Skip to main content
SpringerLink
Log in

Effects of forskolin and cyclic nucleotides in animal models predictive of antidepressant activity: interactions with rolipram

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

Abstract

Forskolin, a direct activator of the catalytic subunit of adenylate cyclase (AC), and the cyclic nucleotide analogs dibutyryl cAMP (dBcAMP), 8-bromo cAMP (8-BrcAMP) and dibutyryl cGMP (dBcGMP) were tested for their ability to reverse the hypothermia or hypokinesia of mice depleted of presynaptic endogenous monoamines by pretreatment with reserpine, α-methyl-p-tyrosine and p-chlorophenylalanine. Forskolin and the cAMP analogs decreased the rectal temperature and inhibited locomotor activity in normal mice. In mice depleted of brain monoamines forskolin reversed the hypothermia and hypokinesia; dBcAMP and 8-BrcAMP antagonized the hypothermia but were only marginally effective in reversing the hypokinesia. DBcGMP was inactive. The antihypothermic action of forskolin or salbutamol was enhanced by the novel antidepressant and cAMP selective phosphodiesterase inhibitor rolipram (4RS-[3-cyclopentyloxy-4-methoxy-phenyl]-2-pyrrolidone). As an indirect effect via release of endogenous monoamines stimulating postsynaptic receptors was precluded by the monoamine-depleting pretreatment, forskolin and the cAMP analogs are thought to exert their antidepressant action by directly increasing brain cAMP availability. This is achieved by forskolin via activation of the catalytic subunit of AC and by the cAMP analogs via substitution for cAMP. These findings suggest that antidepressant activity is crucially linked to enhanced cAMP availability within brain effector cells. The successful treatment of endogenously depressed patients with rolipram supports this assumption.

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

Access this article

Log in via an institution

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

References

  • Arbuthnott GW, Attree TJ, Eccleston D, Loose RW, Martin MJ (1974) Is adenylate cyclase the dopamine receptor? Med Biol 52:350–353

    Google Scholar 

  • Askew BM (1963) A simple screening procedure for imipramine-like antidepressant agents. Life Sci 2:725–730

    Google Scholar 

  • Barraco RA, Phillis JW, Altmann HJ (1985) Depressant effect of forskolin on spontaneous locomotor activity in mice. Gen Pharmacol 16:521–524

    Google Scholar 

  • Bourin M, Poncelet M, Chermat R, Simon P (1983) The value of the reserpine test in psychopharmacology. Arzneim Forsch (Drug Res) 33:1173–1176

    Google Scholar 

  • Butt NM, Collier HOJ, Cuthbert NJ, Francis DL, Saeed SA (1979) Mechanism of quasi-morphine withdrawal behaviour induced by methylxanthines. Eur J Pharmacol 53:375–378

    Google Scholar 

  • Carlsson A (1966) Drugs which block the storage of 5-hydroxytryptamine and related compounds. In: Eichler O, Farah A (eds) Handbook of experimental pharmacology, vol 19, Springer Verlag, Berlin, pp 529–592

    Google Scholar 

  • Davis CW (1985) Assessment of selective inhibition of rat cerebral cortical calcium-independent and calcium-dependent phosphodiesterases in crude extracts using deoxycyclic AMP and potassium ions. Biochim Biophys Acta 797:354–362

    Google Scholar 

  • Dubey MP, Srimal RC, Nityanand S, Dhawan BN (1981) Pharmacological studies on coleonol, a hypotensive diterpene from Coleus forskohlii. J Ethnopharmacol 3:1–13

    Google Scholar 

  • Ebstein RP, Seamon K, Creveling CR, Daly JW (1982) Release of norepinephrine from brain vesicular preparations: Effects of an adenylate cyclase activator, forskolin, and a phosphodiesterase inhibitor. Cellular Mol Neurobiol 2:179–192

    Google Scholar 

  • Gehlert DR, Dawson TM, Yamamura HI, Wamsley JK (1985) Localization of [3H]forskolin binding sites in the rat brain using quantitative autoradiography. Eur J Pharmacol 106:223–225

    Google Scholar 

  • Henion WF, Sutherland EW, Posternak T (1967) Effects of derivatives of adenosine 3′,5′-phosphate on liver slices and intact animals. Biochim Biophys Acta 148:106–113

    Google Scholar 

  • Horowski R, Sastre-y-Hernandez M (1985) Clinical effects of the neurotropic selective cAMP phosphodiesterase inhibitor rolipram in depressed patients: Global evaluation of the preliminary reports. Curr Ther Res 38:23–29

    Google Scholar 

  • 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 29:369–373

    Google Scholar 

  • Kehr W, Debus G, Neumeister R (1985) Effects of rolipram, a novel antidepressant, on monoamine metabolism in rat brain. J Neural Transm 63:1–12

    Google Scholar 

  • Kincaid RL, Manganiello VC, Odya CE, Osborne JC, Stith-Coleman IE, Danello MA, Vaughan J (1984) Purification and properties of calmodulin-stimulated phosphodiesterase from mammalian brain. J Biol Chem 259:5158–5166

    Google Scholar 

  • Markstein R, Digges K, Marshall NR, Starke K (1984) Forskolin and the release of noradrenaline in cerebrocortical slices. Naunyn-Schmiedebergs Arch Pharmacol 325:17–24

    Google Scholar 

  • Metzger H, Lindner E (1981) The positive inotropic-acting forskolin, a potent adenylate cyclase activator. Arzneim Forsch (Drug Res) 31:1248–1250

    Google Scholar 

  • Nemoz G, Prigent AF, Moueqqit M, Fougier S, Macovschi O, Pacheco H (1985) Selective inhibition of one of the cyclic AMP phosphodiesterases from rat brain by the neurotropic compound rolipram. Biochem Pharmacol 34:2997–3000

    Google Scholar 

  • Przegalinski E, Bigajska K (1983) Antidepressant properties of some phosphodiesterase inhibitors. Pol J Pharm Pharmacol 35:233–240

    Google Scholar 

  • Randt CT, Judge ME, Bonnet KA, Quatermain D (1982) Brain cyclic AMP and memory in mice. Pharmacol Biochem Behav 17:677–680

    Google Scholar 

  • Sano M, Seto-Oshima A, Mizutani A (1984) Forskolin suppresses seizures induced by pentylenetetrazol in mice. Experientia 40:1270–1271

    Google Scholar 

  • Schmidt K, Baer HP (1983) Forskolin binding sites in rat liver and brain membranes. Eur J Pharmacol 94:337–340

    Google Scholar 

  • Schneider HH (1984) Brain response to phosphodiesterase inhibitors in rats killed by microwave irradiation or decapitation. Biochem Pharmacol 33:1690–1693

    Google Scholar 

  • Schoffelmeer ANM, Mulder AH (1983) [3H]Noradrenaline release from rat neocortical slices in the absence of extracellular Ca2+ and its presynaptic α2-adrenergic modulation. Naunyn-Schmiedebergs Arch Pharmacol 323:188–192

    Google Scholar 

  • Schwabe U, Miyake M, Ohga Y, Daly JW (1976) 4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 62 711): A potent inhibitor of adenosine cyclic 3′,5′-monophosphate phosphodiesterases in homogenates and tissue slices from rat brain. Mol Pharmacol 12:900–910

    Google Scholar 

  • Seamon KB, Padgett W, Daly JW (1981) Forskolin: Unique diterpene activator of adenylate cyclase in membranes and in intact cells. Proc Natl Acad Sci (USA) 78:3363–3367

    Google Scholar 

  • Sheppard H, Wiggan G, Tsien WH (1971) Structure-activity relationship for inhibitors of phosphodiesterase from erythrocytes and other tissues. Adv Cyclic Nucleotide Res 1:103–112

    Google Scholar 

  • Stone EA (1983) Problems with current hypotheses of antidepressant agents: Speculations leading to a new hypothesis. Behav Brain Sci 6:535–577

    Google Scholar 

  • Suzdak PD, Browne RG (1985) The effect of chronic infusion of forskolin in noradrenergic receptor sensitivity. Psychopharmacology 87:464–467

    Google Scholar 

  • Teshima Y, Kakiuchi S (1974) Mechanism of stimulation of Ca2+ plus Mg2+-dependent phosphodiesterase from rat cerebral cortex by the modulator protein and Ca2+. Biochem Biophys Res Commun 56:489–495

    Google Scholar 

  • Wachtel H (1982a) Selective cyclic adenosine 3′,5′-monophosphate phosphodiesterase inhibitors — a novel class of antidepressants? Abstr. 13th Congress of the Collegium Internationale Neuropsychopharmacologicum, Jerusalem, p 740

  • Wachtel H (1982b) Characteristic behavioral alterations in rats induced by rolipram and other selctive adenosine cyclic 3′,5′-monophosphate phosphodiesterase inhibitors. Psychopharmacology 77:309–316

    Google Scholar 

  • Wachtel H (1983a) Potential antidepressant activity of rolipram and other selective cyclic adenosine 3′,5′-monophosphate phosphodiesterase inhibitors. Neuropharmocology 22:267–272

    Google Scholar 

  • Wachtel H (1983b) Neurotropic effects of the optical isomers of the selctive adenosine cyclic 3′,5′-monophosphate phosphodiesterase inhibitor rolipram in rats in-vivo. J Pharm Pharmacol 35:440–444

    Google Scholar 

  • Wachtel H (1983c) Species differences in behavioural effects of rolipram and other adenosine cyclic 3′,5′-monophosphate phosphodiesterase inhibitors. J Neural Transm 56:139–152

    Google Scholar 

  • Wachtel H, Schneider HH (1986) Rolipram, a novel antidepressant, reverses the hypothermia and hypokinesia of monoamine-depleted mice by an action beyond postsynaptic monoamine receptors. Neuropharmacology (in press)

  • Weiner M, Olson JW (1973) Behavioural effects of dibutyryl cyclic AMP in mice. Life Sci 12:345–356

    Google Scholar 

  • Weishaar RE, Cain MH, Bristol JA (1985) A new generation of phosphodiesterase inhibitors: Multiple molecular forms of phosphodiesterase and the potential for drug selectivity. J Med Chem 28:537–545

    Google Scholar 

  • Wemer J, Schoffelmeer ANM, Mulder AH (1982) Effects of cyclic AMP analogues and phosphodiesterase inhibitors on K+-induced [3H]-noradrenaline release from rat brain slices and on its presynaptic α-adrenergic modulation. J Neurochem 39:349–356

    Google Scholar 

  • Zeller E, Stief HJ, Pflug B, Sastre-y-Hernandez M (1984) Results of a phase II study of the antidepressant rolipram. Pharmacopsychiatria 17:188–190

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Laboratories of Schering AG, Berlin (West) and Bergkamen

    Helmut Wachtel & Peter A. Löschmann

Authors
  1. Helmut Wachtel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter A. Löschmann
    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

Wachtel, H., Löschmann, P.A. Effects of forskolin and cyclic nucleotides in animal models predictive of antidepressant activity: interactions with rolipram. Psychopharmacology 90, 430–435 (1986). https://doi.org/10.1007/BF00174056

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00174056

Key words

Search

Navigation