Abstract
Purpose: The present study assessed the effects of the GABAA receptor (R) agonist muscimol (MUS), and the GABAAR antagonist bicuculline (BIC) on neocortical and subcortical radioligand binding to dopamine D2/3Rs in relation to motor and exploratory behaviors in the rat.Methods: D2/3R binding was measured with small animal SPECT in baseline and after challenge with either 1 mg/kg MUS or 1 mg/kg BIC, using [123I]IBZM as radioligand. Motor/exploratory behaviors were assessed for 30 min in an open field prior to radioligand administration. Anatomical information was gained with a dedicated small animal MRI tomograph. Based on the Paxinos rat brain atlas, regions of interest were defined on SPECT-MRI overlays. Estimations of the binding potentials in baseline and after challenges were obtained by computing ratios of the specifically bound compartments to the cerebellar reference region.Results: After MUS, D2/3R binding was significantly reduced in caudateputamen, nucleus accumbens, thalamus, substania nigra/ventral tegmental area, and posterior hippocampus relative to baseline (0.005 ≤ p ≤ 0.012). In all these areas, except for the thalamus, D2/3R binding was negatively correlated with grooming in the first half and positively correlated with various motor/exploratory behaviors in the second half of the testing session. After BIC, D2/3R binding was significantly elevated in caudateputamen (p = 0.022) and thalamus (p = 0.047) relative to baseline. D2/3R binding in caudateputamen and thalamus was correlated negatively with sitting duration and sitting frequency and positively with motor/exploratory behaviors in the first half of the testing time.Conclusions: Findings indicate direct GABAergic control over nigrostriatal and mesolimbic dopamine levels in relation to behavioral action. This may be of relevance for neuropsychiatric conditions such as anxiety disorder and schizophrenia, which are characterized by both dopaminergic and GABAergic dysfunction.
Highlights
In the nigrostriatal system, the neostriatum or caudateputamen (CP) receives glutamatergic (GLUergic) afferents from neocortex [motor cortex (MC), somatosensory cortex, frontal cortex (FC), prefronal cortex (PFC)] and thalamus (THAL; Johnson et al, 1968; Jones et al, 1977; Künzle, 1977; Jayaraman, 1985) as well as dopaminergic (DAergic) afferents from the pars compacta of the substantia nigra (SNc; Gerfen et al, 1987)
After MUS (Figure 2), binding potentials (BPs) were significantly reduced in CP (−17%, p = 0.005), nucleus accumbens (NAC) (−20%, p = 0.012), posterior hippocampus (pHIPP) (−19%, p = 0.022), SN/ventral tegmental area (VTA) (−22%, p = 0.008), and THAL (−20%, p = 0.028) relative to BASMUS
There were no differences between BASMUS and MUS in FC, MC, parietal cortex (PC), anterodorsal hippocampus (aHIPP), and CER (0.108 ≤ p ≤ 0.433)
Summary
The neostriatum or caudateputamen (CP) receives glutamatergic (GLUergic) afferents from neocortex [motor cortex (MC), somatosensory cortex, frontal cortex (FC), prefronal cortex (PFC)] and thalamus (THAL; Johnson et al, 1968; Jones et al, 1977; Künzle, 1977; Jayaraman, 1985) as well as dopaminergic (DAergic) afferents from the pars compacta of the substantia nigra (SNc; Gerfen et al, 1987). From the CP, GABAergic projections run either directly or via the external part of the globus pallidus (GPe) and the subthalamic nucleus (STN) to the internal part of the globus pallidus (GPi) and to the pars reticulata of the SN (SNr). From GPi and SNr, further GABAergic efferents project to THAL (ventral anterior, ventrolateral, dorsomedial, and centromedian nucleus), pedunculopontine nucleus, inferior and superior colliculus, and periaqueducatal gray (Kuo and Carpenter, 1973; Graybiel and Ragsdale, 1979; Herkenham, 1979; Coimbra and Brandao, 1993). The NAC receives GABAergic input from the PFC (Lee et al, 2014), and, in turn, sends GABAergic efferents back to the VTA as well as to the ventral GP and from the GP to the dorsomedial thalamic nucleus (Ueki et al, 1977; Yamamoto et al, 1983). The THAL, in turn, sends GLUergic efferents to MC, FC, PFC, and CING
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