Advertisement

Psychopharmacology

, Volume 103, Issue 4, pp 480–492 | Cite as

Time course of transient behavioral depression and persistent behavioral sensitization in relation to regional brain monoamine concentrations during amphetamine withdrawal in rats

  • Pamela E. Paulson
  • Dianne M. Camp
  • Terry E. Robinson
Original Investigations

Abstract

This experiment was designed to characterize the withdrawal syndrome produced by discontinuation of treatment with escalating, non-neurotoxic doses ofd-amphetamine (AMPH). AMPH withdrawal was associated with both transient and persistent changes in behavior and postmortem brain tissue catecholamine concentrations. During the first week of withdrawal rats showed a significant decrease in spontaneous nocturnal locomotor activity. This behavioral depression was most pronounced on the first 2 days after the discontinuation of AMPH pretreatment, was still evident after 1 week, but had dissipated by 4 weeks. Behavioral depression was not due to a simple motor deficit, because AMPH-pretreated animals showed a normal large increase in locomotion when the lights initially went out, but they did not sustain relatively high levels of locomotor activity throughout the night, or show the early morning rise in activity characteristic of controls. Behavioral depression was associated with a transient decrease in the concentration of norepinephrine (NE) in the hypothalamus, and a transient decrease in the ability of an AMPH challenge to alter dopamine (DA) concentrations in the caudateputamen and nucleus accumbens. AMPH pretreatment also produced persistent changes in brain and behavior. The persistent effects of AMPH were not evident in spontaneous locomotor activity, but were revealed by a subsequent challenge injection of AMPH. AMPH pretreated animals were markedly hyper-responsive to the stereotypy-producing effects of an AMPH challenge. This behavioral sensitization was not fully developed until 2 weeks after the discontinuation of AMPH pretreatment, but then persisted undiminished for at least 1 year. It is suggested that the transient changes in brain and behavior described here may represent an animal analogue of the “distress syndrome” seen in humans during AMPH withdrawal, which is associated with symptoms of depression and alterations in catecholamine function. On the other hand, persistent behavioral sensitization may be analogous to the enduring hypersensitivity to the psychotogenic effects of AMPH seen in former AMPH addicts.

Key words

Dopamine Norepinephrine Stimulant drugs Depression Amphetamine psychosis 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aghajanian GK (1978) Tolerance of locus coeruleus neurones to morphine and suppression of withdrawal response by clonidine. Nature 276:186–188CrossRefPubMedGoogle Scholar
  2. Anisman H (1984) Vulnerability to depression: contribution of stress. In: Post RM, Ballenger JC (eds) Neurobiology of mood disorders. Williams & Wilkins, Baltimore, pp 407–431Google Scholar
  3. Antelman S (1988) Time-dependent sensitization as the cornerstone for a new approach to pharmacotherapy: drugs as foreign/stressful stimuli. Drug Dev Res 14:1–30CrossRefGoogle Scholar
  4. Antelman SM, Eichler AJ, Black CA, Kocan D (1980) Interchange-ability of stress and amphetamine in sensitization. Science 207:329–331PubMedGoogle Scholar
  5. Berridge KC, Venier IL, Robinson TE (1989) Taste reactivity analysis of 6-hydroxydopamine-induced aphagia: implications for arousal and anhedonia hypotheses of dopamine function. Behav Neurosci 103:36–45CrossRefPubMedGoogle Scholar
  6. Camp DM, Robinson TE (1988) Susceptibility to sensitization. II. The influence of gonadal hormones on enduring changes in brain monoamines and behavior produced by the repeated administration ofd-amphetamine or restraint stress. Behav Brain Res 30:69–88CrossRefPubMedGoogle Scholar
  7. Carroll ME, Lac ST (1987) Cocaine withdrawal produces behavioral disruptions in rats. Life Sci 40:2183–2190CrossRefPubMedGoogle Scholar
  8. Cassens G, Actor C, Kling M, Schildkraut JJ (1981) Amphetamine withdrawal: effects on threshold of intracranial reinforcement. Psychopharmacology 73:318–322CrossRefPubMedGoogle Scholar
  9. Cassens G, Kuruc A, Orsulak PJ, Schildkraut JJ (1979) Amphetamine withdrawal: effects on brain levels of MHPG-SO4 in the rat. Commun Psychopharmacol 3:217–223PubMedGoogle Scholar
  10. Castañeda E, Becker JB, Robinson TE (1988) The long-term effects of repeated amphetamine treatment in vivo on amphetamine, KCl and electrical stimulation evoked striatal dopamine release in vitro. Life Sci 42:2447–2456CrossRefPubMedGoogle Scholar
  11. Commissiong JW (1985) Monoamine metabolites: their relationship and lack of relationship to monoaminergic neuronal activity. Biochem Pharmacol 34:1127–1131CrossRefPubMedGoogle Scholar
  12. Ellinwood EH (1972) Amphetamine psychosis: individuals, settings, and sequences. In: Ellinwood EH, Cohen S (eds) Current concepts on amphetamine abuse. US Government Printing Office, Washington D.C., pp 143–157Google Scholar
  13. Fibiger HC, Phillips AG (1981) Increased intracranial self-stimulation in rats after long-term administration of desipramine. Science 214:683–685PubMedGoogle Scholar
  14. Gawin FH, Ellinwood EJ (1988) Cocaine and other stimulants. Actions, abuse, and treatment. N Engl J Med 318:1173–1182PubMedGoogle Scholar
  15. Gawin FH, Kleber HD, Byck R, Rounsaville BJ, Kosten TR, Jatlow PI, Morgan C (1989) Desipramine facilitation of initial cocaine abstinence. Arch Gen Psychiatry 46:117–121PubMedGoogle Scholar
  16. Grant SJ, Galloway MP, Mayor R, Fenerty JP, Finkelstein MF, Roth RH, Redmond DJ (1985) Precipitated diazepam withdrawal elevates noradrenergic metabolism in primate brain. Eur J Pharmacol 107:127–132Google Scholar
  17. Heffner TG, Hartman JA, Seiden LS (1980) A rapid method for the regional dissection of the rat brain. Pharmacol Biochem Behav 13:453–456CrossRefPubMedGoogle Scholar
  18. Herman ZS, Trzeciak H, Chrusciel TL, Kmieciak KK, Drybanski A, Sokola A (1971) The influence of prolonged amphetamine treatment and amphetamine withdrawal on brain biogenic amine content and behaviour in the rat. Psychopharmacologia 21:74–81CrossRefPubMedGoogle Scholar
  19. Hitzemann RJ, Tseng LF, Hitzemann BA, Sampath KS, Loh HH (1977) Effects of withdrawal from chronic amphetamine intoxication on exploratory and stereotyped behaviors in the rat. Psychopharmacology 54:295–302CrossRefPubMedGoogle Scholar
  20. Honma K, Honma S, Hiroshige T (1986) Disorganization of the rat activity rhythm by chronic treatment with methamphetamine. Physiol Behav 38:687–695CrossRefPubMedGoogle Scholar
  21. Kazahaya Y, Akimoto K, Otsuki S (1989) Subchronic methamphetamine treatment enhances methamphetamine- or cocaine-induced dopamine efflux in vivo. Biol Psychiatry 25:903–912CrossRefPubMedGoogle Scholar
  22. Klawans HL, Margolin DI (1975) Amphetamine-induced dopaminergic hypersensitivity in guinea pigs. Implications in psychosis and human movement disorders. Arch Gen Psychiatry 32:725–732PubMedGoogle Scholar
  23. Kokkinidis L (1988) Neurochemical correlates of post-amphetamine depression and sensitization in animals. Anim Models Psychiatr Disord 2:148–173Google Scholar
  24. Kokkinidis L, Zacharko RM (1980) Response sensitization and depression following long-term amphetamine treatment in a self-stimulation paradigm. Psychopharmacology 68:73–76CrossRefPubMedGoogle Scholar
  25. Kokkinidis L, Zacharko RM, Anisman H (1986) Amphetamine withdrawal: a behavioral evaluation. Life Sci 38:1617–1623CrossRefPubMedGoogle Scholar
  26. Kolta MG, Shreve P, De Souza V, Uretsky NJ (1985) Time course of the development of the enhanced behavioral and biochemical responses to amphetamine after pretreatment with amphetamine. Neuropharmacology 24:823–829CrossRefPubMedGoogle Scholar
  27. Kolta MG, Shreve P, Uretsky NJ (1989) Effect of pretreatment with amphetamine on the interaction between amphetamine and dopamine neurons in the nucleus accumbens. Neuropharmacology 28:9–14CrossRefPubMedGoogle Scholar
  28. Kramer J, Fischman V, Littlefield D (1967) Amphetamine abuse. JAMA 201:305–309CrossRefPubMedGoogle Scholar
  29. Leith NJ, Barrett RJ (1976) Amphetamine and the reward system: evidence for tolerance and post- drug depression. Psychopharmacologia 46:19–25CrossRefPubMedGoogle Scholar
  30. Leith NJ, Kuczenski R (1982) Two dissociable components of behavioral sensitization following repeated amphetamine administration. Psychopharmacology 76:310–315CrossRefPubMedGoogle Scholar
  31. Lynch MA, Leonard BE (1978) Effect of chronic amphetamine administration on the behaviour of rats in the open field apparatus: reversal of post-withdrawal depression by two antidepressants. J Pharm Pharmacol 30:798–799PubMedGoogle Scholar
  32. Lynch M, Kenny M, Leonard BE (1977) The effect of chronic administration ofd-amphetamine on regional changes in cate-cholamines in the rat brain. J Neurosci Res 3:295–300CrossRefPubMedGoogle Scholar
  33. Magos L (1969) Persistence of the effect of amphetamine on stereotyped activity on rats. Eur J Pharmacol 6:200–201CrossRefPubMedGoogle Scholar
  34. Maj J, Wedzony K, Klimek V (1987) Desipramine given repeatedly enhances behavioural effects of dopamine andd-amphetamine injected into the nucleus accumbens. Eur J Pharmacol 140:179–185CrossRefPubMedGoogle Scholar
  35. McCown TJ, Barrett RJ (1980) Development of tolerance to the rewarding effects of self-administered (+)-amphetamine. Pharmacol Biochem Behav 12:137–141CrossRefPubMedGoogle Scholar
  36. Pittendrigh CS, Daan S (1976) A functional analysis of circadian pacemakers in nocturnal rodents. V. Pacemaker structure: a clock for all seasons. J Comp Physiol 106:333–355CrossRefGoogle Scholar
  37. Post R (1980) Intermittent versus continuous stimulation: effect of time interval on the development of sensitization or tolerance. Life Sci 26:1275–1282CrossRefPubMedGoogle Scholar
  38. Redmond DJ, Huang YH (1982) The primate locus coeruleus and effects of clonidine on opiate withdrawal. J Clin Psychiatry 25–29Google Scholar
  39. Robinson TE (1988) Stimulant drugs and stress: factors influencing individual differences in the susceptibility to sensitization. In: Kalivas PW, Barnes CD (eds) Sensitization in the nervous system. Telford Press, Caldwell, New Yersey, pp 145–173Google Scholar
  40. Robinson TE (1990) The neurobiology of amphetamine psychosis: evidence from studies with an animal model. In: Nakazawa T (ed) Taniguchi Symposia on Brain Sciences, vol 14, Biological basis of schizophrenic disorders. Japan Scientific Societies Press, Tokyo (in press)Google Scholar
  41. Robinson TE, Becker JB (1982) Behavioral sensitization is accompanied by an enhancement in amphetamine-stimulated dopamine release from striatal tissue in vitro. Eur J Pharmacol 85:253–254CrossRefPubMedGoogle Scholar
  42. Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res Rev 396:157–198CrossRefGoogle Scholar
  43. Robinson TE, Camp DM (1987) Long-lasting effects of escalating doses ofd-amphetamine on brain monoamines, amphetamine-induced stereotyped behavior and spontaneous nocturnal locomotion. Pharmacol Biochem Behav 26:821–827CrossRefPubMedGoogle Scholar
  44. Robinson TE, Becker JB, Presty SK (1982) Long-term facilitation of amphetamine-induced rotational behavior and striatal dopamine release produced by a single exposure to amphetamine: sex differences. Brain Res 253:231–241CrossRefPubMedGoogle Scholar
  45. Robinson TE, Jurson PA, Bennett JA, Bentgen KM (1988) Persistent sensitization of dopamine neurotransmission in ventral striatum (nucleus accumbens) produced by past experience with (+)-amphetamine: a microdialysis study in freely moving rats. Br Res 462:211–222CrossRefGoogle Scholar
  46. Roth RH, Elsworth JD, Redmond DJ (1982) Clonidine suppression of noradrenergic hyperactivity during morphine withdrawal by clonidine: biochemical studies in rodents and primates. J Clin Psychiatry 42–46Google Scholar
  47. Sato M, Chen CC, Akiyama K, Otsuki S (1983) Acute exacerbation of paranoid psychotic state after long-term abstinence in patients with previous methamphetamine psychosis. Biol Psychiatry 18:429–440PubMedGoogle Scholar
  48. Schildkraut JJ, Watson R, Draskoczy PR (1971) Amphetamine withdrawal: depression and MHPG excretion. Lancet II:485–486CrossRefGoogle Scholar
  49. Schmidt C, Sonsalla P, Hanson G, Peat M, Gibb J (1985) Methamphetamine-induced depression of monoamine synthesis in the rat: development of tolerance. J Neurochem 44:852–855PubMedGoogle Scholar
  50. Schreiber H, Bell R, Conely L, Kufner M, Palet J, Wright L (1976) Diminished reaction to a novel stimulus during amphetamine withdrawal in rats. Pharmacol Biochem Behav 5:687–690CrossRefPubMedGoogle Scholar
  51. Segal DS (1975) Behavioral and neurochemical correlates of repeatedd-amphetamine administration. Adv Biochem Psychopharmacol 13:247–262PubMedGoogle Scholar
  52. Segal DS, Mandell AJ (1974) Long-term administration ofd-amphetamine: progressive augmentation of motor activity and stereotypy. Pharmacol Biochem Behav 2:249–255CrossRefPubMedGoogle Scholar
  53. Segal DS, Schuckit MA (1983) Animal models of stimulant-induced psychosis. In: Creese I (ed) Stimulants: neurochemical, behavioral and clinical perspectives. Raven Press, New York, pp 131–167Google Scholar
  54. Segal DS, Weinberger SB, Cahill J, McCunney SJ (1980) Multiple daily amphetamine administration: behavioral and neurochemical alterations. Science 207:905–907PubMedGoogle Scholar
  55. Seiden LS, Ricaurte GA (1987) Neurotoxicity of methamphetamine and related drugs. In: Melzer HY (ed) Psychopharmacology: the third generation of progress. Raven Press, New York, pp 359–366Google Scholar
  56. Seltzer V, Tonge SR (1975) Methylamphetamine withdrawal as a model for the depressive state: antagonism of post-amphetamine depression by imipramine. J Pharm Pharmacol 27:16PGoogle Scholar
  57. Short PH, Shuster L (1976) Changes in brain norepinephrine associated with sensitization tod-amphetamine. Psychopharmacology 48:59–67CrossRefPubMedGoogle Scholar
  58. Simpson DM, Annau Z (1977) Behavioral withdrawal following several psychoactive drugs. Pharmacol Biochem Behav 7:59–64CrossRefPubMedGoogle Scholar
  59. Sorensen SM, Hattox S, Johnson SW, Bickford P, Murphy R, Freedman R (1985) Norepinephrine-dependent and independent mechanisms of persistent effects of amphetamine in rat cerebellum. Life Sci 36:2383–2389CrossRefPubMedGoogle Scholar
  60. Tonge SR (1974) Noradrenaline and 5-hydroxytryptamine metabolism in six areas of rat brain during post-amphethamine depression. Psychopharmacologia 38:181–186CrossRefPubMedGoogle Scholar
  61. Utena H (1966) Behavioral aberrations in methamphetamine-intoxicated animals and chemical correlates in the brain. In: Tokizane T, Schade J (eds) Progress in brain research, Vol. 21B, Coerrelative neurosciences: clinical studies. Elsevier, Amsterdam, pp 192–207Google Scholar
  62. Watson R, Hartmann E, Schildkraut JJ (1972) Amphetamine withdrawal: affective state, sleep patterns, and MHPG excretion. Am J Psychiatry 129:263–269PubMedGoogle Scholar
  63. Winer BJ (1971) Statistical principles in experimental design. McGraw-Hill, New YorkGoogle Scholar
  64. Weiss RD (1988) Relapse to cocaine abuse after initiating desipramine treatment. JAMA 260:2545–2546CrossRefPubMedGoogle Scholar
  65. Weiss JM, Simson PG (1986) Depression in an animal model: focus on the locus ceruleus. Ciba Found Symp 123:191–215PubMedGoogle Scholar
  66. Weiss JM, Bailey WH, Pohorecky LA, Korzeniowski D, Grillione G (1980) Stress-induced depression of motor activity correlates with regional changes in brain norepinephrine but not in dopamine. Neurochem Res 5:9–22CrossRefPubMedGoogle Scholar
  67. Wilcox RA, Robinson TE, Becker JB (1986) Enduring enhancement in amphetamine-stimulated striatal dopamine release in vitro produced by prior exposure to amphetamine or stress in vivo. Eur J Pharmacol 124:375–376CrossRefPubMedGoogle Scholar
  68. Wise RA, Rompre P-P (1989) Brain dopamine and reward. Ann Rev Psychol 40:191–225CrossRefGoogle Scholar
  69. Yamada S, Kojima H, Yokoo H, Tsutsumi T, Takamuki K, Anraku S, Nishi S, Inanaga K (1988) Enhancement of dopamine release from striatal slices of rats that were subchronically treated with methamphetamine. Biol Psychiatry 24:399–408CrossRefPubMedGoogle Scholar
  70. Zacharko R, Anisman H (1989) Pharmacological, biochemical, and behavioral analyses of depression: animal models. In: Koob G (ed) Animal models of depression. Birkhauser, Boston, pp 204–238Google Scholar
  71. Zacharko RM, Bowers WJ, Kelley MS, Anisman H (1984) Prevention of stressor-induced disturbances of self-stimulation by desmethylimipramine. Brain Res 321:175–179CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Pamela E. Paulson
    • 1
  • Dianne M. Camp
    • 1
  • Terry E. Robinson
    • 1
    • 2
  1. 1.Department of PsychologyThe University of MichiganAnn ArborUSA
  2. 2.Department of Neuroscience ProgramThe University of MichiganAnn ArborUSA

Personalised recommendations