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

Abstract

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.

Interactions between neurotransmitter systems in nigrostriatal structures of rat brain after long-term administration of reserpine and haloperidol

“…Typical neuroleptics, including haloperidol, are known to increase acetylcholine content in the striatum via blockage of D2 dopamine receptors [5,17,18]. The inhibition of acetylcholine degradation, which we found in the present study, may indicate an increase in cholinergic transmission.…”

“…cholinergic system of the striatum via at least two pathways: it decreases acetylcholine release due to the activation of D2 receptors and, simultaneously, enhances neurotransmitter release due to the activa tion of D1 receptors [17]. The absence of an effect of reserpine on AChE activity in the caudate nucleus was probably due to an equal decrease in the activation of both the D2 and D1 receptors, which influence the activity of cholinergic neurons in opposite ways.…”

The scientific and clinical basis for the treatment of Parkinson disease (2009)

“…453 Cholinergic interneurons in the striatum bear D1 and D5 dopamine receptors 454 and exert powerful effects on the excitability of MSNs and dopaminergic function. [455][456][457] The precise mechanism of action of anticholinergic drugs in PD is not known, and it is possible that enhanced benefits with a better safety profile could be obtained with antagonists of muscarinic cholinergic receptor subtypes.…”

Innervation of the substantia nigra

“…Indeed, evidence exists for an important role of intranigral D1 receptor-mediated mechanisms based on in vivo experiments in which intranigral injection of the D1 receptor agonist SKF38393 results in changes of locomotor activity (Abercrombie and DeBoer 1997). There is a second retrograde signal, because endocannabinoids released from GABA and dopamine neurons act to reduce GABA release (Yanovsky et al 2003).…”