Regulation of the synthesis and metabolism of striatal dopamine after disruption of nerve conduction in the medial forebrain bundle.
1. After physical (knife-cut) or chemically-mediated (tetrodotoxin 300 nM, 1.5 microliters; 1.0 microliters min-1) interruption of nerve conduction in the nigrostriatal tract, there was a marked increase in the synthesis and metabolism of dopamine in the isolated dopaminergic nerve terminals of the striatum. The effect peaked at 4 h post-transection, at which time 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were increased by 300% and 700% respectively (DOPAC: 27 +/- 13 vs 80 +/- 17 nmol g-1; HVA: 6.66 +/- 3.57 vs 54 +/- 18 nmol g-1). The increases in dopamine content and metabolism are secondary to an increase in the rate of synthesis on the lesioned side, versus the intact, control side. 2. In both experimental situations, haloperidol (1.0 mg kg-1, i.p.) retained its known ability to induce a significant increase in DOPAC and HVA in the striatum, despite the interruption of nerve conduction in the nigrostriatal tract. 3. Six days after cutting the left nigrostriatal tract, dopamine in the left striatum was reduced to less than 5% of the control value, and DOPAC and HVA were not detectable. In the denervated, left striatum, the synthesis of dopamine (from injected L-DOPA), and its metabolism to DOPAC and HVA, occurred to the same degree as in the intact right side. In these DOPA-treated rats, haloperidol (1.0 mg kg-1, i.p.) caused a further increase in DOPAC and HVA in the intact striatum, but not in the denervated striatum. 4. Under non-stressful conditions, using a combination of anaesthetic treatments, electrical stimulation (400 muA, 0.4 ins, 15 Hz, 15 min) of the nigrostriatal tract did not increase DOPAC or HVA in the striatum on the stimulated side. 5. It is concluded (a) that there is a significant presynaptic, and/or local circuit mechanism capable of activating the synthesis and metabolism of dopamine in the isolated, striatal, dopaminergic nerve terminals. Furthermore, haloperidol can act directly on the striatal, dopaminergic nerve terminal, to cause an increase in the synthesis and metabolism of striatal dopamine. (b) After degeneration of the striatal dopaminergic nerves, the denervated striatum retains the ability to synthesize (from L-DOPA) and metabolize dopamine, to the same degree as the intact, innervated, contralateral striatum. (c) When stress is minimized, and release of dopamine is induced by electrical stimulation of the medial forebrain bundle, the catabolism of dopamine (to DOPAC and HVA) during the release-uptake cycle may not be a significant factor under physiological conditions. (d) When dopamine synthesis is increased in the striatum, the normal blood concentration of tyrosine is adequate to sustain the increased synthesis, and precursor availability is not a limiting factor. (e) These results suggest that some of the basic concepts about the neurochemical/neurophysiological regulation of monoaminergic neurones may require further reevaluation.
Commissiong
J W
JW
Department of Physiology, McGill University, Montreal, Quebec, Canada.
Slimovitch
C
C
Toffano
G
G
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism / Q000494:pharmacology; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002849:Chromatography, Gas; D003342:Corpus Striatum / Q000378:metabolism*; D003714:Denervation; D004298:Dopamine / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D006719:Homovanillic Acid / Q000494:pharmacology; D008474:Medial Forebrain Bundle / Q000166:cytology / Q000502:physiology*; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D009431:Neural Conduction; D051381:Rats; D011919:Rats, Inbred Strains; D013779:Tetrodotoxin / Q000494:pharmacology; D014443:Tyrosine / Q000494:pharmacology
D000777:Anesthetics; D015102:3,4-Dihydroxyphenylacetic Acid; D014443:Tyrosine; D013779:Tetrodotoxin; D006220:Haloperidol; D004298:Dopamine; D006719:Homovanillic Acid