Abstract
Repeated exposure to cocaine is known to dysregulate the norepinephrine system, and norepinephrine has also been implicated as having a role in abstinence and withdrawal. The goal of this study was to determine the effects of exposure to cocaine self-administration and subsequent abstinence on regulatory elements of the norepinephrine system in the nonhuman primate brain. Rhesus monkeys self-administered cocaine (0.3 mg/kg/injection, 30 reinforcers/session) under a fixed-interval 3-min schedule of reinforcement for 100 sessions. Animals in the abstinence group then underwent a 30-day period during which no operant responding was conducted, followed by a final session of operant responding. Control animals underwent identical schedules of food reinforcement and abstinence. This duration of cocaine self-administration has been shown previously to increase levels of norepinephrine transporters (NET) in the ventral noradrenergic bundle terminal fields. In contrast, in the current study, abstinence from chronic cocaine self-administration resulted in elevated levels of [3H]nisoxetine binding to the NET primarily in dorsal noradrenergic bundle terminal field structures. As compared to food reinforcement, chronic cocaine self-administration resulted in decreased binding of [3H]RX821002 to α2-adrenoceptors primarily in limbic-related structures innervated by both dorsal and ventral bundles, as well as elevated binding in the striatum. However, following abstinence from responding for cocaine binding to α2-adrenoceptors was not different than in control animals. These data demonstrate the dynamic nature of the regulation of norepinephrine during cocaine use and abstinence, and provide further evidence that the norepinephrine system should not be overlooked in the search for effective pharmacotherapies for cocaine dependence.
Similar content being viewed by others
References
Aston-Jones G, Cohen JD (2005) Adaptive gain and the role of the locus coeruleus-norepinephrine system in optimal performance. J Comp Neurol 493:99–110. doi:10.1002/cne.20723
Aston-Jones G, Delfs JM, Druhan J, Zhu Y (1999) The bed nucleus of the stria terminalis. A target site for noradrenergic actions in opiate withdrawal. Ann N Y Acad Sci 877:486–498
Baraban JM, Aghajanian GK (1981) Noradrenergic innervation of serotonergic neurons in the dorsal raphe: demonstration by electron microscopic autoradiography. Brain Res 204:1–11
Baumann MH, Milchanowski AB, Rothman RB (2004) Evidence for alterations in alpha2-adrenergic receptor sensitivity in rats exposed to repeated cocaine administration. Neuroscience 125:683–690. doi:10.1016/j.neuroscience.2004.02.013
Belej T, Manji D, Sioutis S, Barros HM, Nobrega JN (1996) Changes in serotonin and norepinephrine uptake sites after chronic cocaine: pre- vs. post-withdrawal effects. Brain Res 736:287–296
Bennett BA, Wichems CH, Hollingsworth CK, Davies HM, Thornley C, Sexton T, Childers SR (1995) Novel 2-substituted cocaine analogs: uptake and ligand binding studies at dopamine, serotonin and norepinephrine transport sites in the rat brain. J Pharmacol Exp Ther 272:1176–1186
Beveridge TJ, Smith HR, Nader MA, Porrino LJ (2005) Effects of chronic cocaine self-administration on norepinephrine transporters in the nonhuman primate brain. Psychopharmacology 180:781–788. doi:10.1007/s00213-005-2162-1
Beveridge TJ, Smith HR, Daunais JB, Nader MA, Porrino LJ (2006) Chronic cocaine self-administration is associated with altered functional activity in the temporal lobes of non human primates. Eur J Neurosci 23:3109–3118. doi:10.1111/j.1460-9568.2006.04788.x
Beveridge TJ, Smith HR, Nader MA, Porrino LJ (2009) Abstinence from chronic cocaine self-administration alters striatal dopamine systems in rhesus monkeys. Neuropsychopharmacology 34:1162–1171. doi:10.1038/npp.2008.135
Bowden DM, German DC, Poynter WD (1978) An autoradiographic, semistereotaxic mapping of major projections from locus coeruleus and adjacent nuclei in Macaca mulatta. Brain Res 145:257–276
Brown ZJ, Nobrega JN, Erb S (2011) Central injections of noradrenaline induce reinstatement of cocaine seeking and increase c-fos mRNA expression in the extended amygdala. Behav Brain Res 217:472–476. doi:10.1016/j.bbr.2010.09.025
Buffalari DM, Baldwin CK, See RE (2012) Treatment of cocaine withdrawal anxiety with guanfacine: relationships to cocaine intake and reinstatement of cocaine seeking in rats. Psychopharmacology 223:179–190. doi:10.1007/s00213-012-2705-1
Callado LF, Meana JJ, Grijalba B, Pazos A, Sastre M, Garcia-Sevilla JA (1998) Selective increase of alpha2A-adrenoceptor agonist binding sites in brains of depressed suicide victims. J Neurochem 70:1114–1123
Carmichael ST, Price JL (1996) Connectional networks within the orbital and medial prefrontal cortex of macaque monkeys. J Comp Neurol 371:179–207. doi:10.1002/(SICI)1096-9861(19960722)371:2<179:AID-CNE1>3.0.CO;2-#
Colburn RW, Goodwin FK, Murphy DL, Bunney WE Jr, Davis JM (1968) Quantitative studies of norepinephrine uptake by synaptosomes. Biochem Pharmacol 17:957–964
Dahlstrom A, Fuxe K (1964) Localization of monoamines in the lower brain stem. Experientia 20:398–399
De Vos H, Bricca G, De Keyser J, De Backer JP, Bousquet P, Vauquelin G (1994) Imidazoline receptors, non-adrenergic idazoxan binding sites and alpha 2-adrenoceptors in the human central nervous system. Neuroscience 59:589–598
Delfs JM, Zhu Y, Druhan JP, Aston-Jones GS (1998) Origin of noradrenergic afferents to the shell subregion of the nucleus accumbens: anterograde and retrograde tract-tracing studies in the rat. Brain Res 806:127–140
Ding YS et al (2010) PET imaging of the effects of age and cocaine on the norepinephrine transporter in the human brain using (S, S)-[(11)C]O-methylreboxetine and HRRT. Synapse 64:30–38. doi:10.1002/syn.20696
Dossin O, Mouledous L, Baudry X, Tafani JA, Mazarguil H, Zajac JM (2000) Characterization of a new radioiodinated probe for the alpha2C adrenoceptor in the mouse brain. Neurochem Int 36:7–18
Erb S, Hitchcott PK, Rajabi H, Mueller D, Shaham Y, Stewart J (2000) Alpha-2 adrenergic receptor agonists block stress-induced reinstatement of cocaine seeking. Neuropsychopharmacology 23:138–150. doi:10.1016/S0893-133X(99)00158-X
Fagerholm V et al (2008) Autoradiographic characterization of alpha(2C)-adrenoceptors in the human striatum. Synapse 62:508–515. doi:10.1002/syn.20520
Farfel GM, Kleven MS, Woolverton WL, Seiden LS, Perry BD (1992) Effects of repeated injections of cocaine on catecholamine receptor binding sites, dopamine transporter binding sites and behavior in rhesus monkey. Brain Res 578:235–243
Felten DL, Sladek JR Jr (1983) Monoamine distribution in primate brain V. Monoaminergic nuclei: anatomy, pathways and local organization. Brain Res Bull 10:171–284
Felten DL, Laties AM, Carpenter MB (1974) Monoamine-containing cell bodies in the squirrel monkey brain. Am J Anat 139:153–165. doi:10.1002/aja.1001390202
Flugge G (1996) Alterations in the central nervous alpha 2-adrenoceptor system under chronic psychosocial stress. Neuroscience 75:187–196
Foote SL, Bloom FE, Aston-Jones G (1983) Nucleus locus ceruleus: new evidence of anatomical and physiological specificity. Physiol Rev 63:844–914
Fox HC, Seo D, Tuit K, Hansen J, Kimmerling A, Morgan PT, Sinha R (2012) Guanfacine effects on stress, drug craving and prefrontal activation in cocaine dependent individuals: preliminary findings. J Psychopharmacol 26:958–972. doi:10.1177/0269881111430746
Fricks-Gleason AN, Marshall JF (2008) Post-retrieval beta-adrenergic receptor blockade: effects on extinction and reconsolidation of cocaine-cue memories. Learn Mem 15:643–648. doi:10.1101/lm.1054608
Fritschy JM, Grzanna R (1990) Distribution of locus coeruleus axons within the rat brainstem demonstrated by Phaseolus vulgaris leucoagglutinin anterograde tracing in combination with dopamine-beta-hydroxylase immunofluorescence. J Comp Neurol 293:616–631. doi:10.1002/cne.902930407
Gatter KC, Powell TP (1977) The projection of the locus coeruleus upon the neocortex in the macaque monkey. Neuroscience 2:441–445
Gawin FH, Kleber HD (1986) Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Clinical observations. Arch Gen Psychiatry 43:107–113
Gilsbach R, Albarran-Juarez J, Hein L (2011) Pre-versus postsynaptic signaling by alpha(2)-adrenoceptors. Curr Top Membr 67:139–160. doi:10.1016/B978-0-12-384921-2.00007-0
Giralt MT, Garcia-Sevilla JA (1989) Acute and long-term regulation of brain alpha 2-adrenoceptors after manipulation of noradrenergic transmission in the rat. Eur J Pharmacol 164:455–466
Gobert A, Rivet JM, Audinot V, Newman-Tancredi A, Cistarelli L, Millan MJ (1998) Simultaneous quantification of serotonin, dopamine and noradrenaline levels in single frontal cortex dialysates of freely-moving rats reveals a complex pattern of reciprocal auto- and heteroreceptor-mediated control of release. Neuroscience 84:413–429
Grijalba B, Callado LF, Javier Meana J, Garcia-Sevilla JA, Pazos A (1996) Alpha 2-adrenoceptor subtypes in the human brain: a pharmacological delineation of [3H]RX-821002 binding to membranes and tissue sections. Eur J Pharmacol 310:83–93
Grimm JW, See RE (2000) Dissociation of primary and secondary reward-relevant limbic nuclei in an animal model of relapse. Neuropsychopharmacology 22:473–479. doi:10.1016/S0893-133X(99)00157-8
Grzanna R, Fritschy JM (1991) Efferent projections of different subpopulations of central noradrenaline neurons. Prog Brain Res 88:89–101
Han DD, Gu HH (2006) Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacol 6:6. doi:10.1186/1471-2210-6-6
Happe HK, Coulter CL, Gerety ME, Sanders JD, O’Rourke M, Bylund DB, Murrin LC (2004) Alpha-2 adrenergic receptor development in rat CNS: an autoradiographic study. Neuroscience 123:167–178
Holmberg M, Scheinin M, Kurose H, Miettinen R (1999) Adrenergic alpha2C-receptors reside in rat striatal GABAergic projection neurons: comparison of radioligand binding and immunohistochemistry. Neuroscience 93:1323–1333
Holmberg M, Fagerholm V, Scheinin M (2003) Regional distribution of alpha(2C)-adrenoceptors in brain and spinal cord of control mice and transgenic mice overexpressing the alpha(2C)-subtype: an autoradiographic study with [(3)H]RX821002 and [(3)H]rauwolscine. Neuroscience 117:875–898
Jobes ML, Ghitza UE, Epstein DH, Phillips KA, Heishman SJ, Preston KL (2011) Clonidine blocks stress-induced craving in cocaine users. Psychopharmacology 218:83–88. doi:10.1007/s00213-011-2230-7
Jones BE, Moore RY (1977) Ascending projections of the locus coeruleus in the rat II. Autoradiographic study. Brain Res 127:25–53
Kantak KM, Black Y, Valencia E, Green-Jordan K, Eichenbaum HB (2002) Dissociable effects of lidocaine inactivation of the rostral and caudal basolateral amygdala on the maintenance and reinstatement of cocaine-seeking behavior in rats. J Neurosci 22:1126–1136
Kerfoot EC, Williams CL (2011) Interactions between brainstem noradrenergic neurons and the nucleus accumbens shell in modulating memory for emotionally arousing events. Learn Mem 18:405–413. doi:10.1101/lm.2108911
Krout KE, Belzer RE, Loewy AD (2002) Brainstem projections to midline and intralaminar thalamic nuclei of the rat. J Comp Neurol 448:53–101. doi:10.1002/cne.10236
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
Leri F, Flores J, Rodaros D, Stewart J (2002) Blockade of stress-induced but not cocaine-induced reinstatement by infusion of noradrenergic antagonists into the bed nucleus of the stria terminalis or the central nucleus of the amygdala. J Neurosci 22:5713–5718 20026536
Logan JG, O’Donovan DJ (1980) Noradrenaline uptake by synaptosomes and (Na+-K+) ATPase. Biochem Pharmacol 29:2105–2112
Loughlin SE, Foote SL, Fallon JH (1982) Locus coeruleus projections to cortex: topography, morphology and collateralization. Brain Res Bull 9:287–294
Loughlin SE, Foote SL, Bloom FE (1986) Efferent projections of nucleus locus coeruleus: topographic organization of cells of origin demonstrated by three-dimensional reconstruction. Neuroscience 18:291–306
Macey DJ, Smith HR, Nader MA, Porrino LJ (2003) Chronic cocaine self-administration upregulates the norepinephrine transporter and alters functional activity in the bed nucleus of the stria terminalis of the rhesus monkey. J Neurosci 23:12–16
Marcinkiewicz M, Morcos R, Chretien M (1989) CNS connections with the median raphe nucleus: retrograde tracing with WGA-apoHRP-Gold complex in the rat. J Comp Neurol 289:11–35. doi:10.1002/cne.902890103
Martin LJ, Powers RE, Dellovade TL, Price DL (1991) The bed nucleus-amygdala continuum in human and monkey. J Comp Neurol 309:445–485. doi:10.1002/cne.903090404
McCune SK, Voigt MM, Hill JM (1993) Expression of multiple alpha adrenergic receptor subtype messenger RNAs in the adult rat brain. Neuroscience 57:143–151
McDougle CJ, Black JE, Malison RT, Zimmermann RC, Kosten TR, Heninger GR, Price LH (1994) Noradrenergic dysregulation during discontinuation of cocaine use in addicts. Arch Gen Psychiatry 51:713–719
McKellar S, Loewy AD (1982) Efferent projections of the A1 catecholamine cell group in the rat: an autoradiographic study. Brain Res 241:11–29
Nader MA et al (2002) Effects of cocaine self-administration on striatal dopamine systems in rhesus monkeys: initial and chronic exposure. Neuropsychopharmacology 27:35–46. doi:10.1016/S0893-133X(01)00427-4
Nicholas AP, Pieribone V, Hokfelt T (1993) Distributions of mRNAs for alpha-2 adrenergic receptor subtypes in rat brain: an in situ hybridization study. J Comp Neurol 328:575–594. doi:10.1002/cne.903280409
Ongur D, An X, Price JL (1998) Prefrontal cortical projections to the hypothalamus in macaque monkeys. J Comp Neurol 401:480–505
Ordway GA, Jaconetta SM, Halaris AE (1993) Characterization of subtypes of alpha-2 adrenoceptors in the human brain. J Pharmacol Exp Ther 264:967–976
Otis JM, Dashew KB, Mueller D (2013) Neurobiological dissociation of retrieval and reconsolidation of cocaine-associated memory. J Neurosci 33:1271–1281a. doi:10.1523/JNEUROSCI.3463-12.2013
Pacholczyk T, Blakely RD, Amara SG (1991) Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature 350:350–354. doi:10.1038/350350a0
Paxinos G, Huang XF, Toga AW (2000) The rhesus monkey brain in stereotaxic coordinates. Academic Press, San Diego
Perala M, Hirvonen H, Kalimo H, Ala-Uotila S, Regan JW, Akerman KE, Scheinin M (1992) Differential expression of two alpha 2-adrenergic receptor subtype mRNAs in human tissues. Brain Res Mol Brain Res 16:57–63
Peyron C, Luppi PH, Fort P, Rampon C, Jouvet M (1996) Lower brainstem catecholamine afferents to the rat dorsal raphe nucleus. J Comp Neurol 364:402–413. doi:10.1002/(SICI)1096-9861(19960115)364:3<402:AID-CNE2>3.0.CO;2-8
Pitkanen A, Amaral DG (1993a) Distribution of parvalbumin-immunoreactive cells and fibers in the monkey temporal lobe: the amygdaloid complex. J Comp Neurol 331:14–36. doi:10.1002/cne.903310103
Pitkanen A, Amaral DG (1993b) Distribution of parvalbumin-immunoreactive cells and fibers in the monkey temporal lobe: the hippocampal formation. J Comp Neurol 331:37–74. doi:10.1002/cne.903310104
Pitts DK, Marwah J (1989) Chronic cocaine reduces alpha 2-adrenoceptor elicited mydriasis and inhibition of locus coeruleus neurons. Eur J Pharmacol 160:201–209
Porrino LJ, Lyons D, Smith HR, Daunais JB, Nader MA (2004) Cocaine self-administration produces a progressive involvement of limbic, association, and sensorimotor striatal domains. J Neurosci 24:3554–3562. doi:10.1523/JNEUROSCI.5578-03.2004
Ramamoorthy S, Samuvel DJ, Balasubramaniam A, See RE, Jayanthi LD (2010) Altered dopamine transporter function and phosphorylation following chronic cocaine self-administration and extinction in rats. Biochem Biophys Res Commun 391:1517–1521. doi:10.1016/j.bbrc.2009.12.110
Retson TA, Van Bockstaele EJ (2013) Coordinate regulation of noradrenergic and serotonergic brain regions by amygdalar neurons. J Chem Neuroanat 52:9–19. doi:10.1016/j.jchemneu.2013.04.003
Ritz MC, Cone EJ, Kuhar MJ (1990) Cocaine inhibition of ligand binding at dopamine, norepinephrine and serotonin transporters: a structure-activity study. Life Sci 46:635–645
Rudoy CA, Van Bockstaele EJ (2007) Betaxolol, a selective beta(1)-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats. Prog Neuropsychopharmacol Biol Psychiatry 31:1119–1129. doi:10.1016/j.pnpbp.2007.04.005
Scheinin M, Lomasney JW, Hayden-Hixson DM, Schambra UB, Caron MG, Lefkowitz RJ, Fremeau RT Jr (1994) Distribution of alpha 2-adrenergic receptor subtype gene expression in rat brain. Brain Res Mol Brain Res 21:133–149
Sinha R, Catapano D, O’Malley S (1999) Stress-induced craving and stress response in cocaine dependent individuals. Psychopharmacology 142:343–351
Smith RJ, Aston-Jones G (2011) alpha(2) Adrenergic and imidazoline receptor agonists prevent cue-induced cocaine seeking. Biol Psychiatry 70:712–719. doi:10.1016/j.biopsych.2011.06.010
Smith HR, Beveridge TJ, Porrino LJ (2006) Distribution of norepinephrine transporters in the non-human primate brain. Neuroscience 138:703–714. doi:10.1016/j.neuroscience.2005.11.033
Starke K (2001) Presynaptic autoreceptors in the third decade: focus on alpha2-adrenoceptors. J Neurochem 78:685–693
Stefanik MT, Kalivas PW (2013) Optogenetic dissection of basolateral amygdala projections during cue-induced reinstatement of cocaine seeking. Front Behav Neurosci 7:213. doi:10.3389/fnbeh.2013.00213
Tejani-Butt SM (1992) [3H]nisoxetine: a radioligand for quantitation of norepinephrine uptake sites by autoradiography or by homogenate binding. J Pharmacol Exp Ther 260:427–436
Terenzi MG, Ingram CD (1995) A combined immunocytochemical and retrograde tracing study of noradrenergic connections between the caudal medulla and bed nuclei of the stria terminalis. Brain Res 672:289–297
Trendelenburg AU, Starke K, Limberger N (1994) Presynaptic alpha 2A-adrenoceptors inhibit the release of endogenous dopamine in rabbit caudate nucleus slices. Naunyn Schmiedebergs Arch Pharmacol 350:473–481
Uhlen S, Dambrova M, Nasman J, Schioth HB, Gu Y, Wikberg-Matsson A, Wikberg JE (1998) [3H]RS79948-197 binding to human, rat, guinea pig and pig alpha2A-, alpha2B- and alpha2C-adrenoceptors. Comparison with MK912, RX821002, rauwolscine and yohimbine. Eur J Pharmacol 343:93–101
Volkow ND et al (1997) Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature 386:827–830. doi:10.1038/386827a0
Vranjkovic O, Hang S, Baker DA, Mantsch JR (2012) β-adrenergic receptor mediation of stress-induced reinstatement of extinguished cocaine-induced conditioned place preference in mice: roles for β1 and β2 adrenergic receptors. J Pharacol Exp Ther 342:541–551. doi:10.1124/jpet.112.193615
Wang R, Macmillan LB, Fremeau RT Jr, Magnuson MA, Lindner J, Limbird LE (1996) Expression of alpha 2-adrenergic receptor subtypes in the mouse brain: evaluation of spatial and temporal information imparted by 3 kb of 5′ regulatory sequence for the alpha 2A AR-receptor gene in transgenic animals. Neuroscience 74:199–218
Witter MP, Amaral DG (1991) Entorhinal cortex of the monkey: V. Projections to the dentate gyrus, hippocampus, and subicular complex. J Comp Neurol 307:437–459. doi:10.1002/cne.903070308
Woulfe JM, Hrycyshyn AW, Flumerfelt BA (1988) Collateral axonal projections from the A1 noradrenergic cell group to the paraventricular nucleus and bed nucleus of the stria terminalis in the rat. Exp Neurol 102:121–124
Woulfe JM, Flumerfelt BA, Hrycyshyn AW (1990) Efferent connections of the A1 noradrenergic cell group: a DBH immunohistochemical and PHA-L anterograde tracing study. Exp Neurol 109:308–322
Yavich L, Lappalainen R, Sirvio J, Haapalinna A, MacDonald E (1997) Alpha2-adrenergic control of dopamine overflow and metabolism in mouse striatum. Eur J Pharmacol 339:113–119
Zorrilla EP, Wee S, Zhao Y, Specio S, Boutrel B, Koob GF, Weiss F (2012) Extended access cocaine self-administration differentially activates dorsal raphe and amygdala corticotropin-releasing factor systems in rats. Addict Biol 17:300–308. doi:10.1111/j.1369-1600.2011.00329.x
Acknowledgments
The authors wish to acknowledge Susan Nader and Tonya Calhoun for their assistance in conducting the self-administration studies.
Conflict of interest
The authors declare that they have no conflicts of interest.
Ethical approval
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Smith, H.R., Beveridge, T.J.R., Nader, M.A. et al. Effects of abstinence from chronic cocaine self-administration on nonhuman primate dorsal and ventral noradrenergic bundle terminal field structures. Brain Struct Funct 221, 2703–2715 (2016). https://doi.org/10.1007/s00429-015-1066-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00429-015-1066-z