Transmitter release from transplants of fetal ventral mesencephalon or locus coeruleus in the rat frontal cortex and nucleus accumbens: effects of pharmacological and behaviorally activating stimuli.
The present study was performed in order to establish whether dopamine (DA) release from behaviorally functional intracerebral DA transplants is dependent on changes in neuronal impulse flow, and is under control of the host brain. Rats were subjected to combined intraventricular and ventral tegmental injections of 6-hydroxydopamine (6-OHDA) in order to obtain a severe bilateral lesion of the ascending mesocorticolimbic DA projections. Cell suspension grafts of fetal ventral mesencephalic neurons were thereafter implanted into the medial frontal cortex (MFC) and the nucleus accumbens (NAc). Since the neurotoxin injections removed also the ascending noradrenergic systems, fetal locus coeruleus neurons were added to the graft suspension in one group of animals. Age-matched lesion-only and normal animals served as controls. The lesion-induced alterations in spontaneous, amphetamine- and apomorphine-induced locomotor activity and in a skilled paw reaching task were evaluated before transplantation, and at 3 and 6 months post-grafting. Microdialysis probes were finally implanted in the MFC and NAc in order to monitor extracellular DA and noradrenaline (NA) levels (i) during administration of pharmacological agents which augment or depress catecholamine release in the intact brain; (ii) during exposure of the rats to stressful manipulations (handling and immobilization) or appetitive stimuli (eating) known to enhance cortical and limbic DA or NA release in intact animals. The lesion-induced reduction in amphetamine-induced locomotor activity was reversed in all grafted animals, which also showed a higher than normal spontaneous overnight activity. Daytime spontaneous locomotor activity (which was reduced in the lesion-only rats) as well as apomorphine-induced hyperactivity was reversed by the grafts of DA neurons only. By contrast, the lesion-induced impairment in skilled forelimb use was not alleviated by the grafts. The grafted DA neurons restored normal steady-state DA overflow in the NAc, whereas they enhanced cortical DA overflow to significantly higher than normal levels. Restoration of both cortical and striatal NA overflow was observed in the group that received mixed DA and NA grafts, whereas animals that received DA grafts only did not differ from the lesioned controls. The changes in extracellular DA and NA levels measured in the grafted MFC and NAc under potassium depolarization (100 mM KCl), inhibition of terminal catecholamine reuptake (10 microM nomifensine), and sodium channel blockade (1 microM TTX) indicated that graft-derived DA or NA release had normal neuronal properties, and was dependent on an intact axonal impulse flow.(ABSTRACT TRUNCATED AT 400 WORDS)
Department of Medical Cell Research, University of Lund, Sweden.
M A
MA
Cenci
P
P
Kalén
W M
WM
Duan
A
A
Björklund
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001066:Appetite / Q000187:drug effects; D016380:Brain Tissue Transplantation / Q000502:physiology*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D016332:Fetal Tissue Transplantation / Q000502:physiology*; D005625:Frontal Lobe / Q000187:drug effects / Q000502:physiology*; D008125:Locus Coeruleus / Q000502:physiology / Q000637:transplantation*; D008636:Mesencephalon / Q000502:physiology / Q000637:transplantation*; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000637:transplantation; D009627:Nomifensine / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine / Q000633:toxicity; D011189:Potassium Chloride; D051381:Rats; D017207:Rats, Sprague-Dawley; D013681:Tegmentum Mesencephali / Q000187:drug effects / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D016042:Transplantation, Heterotopic
D009627:Nomifensine; D013779:Tetrodotoxin; D011189:Potassium Chloride; D016627:Oxidopamine; D001058:Apomorphine; D004298:Dopamine; D009638:Norepinephrine