Summary
Repeated doses of direct or indirect CNS stimulants are known to cause behavioral hyper sensitivity. The biochemical basis for hypersensitization remains unclear. Since the dopaminergic system uses a large storage pool that is only slowly mobilized to releasable sites, a change in this relationship may underlie the biochemical changes leading to increased responsiveness to stimulants. To test this hypothesis, rats were first tested with low doses of 2.5 mg/kg amphetamine or 1.0mg/kg amfonelic acid (AFA) for their locomotor response, then 5.0mg/kg amphetamine or 2.5mg/kg AFA were injected daily for 7 days and the rats retested with the lower doses of amphetamine or AFA, respectively. Both drugs produced hypersensitivity, but the cataleptic response to acute dopamine (DA) receptor blockade by haloperidol was unaltered. The ability of haloperidol to increase DA metabolism was unaltered and the ability of acute AFA to synergize with haloperidol was similar in the striatum of stimulant and saline treated rats, but reduced in the medial prefrontal cortex of both AFA and d-amphetamine treated rats. Additional rats had DA2 receptor sensitivity measured in the striatum and frontal cortex, but no significant differences were found. Only amphetamine caused a significant decrease in frontal cortex serotonin type 2 receptors. Since there was no alteration in the ability of AFA to increase neurogenic release of DA in the striatum and a decrease occurred in prefrontal cortex, an increase in the storage to functional pool exchange in the nigrostriatal and mesocortical DA containing neurons seems unlikely. In contrast, both the amphetamine and AFA treatment groups had their brain 5HT and 5HIAA levels reduced by about 50%. This suggests that changes in other transmitter systems may have a permissive effect allowing exaggerated responses to excessive DA release.
Similar content being viewed by others
References
Adell A, Sarna GS, Hutson PH, Curzon G (1989) An in vivo dialysis and behavioral study of the release of 5-HT by p-chloroamphetamine in reserpine treated rats. Br J Pharmacol 97: 206–212
Borison RL, Hitri A, Klawans HL, Diamond BI (1978) A new animal model for schizophrenia: behavioral and receptor binding studies. In: Usdin, Kopin IJ, Barchas J (eds) Catecholamines: basic and clinical frontiers. Pergamon Press, New York, pp 719–722
Carter CJ, Pycock CJ (1979) The effect of 5,7-dihydroxytryptamine lesions of extrapyramidal and mesolimbic sites on spontaneous motor behaviour and amphetamine-induced sterotypy. Naunyn-Schmiedebergs Arch Pharmacol 208: 51–54
Costall B, Naylor RJ, Marsden CD, Pycock CJ (1979) Serotonergic modulation of the dopamine response from the nucleus accumbens. J Pharm Pharmacol 28: 523–526
German DC, Harden H, Sanghera MK, Miller HH, Kiser RS, Shore PA (1979) Dopaminergic neuronal responses to a nonamphetamine CNS stimulant. J Neural Transm 44: 30–49
Howlett DR, Nahorski SR (1979) Acute and chronic amphetamine treatments modulate striatal dopamine receptor binding sites. Brain Res 161: 172–178
Hulme EC, Hill R, North M, Kibby MR (1974) Effects of chronic administration of drugs which modify neurotransmitter re-uptake, storage and turnover on levels of tyrosine and tryptophan hydroxylase in rat brain. Biochem Pharmacol 23: 1393–1404
Jackson DM, Bailey RC, Christie MJ, Crisp EA, Skerritt JH (1981) Long-term d-amphetamine in rats: lack of a change in postsynaptic dopamine receptor sensitivity. Psychopharmacology 73: 276–280
Leith NJ, Kuczenski R (1981) Chronic amphetamine: tolerance and reverse tolerance reflect different behavioral actions of the drug. Pharmacol Biochem Behav 15: 399–404
Lynch M, Kenny M, Leonard BE (1977) The effect of chronic administration of d-amphetamine on regional changes in catecholamines in the rat brain. J Neurosci Res 3: 292–300
Lyness WH, Moore KE (1981) Destruction of 5-hydroxytryptamine neurons and the dynamics of dopamine in nucleus accumbens septi and other forebrain regions in the rat. Neuropharmacology 20: 327–334
McMillen BA (1980) On the mechanism of morphine action on rat striatal dopamine metabolism. Biochem Pharmacol 29: 1432–1435
McMillen BA (1983) CNS stimulants; two distinct mechanism of action for amphetamine-like drugs. Trends Pharmacol Sci 4: 429–432
McMillen BA (1985) Acute and sub-chronic effects of MJ-13859, a potential antipsychotic drug, on rat brain dopaminergic neurotransmission. J Pharmacol Exp Ther 233: 369–375
McMillen BA, German DC, Shore PA (1980) Functional and pharmacological significance of brain dopamine and norepinephrine storage pools. Biochem Pharmacol 29: 3045–3050
McMillen BA, Scott SM, Williams HL, Sanghera MK (1987) Effect of gepirone, an arylpiperazine anxiolytic drug, on aggressive behavior and brain monoaminergic neurotransmission. Naunyn-Schmiedebergs Arch Pharmacol 335: 454–464
Nishikawa T, Mataga N, Takashima M, Toru M (1977) Behavioral sensitization and relative hyperresponsiveness of striatal and limbic dopaminergic neurons after repeated methamphetamine treatment. Eur J Pharmacol 88: 195–203
Riffee WH, Wilcox RE (1985) Effects of multiple pretreatment with apomorphine and amphetamine on amphetamine-induced locomotor activity and its inhibition by apomorphine. Psychopharmacology 85: 97–101
Robinson RE, Becker JB (1982) Behavioral sensitization is acompanied by an enhancement in amphetamine-stimulated dopamine release from striatal tissue in vitro. Eur J Pharmacol 85: 253–254
Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res Rev 11: 157–198
Shore PA (1976) Actions of amfonelic acid and other non-amphetamine stimulants on the dopamine neuron. J Pharm Pharmacol 28: 855–857
Shore PA, Dorris RL (1975) On a prime role for newly synthesized dopamine in striatal function. Eur J Pharmacol 30: 315–318
Taylor DL, Ho BT (1977) Neurochemical effects of cocaine following acute and repeated injections. J Neurosci Res 3: 95–101
Taylor DL, Ho BT, Fagan JD (1979) Increased receptor binding in rat brain by repeated cocaine injections. Comm Psychopharmacol 3: 137–142
Trulson ME, Jacobs BL (1979) Long-term amphetamine treatment decreases brain serotonin metabolism: implications for theories of schizophrenia. Science 205: 1295–1297
Waldmeier PC, Huber H, Heinrich M, Stoecklin K (1985) Discrimination of neuroleptics by means of their interaction with amfonelic acid: an attempt to characterize the test. Biochem Pharmacol 34: 39–44
Wilcox RE, Robinson TE, Becker JB (1986) Enduring enhancement in amphetamine-stimulated striatal dopamine release in vitro produced by prior exposure to amphetamine or stress in vivo. Eur J Pharmacol 124: 375–376
Zar JH (1984) Biostatistical analysis, 2nd edn. Prentice-Hall, Englewood Cliffs, NJ
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
McMillen, B.A., Scott, S.M. & Williams, H.L. Effects of subchronic amphetamine or amfonelic acid on rat brain dopaminergic and serotonergic function. J. Neural Transmission 83, 55–66 (1991). https://doi.org/10.1007/BF01244452
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01244452