3H-SCH 23390 binding sites in the rat substantia nigra: Evidence for a presynaptic localization and innervation by dopamine

183

172

Methamphetamine (METH) has been shown to increase the extracellular concentrations of both dopamine (DA) and glutamate (GLU) in the striatum. Dopamine, glutamate, or their combined effects have been hypothesized to mediate striatal DA nerve terminal damage. Although it is known that METH releases DA via reverse transport, it is not known how METH increases the release of GLU. We hypothesized that METH increases GLU indirectly via activation of the basal ganglia output pathways. METH increased striatonigral GABAergic transmission, as evidenced by increased striatal GAD65 mRNA expression and extracellular GABA concentrations in substantia nigra pars reticulata (SNr). The METH-induced increase in nigral extracellular GABA concentrations was D1 receptor-dependent because intranigral perfusion of the D1 DA antagonist SCH23390 (10 M) attenuated the METH-induced increase in GABA release in the SNr. Additionally, METH decreased extracellular GABA concentrations in the ventromedial thalamus (VM). Intranigral perfusion of the GABA-A receptor antagonist, bicuculline (10 M), blocked the METH-induced decrease in extracellular GABA in the VM and the METHinduced increase in striatal GLU. Intranigral perfusion of either a DA D1 or GABA-A receptor antagonist during the systemic administrations of METH attenuated the striatal DA depletions when measured 1 week later. These results show that METH enhances D1-mediated striatonigral GABAergic transmission (1), which in turn activates GABA-A receptors in the SNr (2), leading to a decrease in GABAergic nigrothalamic activity (3), an increase in corticostriatal GLU release (4), and a consequent long-term depletion of striatal DA content (5).

Section: Discussionmentioning

confidence: 99%

High-Dose Methamphetamine Acutely Activates the Striatonigral Pathway to Increase Striatal Glutamate and Mediate Long-Term Dopamine Toxicity

Mark¹,

Soghomonian²,

Yamamoto³

2004

183

172

“…In rats with 6-OHDA SN, lesions, administration of SKF-38393 results in contralateral receptors in the EP and SN, are located on the terminals of rotation indistinguishable from that produced by apomorphine afferents from the striatum (Altar et al, 1986;Barone and Chase, or L-DOPA (Setler et al, 1978). Recent work has suggested that 1986; Porceddu et al, 1986;Wamsley et al, 1986). What might both the locomotor activity and self-mutilating behavior inbe the physiological role for these D, receptors?…”

Section: Discussionmentioning

confidence: 99%

Selective D1 and D2 dopamine agonists differentially alter basal ganglia glucose utilization in rats with unilateral 6-hydroxydopamine substantia nigra lesions

Trugman¹,

Wooten²

1987

153

he relative roles of D1 and D2 dopamine receptor stimulation in mediating the antiparkinsonian effects of dopaminergic drugs remain unclear. To determine the functional metabolic consequences of selective dopamine receptor stimulation, we used 2-deoxyglucose (2-DG) autoradiography to examine the effects of the D1 agonist SKF-38393 and the D2 agonist LY-171555 on regional cerebral glucose utilization (RCGU) in rats with unilateral 6-hydroxydopamine (6-OHDA) substantia nigra lesions. SKF-38393 (0.5-25.0 mg/kg) and LY-171555 (0.01-5.0 mg/kg) produced indistinguishable behavioral responses, including vigorous contralateral rotation. Treatment with each drug similarly increased glucose utilization, dose-dependently, in the parafascicular thalamus, subthalamic nucleus, deep layers of the superior colliculus, and lateral midbrain reticular formation ipsilateral to the nigral lesion; glucose utilization was decreased in the ipsilateral lateral habenula. By contrast, the D1 and D2 agonists differentially altered glucose utilization in the entopeduncular nucleus (EP) and the substantia nigra pars reticulata (SNr). SKF-38393, 5.0 and 25.0 mg/kg, increased glucose utilization 127 and 275%, respectively, in the pars reticulata ipsilateral to the lesion. LY-171555, 1.0 and 5.0 mg/kg, caused maximal contralateral turning, yet did not alter glucose utilization in the ipsilateral SNr. The glucose utilization response of the ipsilateral EP paralleled that of the SNr demonstrating large increases following administration of SKF-38393 and minimal change following the use of LY-171555. The results demonstrate that the selective D1 agonist reproduces the marked glucose utilization increases (2-3-fold above control values) in the EP and SNr that were previously observed using L-DOPA and apomorphine in this model, whereas the selective D2 agonist does not.(ABSTRACT TRUNCATED AT 250 WORDS)

“…The somatodendritic release of dopamine within substantia nigra is well known (Korf et al, 1976;Chéramy et al, 1981;Robertson et al, 1991;Heeringa and Abercrombie, 1995), and the substantia nigra pars reticulata possesses a density of D 1 receptors that is among the highest of that of any brain region (Savasta et al, 1986;Dawson et al, 1988). Nigral D 1 receptors are localized exclusively on the terminals of the GABAergic striatonigral projection (Porceddu et al, 1986;Yung et al, 1995), and stimulation of these receptors seems to modulate positively the release of GABA from these sites (Floran et al, 1990;C ameron and Williams, 1993). In turn, an enhanced inhibitory drive to the GABAergic nigrothalamic projection neurons could disinhibit thalamocortical activity (Deniau and Chevalier, 1985;Timmerman and Abercrombie, 1996) and increase the level of glutamate input to striatal cholinergic neurons.…”

Section: Dopamine D 1 Receptor; In Vivo Microdialysismentioning

confidence: 99%

Substantia Nigra D₁Receptors and Stimulation of Striatal Cholinergic Interneurons by Dopamine: A Proposed Circuit Mechanism

Abercrombie

Deboer

1997

Dopamine release can regulate striatal acetylcholine efflux in vivo through at least two receptor mechanisms: (1) direct inhibition by dopamine D 2 receptors on the cholinergic neurons, and (2) excitation initiated by dopamine D 1 receptors. The neuroanatomical locus of the latter population of D 1 receptors and the pathway(s) involved in the expression of their influence are controversial issues. We have tested the hypothesis that D 1 receptors in substantia nigra pars reticulata are involved in the excitatory component of dopaminergic actions on striatal acetylcholine output. In vivo microdialysis was used in awake rats. Infusion of the selective D 1 receptor agonist R(ϩ)-1-Phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol (SKF 38393) hydrochloride into pars reticulata of substantia nigra elicited a significant increase in striatal acetylcholine efflux. Likewise, D-amphetamine applied into pars reticulata of substantia nigra by reverse dialysis produced an elevation in acetylcholine output measured at a second microdialysis probe in the striatum. Application of D-amphetamine in the striatum by reverse dialysis elicited a decrease in striatal acetylcholine efflux that could be reversed subsequently by local application of Damphetamine in substantia nigra pars reticulata. A 2 mg/kg intraperitoneal dose of D-amphetamine, which has no net effect on striatal acetylcholine output under control conditions, elicited a significant decrease in acetylcholine efflux when the D 1 receptor antagonist R(ϩ)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390) hydrochloride was applied simultaneously via a second microdialysis probe in substantia nigra pars reticulata. Thus, an excitatory D 1 -mediated influence on striatal acetylcholine output is initiated in substantia nigra pars reticulata, and this influence contributes to the effects of indirect dopaminergic agonists such as D-amphetamine on striatal acetylcholine efflux. These results indicate an important role of somatodendritic dopamine release, in addition to nerve terminal dopamine release, in the regulation of activity in basal ganglia circuits.