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Time course of bromocriptine induced excitation in the rat: behavioural and biochemical studies.

Abstract

The aim of the present study was to further investigate the behavioural and biochemical pharmacology of the directly acting dopamine (DA) receptor agonist bromocriptine (BRC). BRC produced an initial depression of locomotion followed after about an hour by a weak but significant locomotor stimulation. The stimulation was potentiated by concomitant administration of the D1 agonist SKF38393. Ex vivo biochemical determinations indicated that reductions in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels occurred in the striatum after BRC injection without a significant change in DA levels, indicating a reduced DA turnover. An increase in 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid (5HIAA) levels occurred in the striatum leading to a significant increase in turnover (i.e. ratio of 5HIAA to 5HT). Noradrenaline concentrations increased in the striatum. In the cortex, sharp falls in HVA and DOPAC levels without a corresponding change in DA were observed. While there was no significant change in noradrenaline levels in this brain region, an increase in 5HIAA, but not in 5HT, levels occurred. These changes indicate an increase in 5HT turnover (ratio of 5HIAA to 5HT). In vivo dialysis indicated that extracellular levels of DA, DOPAC and HVA in the striata of freely moving rats were sharply reduced for at least 6 h after injection. In vitro binding studies showed that BRC exhibited high (Ki values in low nanomolar range) affinities for DA D2A, D2B, D3, alpha 1 and alpha 2 adrenergic receptors together with unexpectedly high affinity (about 1 nM) for 5HT1A receptors. The data indicate that the initial behavioural depression and later locomotor stimulation induced by BRC are accompanied by a sharp monophasic fall in striatal extracellular DA levels as indicated by dialysis studies. Since the behavioural stimulation was augmented by concomitant D1 receptor stimulation, the data suggest that the reduced DA turnover is influencing the amount of DA available to stimulate postsynaptic D1 receptors. However, the biochemical studies indicated that BRC has a high affinity for 5HT1A receptors and affects the turnover of 5HT in the brain. Thus, the behavioural effects of BRC may depend not only on effects on the DA system but also on 5HT systems.

Authors+Show Affiliations

Department of Behavioural and Biochemical Pharmacology, CNS Preclinical Research and Development, Astra Arcus AB, Södertälje, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

7539523

Citation

Jackson, D M., et al. "Time Course of Bromocriptine Induced Excitation in the Rat: Behavioural and Biochemical Studies." Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 351, no. 2, 1995, pp. 146-55.
Jackson DM, Mohell N, Georgiev J, et al. Time course of bromocriptine induced excitation in the rat: behavioural and biochemical studies. Naunyn Schmiedebergs Arch Pharmacol. 1995;351(2):146-55.
Jackson, D. M., Mohell, N., Georgiev, J., Bengtsson, A., Larsson, L. G., Magnusson, O., & Ross, S. B. (1995). Time course of bromocriptine induced excitation in the rat: behavioural and biochemical studies. Naunyn-Schmiedeberg's Archives of Pharmacology, 351(2), pp. 146-55.
Jackson DM, et al. Time Course of Bromocriptine Induced Excitation in the Rat: Behavioural and Biochemical Studies. Naunyn Schmiedebergs Arch Pharmacol. 1995;351(2):146-55. PubMed PMID: 7539523.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Time course of bromocriptine induced excitation in the rat: behavioural and biochemical studies. AU - Jackson,D M, AU - Mohell,N, AU - Georgiev,J, AU - Bengtsson,A, AU - Larsson,L G, AU - Magnusson,O, AU - Ross,S B, PY - 1995/2/1/pubmed PY - 1995/2/1/medline PY - 1995/2/1/entrez SP - 146 EP - 55 JF - Naunyn-Schmiedeberg's archives of pharmacology JO - Naunyn Schmiedebergs Arch. Pharmacol. VL - 351 IS - 2 N2 - The aim of the present study was to further investigate the behavioural and biochemical pharmacology of the directly acting dopamine (DA) receptor agonist bromocriptine (BRC). BRC produced an initial depression of locomotion followed after about an hour by a weak but significant locomotor stimulation. The stimulation was potentiated by concomitant administration of the D1 agonist SKF38393. Ex vivo biochemical determinations indicated that reductions in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels occurred in the striatum after BRC injection without a significant change in DA levels, indicating a reduced DA turnover. An increase in 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid (5HIAA) levels occurred in the striatum leading to a significant increase in turnover (i.e. ratio of 5HIAA to 5HT). Noradrenaline concentrations increased in the striatum. In the cortex, sharp falls in HVA and DOPAC levels without a corresponding change in DA were observed. While there was no significant change in noradrenaline levels in this brain region, an increase in 5HIAA, but not in 5HT, levels occurred. These changes indicate an increase in 5HT turnover (ratio of 5HIAA to 5HT). In vivo dialysis indicated that extracellular levels of DA, DOPAC and HVA in the striata of freely moving rats were sharply reduced for at least 6 h after injection. In vitro binding studies showed that BRC exhibited high (Ki values in low nanomolar range) affinities for DA D2A, D2B, D3, alpha 1 and alpha 2 adrenergic receptors together with unexpectedly high affinity (about 1 nM) for 5HT1A receptors. The data indicate that the initial behavioural depression and later locomotor stimulation induced by BRC are accompanied by a sharp monophasic fall in striatal extracellular DA levels as indicated by dialysis studies. Since the behavioural stimulation was augmented by concomitant D1 receptor stimulation, the data suggest that the reduced DA turnover is influencing the amount of DA available to stimulate postsynaptic D1 receptors. However, the biochemical studies indicated that BRC has a high affinity for 5HT1A receptors and affects the turnover of 5HT in the brain. Thus, the behavioural effects of BRC may depend not only on effects on the DA system but also on 5HT systems. SN - 0028-1298 UR - https://www.unboundmedicine.com/medline/citation/7539523/Time_course_of_bromocriptine_induced_excitation_in_the_rat:_behavioural_and_biochemical_studies_ L2 - https://www.lens.org/lens/search?q=citation_id:7539523 DB - PRIME DP - Unbound Medicine ER -