Skip to main content
SpringerLink
Log in

Inbred rat strain comparisons indicate different sites of action for cocaine and amphetamine locomotor stimulant effects

  • Original Investigations
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Cocaine and amphetamine produce several behavioral effects, most notably locomotor stimulation. Biochemically, evidence suggests specific involvement of dopaminergic systems, although not necessarily identical sites, in mediating cocaine- and amphetamine-induced locomotor stimulation. This study examined the effects of cocaine or amphetamine on locomotor activity in rats from the ACI, F344, LEW and NBR inbred strains. Dose-dependent increases in locomotor activity were found for both drugs in all strains. However, large potency and efficacy differences were found. Further, significant strain by drug interactions were found, in that the strain rank order for stimulant response to the two drugs was not identical. Since striatal dopaminergic neurons influence locomotor activity, we also assessed ligand affinity and receptor density of dopamine transporters and dopaminergic D1 and D2 receptors in striatal tissue from these same strains of rats. No differences in these receptor binding parameters were found. These findings support the conclusion that these two drugs produce their locomotor stimulant effects through different sites of action, and that genetic differences in response to these drugs at the behavioral level do not appear to be mediated significantly by differences in structure or number of striatal dopaminergic sites. The further use of genetic methods, however, may aid in determining the specific sites of action of these widely used stimulant drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anisman H, Gygan D (1975) Central effects of scopolamine and (+)-amphetamine on locomotor activity: Interaction with strain and stress variables. Neuropharmacology 14:835–840

    Google Scholar 

  • Anisman H (1976a) Effects of scopolamine andd-amphetamine on locomotor activity before and after shock: a diallel analysis in mice. Psychopharmacology 48:165–173

    Google Scholar 

  • Anisman H (1976b) Role of stimulus locale on strain differences in active avoidance after scopolamine ord-amphetamine treatment. Pharmacol Biochem Behav 4:103–106

    Google Scholar 

  • Bejerot N (1970) A comparison of the effects of cocaine and central stimulants. Br J Addict 65:35–37

    Google Scholar 

  • Berger P, Jacobsen AE, Rice KC, Lessor RA, Reith MA (1986) Metaphit, a receptor acylator, inactivates cocaine binding sites in striatum and antagonizes cocaine-induced locomotor stimulation in rodents. Neuropharmacol 25:931–933

    Google Scholar 

  • Billard W, Ruperto V, Crosby G, Iorio LC, Barnett A (1984) Characterization of the binding of3H-SCH 23390, a selective D1 receptor antagonist ligand, in rat striatum. Life Sci 35:1885–1893

    Google Scholar 

  • Blackburn KJ, French PC, Merrills RJ (1967) 5-Hydroxytryptamine uptake by rat brain in vitro. Life Sci 6:1653

    Google Scholar 

  • Broadhurst PL (1979) Drugs and the Inheritance of Behavior: A Survey of Comparative Pharmacogenetics. Plenum Press, New York, p 206

    Google Scholar 

  • Collins AC, Lebsack ME, Yeager TN (1976) Mechanisms that underlie sex-linked and genotypically determined differences in the depressant actions of alcohol. Ann NY Acad Sci 273:303–316

    Google Scholar 

  • Colpaert FC, Niemegeers CJE, Janssen PAJ (1979) Discriminative stimulus properties of cocaine: neuropharmacological characteristics as derived from stimulus generalization experiments. Pharmacol Biochem Behav 10:535–546

    Google Scholar 

  • Crabbe JC, Belknap JK (1980) Pharmacogenetic tools in the study of drug tolerance and dependence. Subst Alc Actions Misuse 1:385–413

    Google Scholar 

  • Creese I, Schneider R, Snyder SH (1977)3H-Spiroperidol labels dopamine receptors in pituitary and brain. Eur J Pharmacol 46:377–381

    Google Scholar 

  • Davis WM, Babbini M, Pong SF, King WT, White CL, (1974) Motility of mice after amphetamine: effects of strain, aggregation and illumination. Pharmacol Biochem Behav 2:803–809

    Google Scholar 

  • Dibner MD, Zahniser NR, Wolfe BB, Rabin RA, Molinoff PB (1980) Brain neurotransmitter receptor systems in mice genetically selected for differences in sensitivity to ethanol. Pharmacol Biochem Behav 12:509–513

    Google Scholar 

  • Dudek BC, Fanelli RJ (1980) Effects of gamma-butyrolactone, amphetamine and haloperidol in mice differing in sensitivity to alcohol. Psychopharmacology 68:89–97

    Google Scholar 

  • Ellinwood EH, Kilbey MM (eds) (1977) Cocaine and other stimulants, Advances in Behavioral Biology, vol 21. Plenum Press, New York

    Google Scholar 

  • Fiebre CM de, Ruth JR, Collins AC (1989) Differential sensitivity to high doses of cocaine in long-sleep and short-sleep mice. Pharmacol Biochem Behav 34:887–893

    Google Scholar 

  • Fischman MW, Schuster CR, Resnekov L, Schick JFE, Krasnegor NA, Fennell W, Freedman DX (1976) Cardiovascular and subjective effects on intravenous cocaine administration in humans. Arch Gen Psychiatry 33:983–989

    Google Scholar 

  • George FR (1989) Cocaine produces low-dose locomotor depressant effects in mice. Psychopharmacology 99:147–150

    Google Scholar 

  • George FR, Goldberg SR (1988) Genetic factors in response to cocaine. National Institute on Drug Abuse Monographs 88:239–249

    Google Scholar 

  • George FR, Porrino LJ, Goldberg SR (1987) Differences in locomotor activation and lethality in response to acute administration of cocaine across several rat genotypes. Behav Genet 17:622

    Google Scholar 

  • George FR, Ritz MC (1991) Cocaine produces locomotor stimulation in SS/Ibg but not LS/Ibg mice. Psychopharmacology 101:18–22

    Google Scholar 

  • Gonzalez FA, Goldberg SR (1977) Effects of cocaine andd-amphetamine on behavior maintained under various schedules of food presentation in squirrel monkeys. J Pharmacol Exp Ther 201:33–43

    Google Scholar 

  • Heikkila RE, Orlansky H, Cohen G (1975a) Studies on the distinction between uptake inhibition and release of (3H) dopamine in rat brain tissue slices. Biochem Pharmacol 24:847–852

    Google Scholar 

  • Heikkila RE, Orlansky H, Mytilineou H, Cohen G (1975b) Amphetamine: evaluation ofd- andl-isomers as releasing agents and uptake inhibitors for 3H-dopamine and 3H-norepinephrine in slices of rat neostriatum and cerebral cortex. J Pharmacol Exp Ther 194:47–56

    Google Scholar 

  • Hess EJ, Battaglia G, Norman AB, Iorio LC, Creese I (1986) Guanine nucleotide regulation of agonist interactions at [3H]SCH23390-labeled D1 dopamine receptors in rat striatum. Eur J Pharmacol 121:31–38

    Google Scholar 

  • Horn AS, Cuello C, Miller RJ (1974) Dopamine in the mesolimbic system of the rat brain: endogenous levels and the effects of drug on the uptake mechanism and stimulation of adenylate cyclase activity. J Neurochem 22:265–270

    Google Scholar 

  • Huang D, Wilson MC (1986) Comparative discriminative stimulus properties ofdl-cathinone,d-amphetamine, and cocaine in rats. Pharmacol Biochem Behav 24:205–210

    Google Scholar 

  • Javitch JA, Blaustein RO, Snyder SH (1984) [3H] Mazindol binding associated with neuronal dopamine and norepinephrine uptake sites. Mol Pharmacol 26:35–44

    Google Scholar 

  • Kalivas PW, Duffy P, DuMars LE, Skinner C (1988) Behavioral and neurochemical effects of acute and daily cocaine administration in rats. J Pharmacol Exp Ther 245:485–492

    Google Scholar 

  • Langer SZ, Arbilla S (1984) The amphetamine paradox in dopaminergic neurotransmission. TIPS 4:387–390

    Google Scholar 

  • List SJ, Seeman P (1981) Resolution of dopamine and serotonin receptor components of [3H]spiperone binding to rat brain regions. Proc Natl Acad Sci USA 78:2620–2624

    Google Scholar 

  • McClearn GE, Rodgers DA (1961) Genetic factors in alcohol preference of laboratory mice. J Comp Phys Psych 54:116–119

    Google Scholar 

  • Moisset B (1977) Genetic analysis of cerebral norepinephrine uptake and open-field activity. Behav Genet 7:78–79

    Google Scholar 

  • Munson PJ, Rodbard D (1980) LIGAND: A versatile approach for the characterization of ligand binding systems. Anal Biochem 107:220–239

    Google Scholar 

  • Porrino LJ, Ritz MC, Goodman NL, Sharpe LG, Kuhar MJ, Goldberg SR (1989) Differential effects of the pharmacological manipulation of serotonin systems on cocaine and amphetamine self-administration in rats. Life Sci 45:1529–1535

    Google Scholar 

  • Post RM, Contel NR (1983) Human and animal studies of cocaine: implications for development of behavioral pathology. In: Creese I (ed) Stimulatns: neurochemical, behavioral and clinical perspectives. Raven Press, New York, pp 169–203

    Google Scholar 

  • Ritchie JM, Greene NM (1985) Local anesthetics. In: Gilman AG, Goodman LS, Rall TW, Murad F (eds) The pharmacological basis of therapeutics, 7th edn. McMillan, New York, pp 302–321

    Google Scholar 

  • Ritz MC, Kuhar MJ (1989) Relationship between self-administration of amphetamine and monoamine receptors in brain: comparison with cocaine. J Pharmacol Exp Ther 248:1010–1017

    Google Scholar 

  • Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ (1987) Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237:1219–1223

    Google Scholar 

  • Ruth JA, Ullman EA, Collins AC (1988) An analysis of cocaine effects on locomotor activities and heart rate in four inbred mouse strains. Pharmacol Biochem Behav 29:157–162

    Google Scholar 

  • Scheel-Kruger J, Graestrup C, Nielson M, Golembiowski K, Mogilmicka E (1977) Cocaine: discussion on the role of dopamine in the biochemical mechanism of action In: Ellinwood EH, Kilbey MM (eds) Advances in behavioral biology, vol 21: Cocaine and other stimulants. Plenum Press, New York, pp 373–407

    Google Scholar 

  • Sharkey J, Ritz MC, Schenden JA, Hanson RC, Kuhar MJ (1988a) Cocaine inhibits muscarinic cholinergic receptors in heart and brain. J Pharmacol Exp Ther 246:1048–1052

    Google Scholar 

  • Sharkey J, Glen KA, Wolfe S, Kuhar MJ (1988b) Cocaine binding at sigma receptors. Eur J Pharmacol 149:171–174

    Google Scholar 

  • Shuster L, Yu G, Bates A (1977) Sensitization to cocaine stimulation in mice. Psychopharmacology 52:185–190

    Google Scholar 

  • Spealman RD, Kelleher RT, Goldberg SR (1983) Stereoselective behavioral effects of cocaine and a phenyltropane analog. J Pharmacol Exp Ther 225:509–514

    Google Scholar 

  • Thompson ML, Schuster L, Casey E, Kanel GC (1984) Sex and strain differences in response to cocaine. Biochem Pharmacol 33:1299–1307

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychology, Center on Alcoholism, Substance Abuse and Addictions, University of New Mexico, 87131, Albuquerque, NM, USA

    Frank R. George & Mary C. Ritz

  2. Preclinical Pharmacology Branch, National Institute on Drug Abuse, Addiction Research Center, 4940 Eastern Avenue, 21224, Baltimore, MD, USA

    Frank R. George, Mary C. Ritz & Steven R. Goldberg

  3. Unit on Brain Imaging, National Institute on Neurological Disorders and Stroke, 20892, Bethesda, MD, USA

    Linda J. Porrino

Authors
  1. Frank R. George
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Linda J. Porrino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mary C. Ritz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Steven R. Goldberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

George, F.R., Porrino, L.J., Ritz, M.C. et al. Inbred rat strain comparisons indicate different sites of action for cocaine and amphetamine locomotor stimulant effects. Psychopharmacology 104, 457–462 (1991). https://doi.org/10.1007/BF02245649

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02245649

Key words

Search

Navigation