, Volume 77, Issue 4, pp 309–316 | Cite as

Characteristic behavioral alterations in rats induced by rolipram and other selective adenosine cyclic 3′,5′-monophosphate phosphodiesterase inhibitors

  • Helmut Wachtel
Original Investigations


The significance of a characteristic symptomatology (hypothermia, hypoactivity, forepaw shaking, grooming, head twitches) as a potential in vivo correlate of enhanced availability of brain adenosine cyclic 3′,5′-monophosphate (cAMP) was examined in rats following systemic administration of various doses of dibutyryladenosine cAMP (dBcAMP) or of the phosphodiesterase (PDE) inhibitors rolipram, Ro 20-1724, ICI 63-197, isobutylmethylxanthine (IBMX), theophylline, cartazolate, and papaverine. The various PDE inhibitors could be assigned to three groups according to the pattern of behavioral alterations they induced. Rolipram, Ro 20-1724, and ICI 63-197 (group 1) caused hypothermia, hypoactivity, forepaw shaking, grooming, and head twitches. All behavioral effects were mimicked by dBcAMP but not dBcGMP. The order of potency and effective dosage range to induce the behavioral alterations were, in descending order, rolipram (0.09–1453 μmol/kg IP), ICI 63-197 (0.48–119 μmol/kg IP), Ro 20-1724 (5.6-1438 μmol/kg IP), corresponding with the recently reported efficacy of the drugs to elevate rat brain cAMP in vivo. Comparatively high doses of the alkylxanthine PDE inhibitors IBMX and theophylline (group 2) caused hypothermia, forepaw shaking, grooming, and head twitches concomitantly with a decline of the motor stimulatory effect, suggesting enhanced availability of brain cAMP. The order of potency and the effective dosage range to induce the behavioral alterations were, in descending order, IBMX (28.1–113 μmol/kg IP) and theophylline (139–555 μmol/kg IP). The third group, papaverine (295–1179 μmol/kg IP) and cartazolate (21.5–345 μmol/kg IP), caused only hypothermia and hypoactivity. The differences in the behavioral pattern of the two latter groups of compounds in comparison with dBcAMP and the selective cAMP PDE inhibitors are discussed with regard to their additional interference with adenosine actions besides their nonselective PDE inhibitory action.

Key words

Rolipram Phosphodiesterase inhibitors Cyclic nucleotides Locomotor activity Rectal temperature Forepaw shaking Grooming Head twitches Rat 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Arbuthnott GW, Attree TJ, Eccleston D, Loose RW, Martin MJ (1974) Is adenylate cyclase the dopamine receptor? Med Biol 52:350–353Google Scholar
  2. Beer B, Chasin M, Clody DE, Vogel JR, Horovitz ZP (1972) Cyclic adenosine monophosphate phosphodiesterase in brain: Effect on anxiety. Science 176:428–430Google Scholar
  3. Berkowitz BA, Spector S (1971) The effect of caffeine and theophylline on the disposition of brain serotonin in the rat. Eur J Pharmacol 16:322–325Google Scholar
  4. Burnstock G (1975) Purinergic transmission. In: Iversen LL, Iversen SD, Snyder SH (eds) Handbook of psychopharmacology, vol 5. Plenum, New York London, pp 131–194Google Scholar
  5. Butt NM, Collier HOJ, Cuthbert NJ, Francis DL, Saeed SA (1979) Mechanism of quasi-morphine withdrawal behaviour induced by methylxanthines. Eur J Pharmacol 53:375–378Google Scholar
  6. Collier HOJ, Francis DL (1976) Stereospecific suppression by opiates of the quasi-morphine abstinence syndrome elicited by 3-isobutyl-1-methylxanthine (IBMX). Br J Pharmacol 56:382PGoogle Scholar
  7. Daly J (1975) Role of cyclic nucleotides in the nervous system. In: Iversen LL, Iversen SD, Snyder SH (eds) Handbook of psychopharmacology, vol 5. Plenum, New York London, pp 47–130Google Scholar
  8. DuMoulin A, Schultz J (1975) Effect of some phosphodiesterase inhibitors on two different preparations of adenosine 3′,5′-monophosphate phosphodiesterase. Experientia 31:883–884Google Scholar
  9. Feldberg W, Sherwood SL (1954) Injection of drugs into the lateral ventricle of the cat. J Physiol (Lond) 123:148–167Google Scholar
  10. Francis DL, Roy AC, Collier HOJ (1975) Morphine abstinence and quasi-abstinence effects after phosphodiesterase inhibitors and naloxone. Life Sci 16:1901–1906Google Scholar
  11. Fredholm BB (1980) Are methylxanthine effects due to antagonism of endogenous adenosine? TIPS 1:129–132Google Scholar
  12. Hauliča I, Ababei L, Brănişteanu D, Topoliceanu F (1973) Preliminary data on the possible hypnogenic role of adenosine. J Neurochem 21:1019–1020Google Scholar
  13. Henion WF, Sutherland EW, Posternak T (1967) Effects of derivatives of adenosine 3′,5′-phosphate on liver slices and intact amimals. Biochim Biophys Acta 148:106–113Google Scholar
  14. Huang M, Shimizu H, Daly JW (1972) Accumulation of cyclic adenosine monophosphate in incubated slices of brain tissue. 2. Effect of depolarizing agents, membrane stabilizers, phosphodiesterase inhibitors, and adenosine analogs. J Med Chem 15:462–466Google Scholar
  15. Huang M, Daly JW (1974) Adenosine-elicited accumulation of cyclic AMP in brain slices: Potentiation by agents which inhibit uptake of adenosine. Life Sci 14:489–503Google Scholar
  16. Kakiuchi S, Yamazaki R, Teshima Y, Uenishi K, Miyamoto E (1975) Multiple cyclic nucleotide phosphodiesterase activities from rat tissues and occurrence of calcium-plus-magnesium-ion-dependent phosphodiesterase and its protein activator. Biochem J 146: 109–120Google Scholar
  17. Kant GJ, Meyerhoff JL, Lenox RH (1980) In vivo effects of apomorphine and 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20-1724) on cyclic nucleotides in rat brain and pituitary. Biochem Pharmacol 29:369–373Google Scholar
  18. Kuo JF, Miyamoto E, Reyes PL (1974) Activation and dissociation of adenosine 3′,5′-monophosphate-dependent and guanosine 3′,5′-monophosphate-dependent protein kinases by various cyclic nucleotide analogs. Biochem Pharmacol 23:2011–2021Google Scholar
  19. Mah HD, Daly JW (1976) Adenosine-depdent formation of cyclic AMP in brain slices. Pharmacol Res Commun 8:65–79Google Scholar
  20. Maître M, Ciesielski L, Lehmann A, Kempf E, Mandel P (1974) Protective effect of adenosine and nicotinamide against audiogenic seizure. Biochem Pharmacol 23:2807–2816Google Scholar
  21. Marley E, Nistico G (1972) Effects of catecholamines and adenosine given into the brain of fowls. Br J Pharmacol 46:619–636Google Scholar
  22. Minneman KP (1976) Cyclic nucleotide phosphodiesterase in rat neostriatum: Multiple isoelectric forms with similar kinetic properties. J Neurochem 27:1181–1189Google Scholar
  23. Nahorski SR, Rogers KJ (1975) The effect of phosphodiesterase inhibitors on the stimulation of cerebral cyclic AMP formation by biogenic amines in vitro and in vivo. Br J Pharmacol 54:272PGoogle Scholar
  24. Nathanson JA (1977) Cyclic nucleotides and nervous system function. Physiol Rev 57:157–256Google Scholar
  25. Pöch G, Kukovetz WR (1971) Papaverine-induced inhibition of phosphodiesterase activity in various mammalian tissues. Life Sci 10:133–144Google Scholar
  26. Poole S, Stephenson JD (1977) Some shortcomings of rectal temperature measurements. Physiol Behav 18:203–205Google Scholar
  27. Prasad KN, Becker G, Tripathy K (1975) Differences and similarities between guanosine 3′,5′-cyclic monophosphate phosphodiesterase and adenosine 3′,5′-cyclic monophosphate phosphodiesterase activities in neuroblastoma cells in culture. Proc Soc Exp Biol Med 149:757–762Google Scholar
  28. Sakalis G, Sathanathan G, Collins P, Gershon S (1974) SQ 65 396: A non-sedative anxiolytic? Curr Ther Res 16:861–864Google Scholar
  29. Sattin A, Rall TW (1970) The effect of adenosine and adenine nucleotides on the cyclic adenosine 3′,5′-phosphate content of guinea pig cerebral cortex slices. Mol Pharmacol 6:13–23Google Scholar
  30. Schneider HH, Prozesky KD (1979) Focused microwave power for rapid enzyme inactivation in rat brain. Abstr. 7th Meeting of the International Society of Neurochemistry, Jerusalem, p 573Google Scholar
  31. Schwabe U, Miyake M, Ohga Y, Daly JW (1976) 4-(3-Cyclopentyloxy-4-methoxy)-2-pyrrolidone (ZK 62711): A potent inhibitor of adenosine cyclic 3′,5′-monophosphate phosphodiesterases in homogenates and tissue slices from rat brain. Mol Pharmacol 12:900–910Google Scholar
  32. Sheppard H, Wiggan G, Tsien WH (1971) Structure-activity relationship for inhibitors of phosphodiesterase from erythrocytes and other tissues. Adv Cyclic Nucleotide Res 1:103–112Google Scholar
  33. Smellie FW, Davis CW, Daly JW, Wells JN (1979) Alkylxanthines: Inhibition of adenosine-elicited accumulation of cyclic AMP in brain slices and of brain phoshodiesterase activity. Life Sci 24:2475–2482Google Scholar
  34. Stefanovich V (1979) Influence of theophylline on concentrations of cyclic 3′,5′-adenosine monophosphate and cyclic 3′,5′-guanosine monophosphate of rat brain. Neurochem Res 4:587–594Google Scholar
  35. Tachizawa H, Saito T, Akimoto R (1974) Metabolism of N6,O2′-dibutyryl-3′,5′-cyclic-AMP (dBcAMP). Jpn J Pharmacol (Suppl) 24:51Google Scholar
  36. Thithapandha A, Maling HM, Gilette JR (1972) Effects of caffeine and theophylline on activity or rats in relation to brain xanthine concentrations. Proc Soc Exp Biol Med 139:582–586Google Scholar
  37. Vapaatalo H, Onken D, Neuvonen PJ, Westermann E (1975) Stereospecificity in some central and circulatory effects of phenylisopropyl-adenosine (PIA). Arnzeim Forsch 25:407–410Google Scholar
  38. Vernikos-Danellis J, Harris III CG (1968) The effect of in vitro and in vivo caffeine, theophylline, and hydrocortisone on the phosphodiesterase activity of the pituitary, median eminence, heart, and cerebral cortex of the rat. Proc Soc Exp Biol Med 128:1016–1021Google Scholar
  39. Vocci FJ, Petty SK, Dewey WL (1978) Antinociceptive action of the butyryl derivatives of cyclic guanosine 3′:5′-monophosphate. J Pharmacol Exp Ther 207:892–898Google Scholar
  40. Wachtel H (1975) ZK 62-711: Evidence for selective neurotropic cAMP phosphodiesterase inhibitory action. Schering Research Report, BerlinGoogle Scholar
  41. Wachtel H (1978) Effects of different phosphodiesterase (PDE) inhibitors and cyclic nucleotides on motor behaviour and body temperature in rats. Abstr. 11th Congress of the Collegium Internationale Neuropsychopharmacologicum, Vienna, p 428Google Scholar
  42. Wachtel H, Schmiechen R, Zehleke P (1980) Induction of a characteristic behavioural syndrome in rats by rolipram and other selective adenosine 3′,5′-monophosphate (cAMP) phosphodiesterase (PDE) inhibitors. Naunyn Schmiedebergs Arch Pharmacol (Suppl) 313:R30Google Scholar
  43. Weinryb J, Chasin M, Free CA, Harris DN, Goldenberg H, Michel IM, Paik VS, Phillips M, Samaniego S, Hess M (1972) Effects of therapeutic agents on cyclic AMP metabolism in vitro. J Pharm Sci 61:1556–1567Google Scholar
  44. Weinryb J, Beer B, Chasin M, Proctor EB, Hess SM (1975) Studies in vitro and in vivo with SQ 20-009: An inhibitor of cyclic nucleotide phosphodiesterase with central nervous system activity. In: Boissier JR, Hippius H, Pichot P (eds) Neuropharmacology: Proceedings of the Ninth Congress of the Collegium Internationale Neuropsychopharmacologicum. Excerpta Medica Elsevier, Amsterdam New York, pp 857–865Google Scholar
  45. Weiss B, Costa E (1968) Regional and subcellular distribution of adenyl cyclase and 3′,5′-cyclic nucleotide phosphodiesterase in brain and pineal gland. Biochem Pharmacol 17:2107–2116Google Scholar
  46. Wright LS, Horn HJ, Woodard G (1962) Activity patterns in mice tested singly and in groups as a drug screening tool. Fed Proc 21:420Google Scholar

Copyright information

© Springer-Verlag 1982

Authors and Affiliations

  • Helmut Wachtel
    • 1
  1. 1.Department of NeuropsychopharmacologySchering AGBerlin 65

Personalised recommendations