Paleocerebellar stimulation induces in vivo release of endogenously synthesized [3H]dopamine and [3H]norepinephrine from rat caudal dorsomedial nucleus accumbens

Dempesy, Colby W.; Richardson, Donald E.

doi:10.1016/0306-4522(87)90142-4

Cited by 9 publications

(4 citation statements)

References 22 publications

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“…The cerebellum is critical to motor coordination (Manto & Oulad Ben Taib, 2013) and may compensate for the loss of basal ganglia inputs to cortex in Parkinson’s disease (Martinu & Monchi, 2013). Lesions of the cerebellum caused upregulation of dopamine D1 receptors in the basal ganglia and electrical stimulation of the cerebellum affects dopaminergic signaling in the midbrain and striatum (Dempsey & Richardson, 1987; Nieoullon & Dusticier, 1980), suggesting a dopaminergic process in this cerebellar mechanism. Recent research also indicates an important role of the cerebellum in cognitive functioning (Koziol, Budding, & Chidekel, 2012; Leiner, Leiner, & Dow, 1986; Stoodley, 2012), such as “training” frontal cortices in anticipating behavioral outcomes (Koziol et al, 2012) and facilitating prefrontal cortical processes in decision making (Cisek & Kalaska, 2005), processes that involve catecholamines and saliency processing (Hershey et al, 2004; Kelly et al, 2009; Rogers et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

The effects of methylphenidate on cerebral activations to salient stimuli in healthy adults.

Farr¹,

Hu²,

Matuskey³

et al. 2014

Experimental and Clinical Psychopharmacology

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Detection of a salient stimulus is critical to cognitive functioning. A stimulus is salient when it appears infrequently, carries high motivational value, and/or when it dictates changes in behavior. Individuals with neurological conditions that implicate altered catecholaminergic signaling, such as those with attention deficit hyperactivity disorder, are impaired in detecting salient stimuli, a deficit that can be remediated by catecholaminergic medications. However, the effects of these catecholaminergic agents on cerebral activities during saliency processing within the context of the stop signal task are not clear. Here, we examined the effects of a single oral dose (45 mg) of methylphenidate in 24 healthy adults performing the stop signal task during functional magnetic resonance imaging (fMRI). Compared to 92 demographically matched adults who did not receive any medications, the methylphenidate group showed higher activations in bilateral caudate head, primary motor cortex, and the right inferior parietal cortex during stop as compared to go trials (p<0.05, corrected for family-wise error of multiple comparisons). These results show that methylphenidate enhances saliency processing by promoting specific cerebral regional activities. These findings may suggest a neural basis for catecholaminergic treatment of attention disorders.

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Section: Discussionmentioning

confidence: 99%

The effects of methylphenidate on cerebral activations to salient stimuli in healthy adults.

Farr¹,

Hu²,

Matuskey³

et al. 2014

Experimental and Clinical Psychopharmacology

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“…However, the cerebellum also communicates with brain regions specifically associated with EtOH reward, including the ventral tegmental area (VTA) (Ikai et al 1992(Ikai et al , 1994Mittleman et al 2008;Rogers et al 2011Rogers et al , 2013, amygdala (Tomasi and Volkow 2011), and nucleus accumbens (Dempsey and Richardson 1987). Connections to the VTA are particularly intriguing because electrical stimulation of Purkinje cells (the sole output of the cerebellar cortex) significantly increases dopamine release in the prefrontal cortex, with~50% of the release being from the VTA (Mittleman et al 2008;Rogers et al 2011Rogers et al , 2013.…”

Section: Discussionmentioning

confidence: 99%

Recreational concentrations of alcohol enhance synaptic inhibition of cerebellar unipolar brush cells via pre- and postsynaptic mechanisms

Richardson

Rossi

2017

Journal of Neurophysiology

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Variation in cerebellar sensitivity to alcohol/ethanol (EtOH) is a heritable trait associated with alcohol use disorder in humans and high EtOH consumption in rodents, but the underlying mechanisms are poorly understood. A recently identified cellular substrate of cerebellar sensitivity to EtOH, the GABAergic system of cerebellar granule cells (GCs), shows divergent responses to EtOH paralleling EtOH consumption and motor impairment phenotype. Although GCs are the dominant afferent integrator in the cerebellum, such integration is shared by unipolar brush cells (UBCs) in vestibulocerebellar lobes. UBCs receive both GABAergic and glycinergic inhibition, both of which may mediate diverse neurological effects of EtOH. Therefore, the impact of recreational concentrations of EtOH (~10-50 mM) on GABA receptor (GABAR)- and glycine receptor (GlyR)-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) of UBCs in cerebellar slices was characterized. Sprague-Dawley rat (SDR) UBCs exhibited sIPSCs mediated by GABARs, GlyRs, or both, and EtOH dose-dependently (10, 26, 52 mM) increased their frequency and amplitude. EtOH increased the frequency of glycinergic and GABAergic sIPSCs and selectively enhanced the amplitude of glycinergic sIPSCs. This GlyR-specific enhancement of sIPSC amplitude resulted from EtOH actions at presynaptic Golgi cells and via protein kinase C-dependent direct actions on postsynaptic GlyRs. The magnitude of EtOH-induced increases in UBC sIPSC activity varied across SDRs and two lines of mice, in parallel with their respective alcohol consumption/motor impairment phenotypes. These data indicate that Golgi cell-to-UBC inhibitory synapses are targets of EtOH, which acts at pre- and postsynaptic sites, via Golgi cell excitation and direct GlyR enhancement. Genetic variability in cerebellar alcohol/ethanol sensitivity (ethanol-induced ataxia) predicts ethanol consumption phenotype in rodents and humans, but the cellular and molecular mechanisms underlying genetic differences are largely unknown. Here it is demonstrated that recreational concentrations of alcohol (10-30 mM) enhance glycinergic and GABAergic inhibition of unipolar brush cells through increases in glycine/GABA release and postsynaptic enhancement of glycine receptor-mediated responses. Ethanol effects varied across rodent genotypes parallel to ethanol consumption and motor sensitivity phenotype.

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“…2) (Ito 2008; Schmahmann 2010; Strick et al 2009). The cerebellum also communicates (see below for further details) with brain regions associated with EtOH reward [ventral tegmental area (Ikai et al 1992, 1994), amygdala (Tomasi and Volkow 2011), and nucleus accumbens (Dempsey and Richardson 1987)], and with consummatory behavior (hypothalamus (Zhu et al 2006; Zhu and Wang 2008)).…”

Section: Introduction To and Review Of The Cerebellum And Its Relatmentioning

confidence: 99%

“…One possible brain region that could mediate EtOH’s effects in the VTA may be the cerebellum, since it is exquisitely sensitive to low [EtOH] (see above). A functional synaptic connection between cerebellar nuclear neurons and the VTA was demonstrated by studies in which electrical stimulation of the dentate nucleus or Purkinje cells caused increased dopamine levels in the nucleus accumbens (Dempsey and Richardson 1987) or PFC in a manner that was blocked by local pharmacological inhibition of the VTA (Rogers et al 2011, 2013; Mittleman et al 2008). The as yet poorly understood cerebellar efferent pathway to VTA that increases dopamine release in the PFC, nucleus accumbens, and amygdala (Inglis and Moghaddam 1999; Oades and Halliday 1987; Loughlin and Fallon 1983; Beckstead et al 1979; Fallon et al 1978) may couple with the activity of a direct projections from the fastigial nucleus to the nucleus accumbens and amygdala which have been demonstrated in primate, cat, and rat (Harper and Heath 1973; Heath and Harper 1974; Oades and Halliday 1987).…”

Section: Introduction To and Review Of The Cerebellum And Its Relatmentioning

confidence: 99%

The Cerebellar GABAAR System as a Potential Target for Treating Alcohol Use Disorder

Rossi¹,

Richardson²

2018

The Neuropharmacology of Alcohol

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In the brain, fast inhibitory neurotransmission is mediated primarily by the ionotropic subtype of the gamma-aminobutyric acid (GABA) receptor subtype A (GABAR). It is well established that the brain's GABAR system mediates many aspects of neurobehavioral responses to alcohol (ethanol; EtOH). Accordingly, in both preclinical studies and some clinical scenarios, pharmacologically targeting the GABAR system can alter neurobehavioral responses to acute and chronic EtOH consumption. However, many of the well-established interactions of EtOH and the GABAR system have been identified at concentrations of EtOH ([EtOH]) that would only occur during abusive consumption of EtOH (≥40 mM), and there are still inadequate treatment options for prevention of or recovery from alcohol use disorder (AUD, including abuse and dependence). Accordingly, there is a general acknowledgement that more research is needed to identify and characterize: (1) neurobehavioral targets of lower [EtOH] and (2) associated brain structures that would involve such targets in a manner that may influence the development and maintenance of AUDs.Nearly 15 years ago it was discovered that the GABAR system of the cerebellum is highly sensitive to EtOH, responding to concentrations as low as 10 mM (as would occur in the blood of a typical adult human after consuming 1-2 standard units of EtOH). This high sensitivity to EtOH, which likely mediates the well-known motor impairing effects of EtOH, combined with recent advances in our understanding of the role of the cerebellum in non-motor, cognitive/emotive/reward processes has renewed interest in this system in the specific context of AUD. In this chapter we will describe recent advances in our understanding of cerebellar processing, actions of EtOH on the cerebellar GABAR system, and the potential relationship of such actions to the development of AUD. We will finish with speculation about how cerebellar specific GABAR ligands might be effective pharmacological agents for treating aspects of AUD.

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Paleocerebellar stimulation induces in vivo release of endogenously synthesized [3H]dopamine and [3H]norepinephrine from rat caudal dorsomedial nucleus accumbens

Cited by 9 publications

References 22 publications

The effects of methylphenidate on cerebral activations to salient stimuli in healthy adults.

The effects of methylphenidate on cerebral activations to salient stimuli in healthy adults.

Recreational concentrations of alcohol enhance synaptic inhibition of cerebellar unipolar brush cells via pre- and postsynaptic mechanisms

The Cerebellar GABAAR System as a Potential Target for Treating Alcohol Use Disorder

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