Neurotransmitter Interactions In The Substantia Nigra And In The Neostriatum Following Nigral Grafts
Date of Award
Doctor of Philosophy
Direct synaptic contact between substance P (SP)-immunoreactive terminals and glutamic acid decarboxylase (GAD)-positive neurons was more often observed in the substantia nigra pars lateralis (SNL) than in the substantia nigra pars reticulata (SNR) and was rarely observed in the substantia nigra pars compacta (SNC). Substance P terminals also formed synapses with cell bodies and dendrites of tyrosine hydroxylase (TH)-positive, dopaminergic neurons in the SNC and SNR. Multiple SP terminals were often observed with symmetrical and, less frequently, asymmetrical synapses on individual TH-containing dendrites. Evidence of SP-containing terminals contacting both GABAergic and dopaminergic neurons in the substantia nigra suggests a direct excitatory control on nigral neurons.;Glutamic acid decarboxylase (GAD)-containing terminals formed symmetrical synaptic contacts, with TH-immunoreactive neurons in the SNC and SNR. Neurons that contained GAD also received a GABAergic input in the SNR and SNL. The proportion of GAD-GAD contacts appeared to be highest in the SNL where virtually all GAD positive terminals were found to be in synaptic contact with, or apposed to, GAD positive profiles. A large, presumably inhibitory, GABAcrgic input onto nigral dopaminergic neurons and GABAergic neurons in the SNR and SNL was thus demonstrated. This GABAergic and SP influence which is ostensibly striatal and/or pallidal in origin is particularly prominent in relation to the SNL-mediated nigro-collicular pathway.;In the second part of the project, fetal substantia nigra cell suspensions were stereotactically implanted into the deafferented neostriatum of Wistar rats 2 weeks after a unilateral 6-hydroxydopamine (6-OHDA) lesion was placed in the ipsilateral substantia nigra or medial forebrain bundle (MFB). Striatal dopaminergic deafferentation resulted in pharmacologically-induced rotational asymmetry following the administration of apomorphine or amphetamine. Complete reversal of the rotational asymmetry was observed routinely in grafted animals up to twelve months post-grafting.;Graft-host interactions were studied by employing a double labeling technique. Tyrosine hydroxylase and SP-immunoreactive structures were simultaneously demonstrated in the host striatum. Tyrosine hydroxylase-immunoreactive terminals of axons originating from the grafted neurons made synaptic contacts with SP-positive cell bodies and dendrites from the host. These results indicate that at least partial restoration of the normal nigrostriatal circuitry is achieved following nigral grafts. The demonstration of synaptic input from grafted neurons onto host SP neurons provides an anatomical basis for direct functional modulation of the deafferented host neostriatum by the nigral graft.;It was next undertaken to investigate the expression of messenger ribonucleic acid (mRNA) that codes for enkephalin (ENK) and SP in lesioned rats with long term nigral grafts. Striatal dopamine depletion after nigral 6-OHDA lesions produced an increase in ipsilateral proenkephalin mRNA expression and a decrease in preprotachykinin mRNA expression. Twelve months following grafting, proenkephalin and preprotachykinin mRNA returned to near normal levels in contrast to control, nongrafted, lesioned animals. Reestablishment of the dopaminergic input thus appeared to restore regulation of proenkephalin and preprotachykinin mRNA in host striatal neurons.;The observed effects suggest graft-dependent restoration of damaged nigrostriatal circuitry and may reflect the mechanism by which grafts produce locomotor recovery in lesioned animals. (Abstract shortened by UMI.)
Mendez, Ivar Marcelo, "Neurotransmitter Interactions In The Substantia Nigra And In The Neostriatum Following Nigral Grafts" (1993). Digitized Theses. 2361.