Skip to main content
SpringerLink
Log in

The 5-HT1A receptor antagonist (S)-UH-301 decreases dopamine release in the rat nucleus accumbens and striatum

  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Summary

In this study we employed in vivo microdialysis to examine the effects of the selective 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-UH-301] on extracellular concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens (NAC) and dorsal striatum of awake freely moving rats. Systemic administration of (S)-UH-301 (1.25, 2.5, 5.0mg/kg s.c.) dose-dependently decreased extracellular concentrations of DA, DOPAC and HVA in the NAC. (S)-UH-301 (2.5mg/kg s.c.) also decreased DA, but not DOPAC and HVA, concentrations in the striatum. Infusion of low concentrations (1, 10 μM) of (S)-UH-301 into either the NAC or the striatum did not affect DA levels, while only the highest concentration (1,000 μM) significantly decreased DA levels in both areas. Similarly, infusion of the selective 5-HT1A receptor agonist (R)-8-hydroxy-2-(di-n-propylamino)tetralin [(R)-S-OH-DPAT] only in high concentrations (100, 1,000 μM) decreased DA levels in both regions. These data suggest that (S)-UH-301 decreases DA release both in the NAC and the striatum probably indirectly via its purported DA-D2/D3 receptor agonistic properties. However, the observed inhibitory effect of (S)-UH-301 on DA release in the studied brain regions may also be explained, at least partly, by a serotonergic influence on the DA systems, acting at 5-HT1A receptor sites located elsewhere in the brain.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Aghajanian GK, Bunney BS (1974) Dopaminergic and non-dopaminergic neurons of the substantia nigra: differential responses to putative transmitters. In: Boissier JR, Hippius H, Pichot P (eds) Proceedings, 9th International Congress of the C.I.N.P. Excerpta Medica, Amsterdam, pp 444–452

    Google Scholar 

  • Andén N-E, Nilsson H, Ros E, Thornström U (1983) Effects of B-HT 920 and B-HT 933 on dopamine and noradrenaline autoreceptors in the rat brain. Acta Pharmacol Toxicol 52: 51–56

    Google Scholar 

  • Arborelius L, Chergui K, Murase S, Nomikos GG, Backlund Höök B, Chouvet G, Hacksell U, Svensson TH (1993a) The 5-HT1A receptor selective ligands, (R)-8-OH-DPAT and (S)-UH-301, differentially affect the activity of midbrain dopamine neurons. Naunyn Schmiedebergs Arch Pharmacol 347: 353–362

    PubMed  Google Scholar 

  • Arborelius L, Nomikos GG, Hacksell U, Svensson TH (1993b) (R)-8-OH-DPAT preferentially increases dopamine release in rat medial prefrontal cortex. Acta Physiol Scand 148: 465–466

    PubMed  Google Scholar 

  • Arborelius L, Backlund Höök B, Hacksell U, Svensson TH (1994) The 5-HT1A receptor antagonist (S)-UH-301 blocks the (R)-8-OH-DPAT-induced inhibition of serotonergic dorsal raphe cell firing in the rat. J Neural Transm [Gen Sect] 96: 179–186

    Google Scholar 

  • Arborelius L, Nomikos GG, Grillner P, Hertel P, Backlund Höök B, Hacksell U, Svensson TH (1995) 5-HT1A receptor antagonists increase the activity of serotonergic cells in the dorsal raphe nucleus in rat treated acutely or chronically with citalopram. Naunyn Schmiedebergs Arch Pharmacol 352: 157–165

    PubMed  Google Scholar 

  • Arborelius L, Nomikos GG, Hertel P, Salmi P, Grillner P, Backlund Höök B, Hacksell U, Svensson TH (1996) The 5-HT1A receptor antagonist (S)-UH-301 augments the increase in extracellular concentrations of 5-HT in the frontal cortex produced by both acute and chronic treatment with citalopram. Naunyn Schmiedebergs Arch Pharmacol (in press)

  • Artigas F, Perez V, Alvarez E (1994) Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors. Arch Gen Psychiatry 51: 248–251

    PubMed  Google Scholar 

  • Benloucif S, Galloway MP (1991) Facilitation of dopamine release in vivo by serotonin agonists: studies with microdialysis. Eur J Pharmacol 200: 1–8

    PubMed  Google Scholar 

  • Benloucif S, Keegan MJ, Galloway MP (1993) Serotonin-facilitated dopamine release in vivo: pharmacological characterization. J Pharmacol Exp Ther 265: 373–377

    PubMed  Google Scholar 

  • Björk L, Cornfield LJ, Nelson DL, Hillver S-E, Andén N-E, Lewander T, Hacksell U (1991) Pharmacology of the novel 5-hydroxytryptamine1A receptor antagonist (S)-5-fluoro-2-(dipropylamino)-tetralin: inhibition of (R)-8-hydroxy-2 (dipropylamino)tetralin-induced effects. J Pharmacol Exp Ther 258: 58–65

    PubMed  Google Scholar 

  • Björk L, Fredriksson A, Hacksell U, Lewander T (1992) Effects of (R)-8-OH-DPAT and the enantiomers of UH-301 on motor activities in the rat: antagonism of (R)-8-OH-DPAT-induced effects. Eur Neuropsychopharmacol 2: 141–147

    PubMed  Google Scholar 

  • Blier P, Bergeron R (1995) Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression. J Clin Psychopharmacol 15: 217–222

    PubMed  Google Scholar 

  • Chen N-H, Reith MEA (1995) Monoamine interactions measured by microdialysis in the ventral tegmental area of rats treated systemically with (±)-8-hydroxy-2-(di-n-propylamino)tetralin. J Neurochem 64: 1585–1597

    PubMed  Google Scholar 

  • Clark D, Hjorth S, Carlsson A (1985) Dopamine-receptor agonists: mechanisms underlying autoreceptor selectivity. I. Review of evidence. J Neural Transm 62: 1–52

    PubMed  Google Scholar 

  • Consolazione A, Cuello AC (1982) CNS serotonin pathways. In: Osborne NN (ed) Biology of serotonergic transmission. John Wiley, Chichester, pp 29–61

    Google Scholar 

  • Cornfield LJ, Lambert G, Arvidsson L-E, Mellin C, Vallgårda J, Hacksell U, Nelson DL (1991) Intrinsic activity of enantiomers of 8-hydroxy-2-(di-n-propylamino)tetralin and its analogs at 5-hydroxytryptamine1A receptors that are negatively coupled to adenylate cyclase. Mol Pharmacol 39: 780–787

    PubMed  Google Scholar 

  • Damsma G, Bottema T, Westerink BHC, Tepper PG, Djikstra D, Pugsley TA, MacKenzie RG, Heffner TG, Wikström H (1993) Pharmacological aspects of R-(+)-7-OH-DPAT, a putative dopamine D3 receptor ligand. Eur J Pharmacol 249: R9-R10

    PubMed  Google Scholar 

  • De Boer P, Damsma G, Schram Q, Stoof JC, Zaagsma J, Westerink (1992) The effects of intrastriatal application of directly and indirectly acting dopamine agonists and antagonists on the in vivo release of acetylcholine measured by brain microdialysis. Naunyn Schmiedebergs Arch Pharmacol 345: 144–152

    PubMed  Google Scholar 

  • Di Chiara G (1990) Brain dialysis of neurotransmitters: a commentary. J Neurosci Meth 103: 343–350

    Google Scholar 

  • Dray A, Gonye TJ, Oakley NR, Tanner T (1976) Evidence for the existence of a raphe projection to the substantia nigra in rat. Brain Res 113: 45–57

    Google Scholar 

  • Gonon FG (1988) Nonlinear relationship between impulse flow and dopamine released by rat midbrain dopminergic neurons as studied by in vivo electrochemistry. Neuroscience 24: 19–28

    PubMed  Google Scholar 

  • Hervé D, Pickel VM, Joh TH, Beaudet A (1987) Serotonin axon terminals in the ventral tegmental area of the rat: fine structure and synaptic input to dopaminergic neurons. Brain Res 435: 71–83

    PubMed  Google Scholar 

  • Hillver S-E, Björk L, Li Y-L, Svensson B, Ross S, Andén N-E, Hacksell U (1990) (S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin: a putative 5-HT1A-receptor antagonist. J Med Chem 33: 1541–1544

    PubMed  Google Scholar 

  • Hjorth S, Sharp T (1991) Effects of the 5-HT1A receptor agonist 8-OH-DPAT on the release of 5-HT in dorsal and median raphe-innervated rat brain regions as measured by in vivo microdialysis. Life Sci 48: 1779–1786

    PubMed  Google Scholar 

  • Ichikawa J, Meltzer HY (1995) Effect of antidepressants on striatal and accumbens extracellular dopamine levels. Eur J Pharmacol 281: 255–261

    PubMed  Google Scholar 

  • Imperato A, Di Chiara G (1988) Effects of locally applied D-1 and D-2 receptor agonists and antagonists studied with brain dialysis. Eur J Pharmacol 156: 385–393

    Google Scholar 

  • Imperato A, Tanda G, Frau R, Di Chiara G (1988) Pharmacological profile of dopamine receptor agonists as studied by brain dialysis in behaving rats. J Pharmacol Exp Ther 245: 257–264

    PubMed  Google Scholar 

  • Kelland MD, Freeman AS, Chiodo LA (1990) Serotonergic afferent regulation of the basal physiology and pharmacological responsiveness of nigrostriatal dopamine neurons. J Pharmacol Exp Ther 253: 803–811

    PubMed  Google Scholar 

  • Kelland MD, Freeman AS, Rubin J, Chiodo LA (1993) Ascending afferent regulation of rat midbrain dopamine neurons. Brain Res Bull 31: 539–546

    PubMed  Google Scholar 

  • Le Moal M, Simon H (1991) Mesocorticolimbic dopaminergic network: functional and regulatory roles. Physiol Rev 71: 155–234

    PubMed  Google Scholar 

  • Miquel M-C, Doucet E, Boni C, El Mestikawy S, Matthiessen L, Daval G, Verge D, Hamon M (1991) Central serotonin1A receptors: respective distributions of encoding mRNA, receptor protein and binding sites by in situ hybridisation histochemistry, radioimmunohistochemistry and autoradiographic mapping in the rat brain. Neurochem Int 19: 453–465

    Google Scholar 

  • Nedergaard S, Bolam JP, Greenfield SA (1988) Facilitation of a dendritic calcium conductance by 5-hydroxytryptamine in the substantia nigra. Nature 333: 174–177

    PubMed  Google Scholar 

  • Nedergaard S, Flatman JA, Engberg I (1991) Excitation of substantia nigra pars compacta neurones by 5-hydroxytryptamine in-vitro. NeuroReport 2: 329–332

    PubMed  Google Scholar 

  • Nomikos GG, Damsma G, Wenkstern D, Fibiger HC (1989) Acute effects of bupropion on extracellular dopamine concentrations in rat striatum and nucleus accumbens studied by in vivo microdialysis. Neuropsychopharmacology 2: 273–281

    PubMed  Google Scholar 

  • Nomikos GG, Damsma G, Wenkstern D, Fibiger HC (1991) Chronic desipramine enhances amphetamine-induced increases in interstital concentrations of dopamine in the nucleus accumbens. Eur J Pharmacol 195: 63–73

    PubMed  Google Scholar 

  • Nomikos GG, Arborelius L, Svensson TH (1992) The novel 5-HT1A receptor antagonist (S)-UH-301 prevents (R)-8-OH-DPAT-induced decrease in interstitial concentrations of serotonin in the rat hippocampus. Eur J Pharmacol 216: 373–378

    PubMed  Google Scholar 

  • Parsons LH, Justice JB Jr (1993) Perfusate serotonin increases extracellular dopamine in the nucleus accumbens as measured by in vivo microdialysis. Brain Res 606: 195–199

    PubMed  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, Sydney

    Google Scholar 

  • Pazos A, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res 346: 205–230

    PubMed  Google Scholar 

  • Pellegrino LJ, Pellegrino AS, Cushman AJ (1979) A stereotaxic atlas of the rat brain. Plenum, New York

    Google Scholar 

  • Perry KW, Fuller RW (1992) Effect of fluoxetine on serotonin and dopamine concentration in microdialysis fluid from rat striatum. Life Sci 50: 1683–1690

    PubMed  Google Scholar 

  • Pessia M, Jiang Z-G, North RA, Johnson SW (1994) Actions of 5-hydroxytryptamine on ventral tegmental area neurons of the rat in vitro. Brain Res 654: 324–330

    PubMed  Google Scholar 

  • Rasmusson AM, Goldstein LE, Deutch AY, Bunney BS, Roth RH (1994) 5-HT1A agonist ±8-OH-DPAT modulates basal and stress-induced changes in medial prefrontal cortical dopamine. Synapse 18: 218–224

    PubMed  Google Scholar 

  • Smith CFC, Cutts S (1990) Dopamine agonist activity of 8-OH-DPAT. Arch Int Pharmacodyn 306: 106–113

    PubMed  Google Scholar 

  • Tanda G, Carboni E, Frau R, Di Chiara G (1994) Increase of extracellular dopamine in the prefrontal cortex: a trait of drugs with antidepressant potential? Psychopharmacology 115: 285–288

    PubMed  Google Scholar 

  • Timmerman W, Tepper PG, Dijkstra D, Stoelwinder H, Grol CJ, Westerink BHC, Horn AS (1991) Enantiomers of monohydroxy-2-aminotetralin derivatives and their activity at dopamine autoreceptors as studied by brain dialysis. Eur J Pharmacol 199: 145–151

    PubMed  Google Scholar 

  • Yadid G, Pacak K, Kopin IJ, Goldstein DS (1994) Endogenous serotonin stimulates striatal dopamine release in conscious rats. J Pharmacol Exp Ther 270: 1158–1165

    PubMed  Google Scholar 

  • Zetterström T, Ungerstedt U (1984) Effects of apomorphine on the in vivo release of dopamine and its metabolites, studied by brain dialysis. Eur J Pharmacol 97: 29–36

    Google Scholar 

  • Zis AP, Nomikos GG, Damsma G, Fibiger HC (1991) In vivo neurochemical effects of electroconvulsive shock studied by microdialysis in the rat striatum. Psychopharmacology 103: 343–350

    PubMed  Google Scholar 

Download references

Author information

Author notes

  1. T. H. Svensson

    Present address: Department of Physiology and Pharmacology, Division of Pharmacology, Karolinska Institutet, Stockholm

Authors and Affiliations

  1. Department of Physiology and Pharmacology, Division of Pharmacology, Karolinska Institutet, Stockholm

    G. G. Nomikos & L. Arborelius

  2. Department of Organic Pharmaceutical Chemistry, Uppsala University, Uppsala, Sweden

    B. Backlund Höök & U. Hacksell

Authors
  1. G. G. Nomikos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Arborelius
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. Backlund Höök
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. U. Hacksell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. H. Svensson
    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

Nomikos, G.G., Arborelius, L., Höök, B.B. et al. The 5-HT1A receptor antagonist (S)-UH-301 decreases dopamine release in the rat nucleus accumbens and striatum. J. Neural Transmission 103, 541–554 (1996). https://doi.org/10.1007/BF01273152

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01273152

Keywords

Search

Navigation