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Effects of tetrahydropapaveroline and salsolinol on cerebral monoamine metabolism and their interactions with psychopharmacological drugs

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Summary

The effects of the tetrahydroisoquinoline alkaloids: tetrahydropapaveroline (THP) and salsolinol alone or in combination with psychopharmacological drugs on cerebral monoamine metabolism in the rat were studied.

  1. 1.

    d,l-THP administered intraventricularly to rats in doses of 70\2-250 \gmg induced a sustained fall in striatal dopamine concentrations with a maximum depletion occurring at 3\2-6 h after drug administration. The striatal homovanillic acid (HVA) concentration was increased significantly at 3 h after THP administration.

    Striatal 5-hydroxytryptamine (5-HT) and diencephalic noradrenaline or 5-HT levels were decreased following the THP administration.

    THP was not found to induce any in vivo alterations in monoamineoxidase (MAO) or catechol-O-methyl transferase (COMT) activities in rat brain.

  2. 2.

    Salsolinol (250 \gmg intraventricularly) caused a delayed rise in striatal dopamine concentration which at 6 h after the drug administration rose to about 3 times the control value. The effects of salsolinol on striatal HVA showed a fall 3 h after drug administration. Diencephalic noradrenaline and 5-HT concentrations were lower than controls 6 h after drug administration.

  3. 3.

    In order to investigate the mechanisms underlying the biochemical effects of THP or salsolinol on brain catecholamines and 5-HT, psychopharmacological drugs were given to rats together with THP or salsolinol (250 \gmg intraventricularly).

    Haloperidol (5 mg/kg, i.p.) pretreatment 45 min before THP partially prevented the striatal dopamine reduction and the HVA increase induced by THP alone; furthermore, haloperidol reversed the THP effect on diencephalic noradrenaline but not 5-HT.

    Desmethylimipramine (25 mg/kg, i.p.) administered 45 min before THP prevented the THP induced depletions of the monoamines.

    On the other hand, gamma-hydroxybutyrate pretreatments of the rats were not found to affect the THP induced alterations in catecholamines.

    the salsolinol induced rise in striatal dopamine was prevented by α-methyl-p-tyrosine (300 mg/kg, i.p., administered twice in 24 h) pretreatment while the salsolinol induced fall in diencephalic noradrenaline was not affected.

    Reserpine (5 mg/kg, s.c.) pretreatment of rats prevented the salsolinol induced rise in striatal dopamine and similarly haloperidol (5 mg/kg, i.p.) affected the dopamine but not the noradrenaline changes caused by salsolinol.

  4. 4.

    For the mode of action of THP it is likely that the alkaloid is taken up in catecholaminergic, and possibly to a small extent serotonergic, neurones and thereby displacing dopamine or noradrenaline from storage sites. THP or a metabolite may act as a false transmitter and/or affecting catecholaminergic receptors directly and independently of a presynaptic release.

    THP and salsolinol appear to have some basic differences in their mode of action on dopaminergic, but probably not on noradrenergic, mechanisms. For salsolinol the concept of a false transmitter seems most unlikely for the effect on dopaminergic neurones and, in fact, it may be that salsolinol in addition to actually causing increased synthesis of dopamine, has agonistic, while THP has antagonistic, properties in acting on dopamine receptors.

  5. 5.

    Salsolinol was found to cause hypothermia while THP caused hyperthermia in the rat.

THP and salsolinol induced abnormal motor behaviour in rats in the form of gnawing, licking, chewing, head-neck rocking and increased motor activity and the motor dysfunctions were most apparent for THP. These dyskinetic phenomena are discussed briefly in relation to dopaminergic mechanisms.

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  1. Department of Pharmacology and Clinical Pharmacology with Toxicology, University of Trondheim, Regional Hospital, N-7000, Trondheim, Norway

    N. Awazi & H. C. Guldberg

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Awazi, N., Guldberg, H.C. Effects of tetrahydropapaveroline and salsolinol on cerebral monoamine metabolism and their interactions with psychopharmacological drugs. Naunyn-Schmiedeberg's Arch. Pharmacol. 306, 135–146 (1979). https://doi.org/10.1007/BF00498983

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