Specificity and impact of adrenergic projections to the midbrain dopamine system

Mejías-Aponte, Carlos A.

doi:10.1016/j.brainres.2016.01.036

Cited by 51 publications

(44 citation statements)

References 147 publications

(200 reference statements)

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“…The midbrain dopaminergic system is regulated by the central adrenergic system [125]. The moderate increase in adrenaline levels observed after Atremorine administration may also contribute to enhancing dopaminergic neurotransmission in PD [18].…”

Section: Novel Treatmentsmentioning

confidence: 99%

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Cacabelos

2017

IJMS

429

300

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Parkinson’s disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer’s disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson’s disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson’s disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin–proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina), and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). The chronic administration of antiparkinsonian drugs currently induces the “wearing-off phenomenon”, with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in addition to enhancing dopaminergic neurotransmission. Since biochemical changes and therapeutic outcomes are highly dependent upon the genomic profiles of PD patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutics.

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Section: Novel Treatmentsmentioning

confidence: 99%

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Cacabelos

2017

IJMS

429

300

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“…) . Since then, a large body of evidence has been gathered, both from in vitro slice recordings and from anesthetized animals (for comprehensive review, see Mejias‐Aponte ), showing differential regulation of VTA DAergic neurons via ARs. This includes a variety of putative mechanisms, both pre‐ and postsynaptic, involving primarily α 1 ‐ARs, whose presence in the VTA is well established (Rommelfanger et al .…”

Section: Discussionmentioning

confidence: 99%

“…; Rommelfanger et al . ; Mejias‐Aponte ). This might be particularly relevant in behavioral contexts, such as acute fear or following administration of drugs of abuse, which are thought to result in strong elevations in NAergic tone in the VTA (Mejias‐Aponte ).…”

Section: Discussionmentioning

confidence: 99%

“…; Mejias‐Aponte ). This might be particularly relevant in behavioral contexts, such as acute fear or following administration of drugs of abuse, which are thought to result in strong elevations in NAergic tone in the VTA (Mejias‐Aponte ). Accordingly, intra‐VTA α 1 ‐AR blockade attenuates stress responses during fear conditioning and cocaine seeking in cocaine‐abstinent rats (Solecki et al .…”

Section: Discussionmentioning

confidence: 99%

“…; Rommelfanger et al . ; Mejias‐Aponte ). Thus, NA can act predominantly via α 1 ‐ and α 2 ‐ARs to modulate the activity of DAergic neurons and non‐DA cells (presumably interneurons) either directly (Goertz et al .…”

mentioning

confidence: 99%

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Differential regulation of phasic dopamine release in the forebrain by the VTA noradrenergic receptor signaling

Kielbinski

Bernacka

Solecki

2019

Journal of Neurochemistry

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Phasic dopamine (DA) release from the ventral tegmental area (VTA) into forebrain structures is implicated in associative learning and conditional stimulus (CS)‐evoked behavioral responses. Mounting evidence points to noradrenaline signaling in the VTA as an important regulatory input. Accordingly, adrenergic receptor (AR) blockade in the VTA has been shown to modulate CS‐dependent behaviors. Here, we hypothesized that α1‐ and α2‐AR (but not β‐AR) activity preferentially modulates phasic, in contrast to tonic, DA release. In addition, these effects could differ between forebrain targets. We used fast‐scan cyclic voltammetric measurements in rats to assess the effects of intra‐VTA microinfusion of terazosin, a selective α1‐AR antagonist, on electrically evoked phasic DA release in the nucleus accumbens (NAc) core and medial prefrontal cortex (mPFC). Terazosin dose‐dependently attenuated phasic, but not tonic, DA release in the NAc core, but not in the mPFC. Next, we measured the effects of intra‐VTA administration of the α2‐AR selective antagonist RX‐821002 on evoked DA in the NAc core. Similar to the effects of α1‐AR blockade, intra‐VTA α2‐AR blockade with RX‐0821002 strongly and dose‐dependently attenuated phasic, but not tonic, DA release. In contrast, no regulation by RX‐821002 was observed in the mPFC. This effect was sensitive to intra‐VTA blockade of D2 receptors with raclopride. Finally, the β‐AR antagonist propranolol ineffectively modulated DA release in the NAc core. These findings revealed both α1‐ and α2‐ARs in the VTA as selective regulators of phasic DA release. Importantly, we demonstrated that AR blockade modulated mesolimbic, in contrast to mesocortical, DA release in previously unstudied heterogeneity in AR regulation of forebrain phasic DA.

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Atremorine in Parkinson's disease: From dopaminergic neuroprotection to pharmacogenomics

Cacabelos

Carrera

Martínez

et al. 2021

Medicinal Research Reviews

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Atremorine is a novel bioproduct obtained by nondenaturing biotechnological processes from a genetic species of Vicia faba.Atremorine is a potent dopamine (DA) enhancer with powerful effects on the neuronal dopaminergic system, acting as a neuroprotective agent in Parkinson's disease (PD). Over 97% of PD patients respond to a single dose of Atremorine (5 g, p.o.) 1 h after administration. This response is gender-, time-, dose-, and genotype-dependent, with optimal doses ranging from 5 to 20 g/day, depending upon disease severity and concomitant medication. Drug-free patients show an increase in DA levels from 12.14 ± 0.34 pg/ml to 6463.21 ± 1306.90 pg/ ml; and patients chronically treated with anti-PD drugs show an increase in DA levels from 1321.53 ± 389.94 pg/ml to 16,028.54 ± 4783.98 pg/ml, indicating that Atremorine potentiates the dopaminergic effects of conventional anti-PD drugs. Atremorine also influences the levels of other neurotransmitters (adrenaline, noradrenaline) and hormones which are regulated by DA (e.g., prolactin, PRL), with no effect on serotonin or histamine. The variability in Atremorine-induced DA response is highly attributable to pharmacogenetic factors.

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Specificity and impact of adrenergic projections to the midbrain dopamine system

Cited by 51 publications

References 147 publications

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Differential regulation of phasic dopamine release in the forebrain by the VTA noradrenergic receptor signaling

Atremorine in Parkinson's disease: From dopaminergic neuroprotection to pharmacogenomics

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