Characterization of Unconditioned Behavioral Effects of Dopamine D3/D2 Receptor Agonists1

  1. Beth Geter-Douglass,
  2. Jonathan L. Katz,
  3. Ken Alling,
  4. Jane B. Acri and
  5. Jeffrey M. Witkin
  1. Drug Development Group, Preclinical Pharmacology Laboratory, NIDA Addiction Research Center, National Institutes of Health, Baltimore, Maryland

    Abstract

    A series of experiments examined the ability of dopamine D3/D2 receptor agonists [(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride (PD 128,907), (±)-7-hydroxy-dipropylaminotetralin hydrobromide (7-OH-DPAT), quinpirole and bromocriptine] to produce a variety of dopaminergically mediated behaviors. The effects of these drugs with selectivity for D3/D2 receptors over D1 receptors were compared with those produced by the selective D1 agonists [(±)-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF 38393), (±)-6-Chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 82958)], a nonselective dopaminergic agonist (apomorphine), and an indirect dopamine agonist (cocaine). The D3/D2 agonists decreased locomotor activity, had no effect on gnawing and only inconsistently induced climbing in mice. Further, these agonists dose-dependently produced scratching in squirrel monkeys. In contrast, the D1 agonists, SKF 82958 and SKF 38393, did not produce scratching in squirrel monkeys. Whereas the full D1 agonist, SKF 82958, produced increases in locomotor activity and in climbing and gnawing, the partial D1 agonist, SKF 38393, did not increase the frequencies of these behaviors. The nonselective dopamine agonist, apomorphine, produced decreases in locomotor activity and increases in climbing and gnawing in mice. Apomorphine dose-dependently produced scratching in squirrel monkeys. The indirect dopamine agonist, cocaine, produced increases in locomotor activity and climbing, but had no effect on climbing or gnawing in mice and did not produce scratching in squirrel monkeys. These findings suggest that D3/D2agonists can be distinguished on various behavioral measures from the nonselective agonist, apomorphine (gnawing), D1 agonists (scratching) and the indirect agonist, cocaine (locomotor activity and scratching). Behaviors once attributed to stimulation of D2(locomotor activity and scratching) or D1/D2(climbing and gnawing) receptors may also involve dopamine D3 receptors.

    Footnotes

    • Send reprint requests to: Dr. Beth Geter-Douglass, Drug Development Group, Preclinical Pharmacology Laboratory, NIDA Addiction Research Center, P.O. Box 5180, Baltimore, MD 21224.

    • ↵1 Animals used in this study were maintained in facilities fully accredited by the American Association for the Accreditation of Animal Laboratory Care and all experimentation was conducted in accordance with the guidelines of the Institutional Care and Use Committee of the Division of Intramural Research, National Institute of Drug Abuse, NIH, and the guide for Care and Use of Laboratory Animals of the Institute of Laboratory Animals Resources, National Research Council, Department of Health, Education and Welfare, Publication (NIH) 85–23, revised 1985. Preliminary reports of this data have been presented previously; Geter-Douglass, B., Alling, K. L., Acri, J. B., Katz, J. L. and Witkin, J. M. Characterization of the behavioral effects of (±)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT). The College on Problems of Drug Dependence, NIDA Research Monograph 153, Problems of Drug Dependence, 367, 1994.

    • Abbreviations:
      7-OH-DPAT
      (±)-7-hydroxy-dipropylaminotetralin hydrobromide
      AJ 76
      cis-(+)-5-methoxy-1-methyl-2-(n-propylamino)tetralin
      (-)-NPA
      R(-)-propyl-norapomorphine hydrochloride
      PD 128
      907: (+)-(4aR,10bR)-3,4,4a,10b-Tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride
      Ru 24213
      N-n-propyl-N-phenylethyl-p(3-hydroxyphenyl)ethylamine hydrochloride
      S 14297
      (+)-[7-(N, N-dipropylamino)-5,6,7,8-tetrahydro-naptho(2,3b)dihydro,2,3-furane]
      SKF 38393
      (±)-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride
      SKF 82958
      (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide
      CI
      confidence interval
      • Received February 21, 1997.
      • Accepted June 12, 1997.
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    1. JPET October 1, 1997 vol. 283 no. 1 7-15
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