Spanagel R, Almeida OF, Shippenberg TS (1993) Long lasting changes in morphine-induced mesolimbic dopamine release after chronic morphine exposure. Synapse 14(3): 243–5.
[48]
Vanderschuren LJ, Tjon GH, Nestby P, Mulder AH, Schoffelmeer AN, et al. (1997) Morphine-induced long-term sensitization to the locomotor effects of morphine and amphetamine depends on the temporal pattern of the pre-treatment regimen. Psychopharm (Berl) 131(2): 115–122.