Dopamine Effects in Substantia Nigra Reticulata

Matthews, Robert

Abstract

Dopamine (DA) neurons of the mammalian mesencephalon have been implicated in a variety of normal behaviors and in several mental illnesses. For example, animal experiments have suggested DA involvement in motor control, feeding, drinking, sleep, and learning. In addition, DA appears to play a key role in schizophrenia and some mood disorders such as depression. The actions of DA at DA nerve terminals and their post-synaptic receptors have been extensively studied, but recent evidence suggests an important role of DA neurotransmission at the level of DA neuron dendrites as well. DA is synthesized in and released from the dendritic trees of substantia nigra zona compacta DA neurons. DA dendrites are found in the compacta and also throughout the substantia nigra zona reticulata (SNR). DA in the SNR has been shown to increase spontaneous activity of non-DA nigrofugal neurons. The neurophysiology of DA neurotransmission in the SNR is the focus of this proposal. Three types of DA receptors have been found in the substantia nigra: autoreceptors on DA neurons, D-2 type receptors on SNR neurons and D-1 type receptors on striatonigral terminals. Recent data from this laboratory suggest that the excitatory effect of DA on SNR neurons is mediated by a D-1 receptor. Since D-1 receptors are found only on striatonigral nerve terminals, the hypothesis to be tested is that DA modulates the activity of SNR neurons indirectly by effecting the release of neurotransmitter from striatonigral nerve terminals. This hypothesis will be tested with single neuron recording and microiontophoretic techniques in rats with lesions or pharmacological blockade of the nigrostriatal pathway. More specifically, DA will be microiontophoresed onto single SNR neurons and changes in spontaneous firing rates will be monitored by standard unit recording techniques. Striatonigral neurotransmission will be blocked by either 1) electrolytic lesions of descending fibers, 2) destruction of striatal neurons with neurotoxin, or 3) systemic administration of receptor antagonists to striatonigral neurotransmitters. Attenuation of DA excitation of SNR neurons by these treatments will suggest that stimulation of D-1 receptors on striatonigral nerve terminals modulates nigral efferent activity. This study will expand our knowledge about the effects of DA in the SNR and will contribute to the long-term goals of this laboratory in understanding the role of the basal ganglia and DA in mental illness and tardive dyskinesia.