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At least 19 recordsLinked to original sources
PubMed1976

Dopaminergic stimulants and cyclic nucleotides in mouse brain. Effects of dopaminergic antagonists, cholinolytics, and GABA agonists.

The effects of dopaminergic stimulants on the cyclic GMP content in the medial forebrain and the cerebellum were studied in mice pretreated with dopaminergic antagonists, cholinolytics and agents enhancing GABAergic transmission. Low doses of butyrophenones (haloperidol and spiroperidol) inhibited the rise in cyclic GMP levels and the stereotyped behaviour induced by amphetamine, but were without effect on the same biochemical and behavioural changes elicited by apomorphine. Higher doses effectively blocked the rise in cyclic GMP levels and the stereotyped behaviour elicited by both drugs. These findings suggest that low doses of the dopaminergic antagonists may predominantly act by interfering with the release of dopamine from presynaptic stores, while high doses may act by blockade of the postsynaptic dopaminergic receptor. The rise in cerebellar cyclic GMP levels elicited by dopaminergic stimulants appears not to involve cholinergic transmission, since atropine did not block the effects of the dopaminergic stimulants. Enhancement of GABAergic transmission by diazepam or aminooxyacetic acid antagonized the rise in cerebellar cyclic GMP content induced by the dopaminergic stimulants, but was without effect on the cyclic GMP content in the medial forebrain. Cyclic AMP levels were not affected by any of the drugs in both parts of the brain.

Aminobutyrates↗
PubMed1978

Topographical distribution of dopaminergic innervation and dopaminergic receptors of the anterior cerebral cortex of the rat.

The quantitative topographical distribution of the dopaminergic innervation and the DA-sensitive adenylate cyclase were estimated in the anterior cerebral cortex of the rat. The high affinity uptake of [3H]DA and endogenous levels of DA were used as markers of the dopaminergic innervation. [3H]DA uptake, DA levels and DA-sensitive adenylate cyclase were estimated in microdiscs of tissues punched out from frozen serial frontal slices. The uptake of [3H]DA was measured on sucrose homogenates prepared from such microdiscs. The ventral part of the frontal cortex contained the highest DA concentration and DA-sensitive adenylate cyclase activity; the other structures rich in DA and in DA receptors were the cingular (close to the corpus callsoum) and the rhinal cortices. All of these cortical areas were rich in [3H]DA uptake sites. However, curiously, the dorsal part of the frontal cortex, which contained only moderate amounts of DA and of DA-sensitive adenylate cyclase, presented the highest number of [3H]DA uptake sites. Nevertheless, the uptake of [3H]DA in this region decreased by 60% after bilateral electrolytical lesions of the ventral tegmental area (A10 group). The parietal cortex was practically devoid of dopaminergic innervation and of DA-sensitive adenylate cyclase. The activity of the DA-sensitive adenylate cyclase in the frontal, cingular and rhinal cortices was 10-fold higher than that found in the striatum when compared to their respective DA levels.

Adenylyl Cyclases↗
PubMed1978

Intranigral kainic acid: evidence for nigral non-dopaminergic neurons controlling posture and behavior in a manner opposite to the dopaminergic ones.

The unilateral, intranigral administration of kainic acid (k.a.) produced a syndrome characterized by early sequelae of contra- and ipsilateral circling and by a chronic contralateral turning associated with moderate loss of neurons in the pars reticulata. The acute contralateral circling seems to be related to dopaminergic nigro-neostriatal neuron stimulation, since it was prevented by previous intranigral injections of 6-OHDA. The acute ipsilateral circling and the chronic contralateral turning, on the other hand, seem to be independent of the integrity of the dopaminergic system and may be due to an initial stimulation, followed by destruction, of a nigral neuronal system which mediates turning behavior in a manner opposite to that of nigro-striatal dopamine. Treatment with D-amphetamine or apomorphine changed the contralateral into ipsilateral turning, while haloperidol potentiated the contralateral turning. Bilateral injection of k.a. into the nigra resulted in chronic stereotyped sniffing and gnawing, which were not inhibited by haloperidol. Moreover, haloperidol did not produce catalepsy in these animals. It is suggested that the intranigral k.a. injection destroyed a neuronal system antagonistic to dopamine and resulted in a reduction of the response to DA-receptor stimulation of the c. striatum.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2025

Interactions of Oligodendrocyte Precursor Cells and Dopaminergic Neurons in the Mouse Substantia Nigra.

Parkinson's disease (PD) is a prevalent neurodegenerative disease caused by the death of dopaminergic neurons within the substantia nigra pars compacta (SNpc) region of the midbrain. Recent genomic and single cell sequencing data identified oligodendrocytes and oligodendrocyte precursor cells (OPCs) to confer genetic risk in PD, but their biological role is unknown. Although SNpc dopaminergic neurons are scarcely or thinly myelinated, there is a gap in the knowledge concerning the physiological interactions between dopaminergic neurons and oligodendroglia. We sought to investigate the distribution of OPCs with regard to the myelination state in the mouse substantia nigra (SN) by high-resolution imaging to provide a morphological assessment of OPC-dopaminergic neuron interactions and quantification of cell numbers across different age groups. OPCs are evenly distributed in the midbrain throughout the lifespan and they physically interact with both the soma and axons of dopaminergic neurons. The presence of OPCs and their interaction with dopaminergic neurons does not correlate with the distribution of myelin. Myelination is sparse in the SNpc, including dopaminergic fibers originating from the SNpc and projecting through the substantia nigra pars reticulata (SNpr). We report that OPCs and dopaminergic neurons exist in a 1:1 ratio in the SNpc, with OPCs accounting for 15%-16% of all cells in the region across all age groups. This description of OPC-dopaminergic neuron interaction in the midbrain provides a first look at their longitudinal distribution in mice, suggesting additional functions of OPCs beyond their differentiation into myelinating oligodendrocytes.

Animals↗
PubMed1977

Effects of dopaminergic agonists and antagonists of feeding in intact and 6-hydroxydopamine-treated rats.

The effects on food intake of treatments which alter central dopaminergic function were examined in rats. Doses of d-amphetamine that increased the conversion of 3H-tyrosine to 3H-dopamine in the brain were found to decrease food intake, an effect that was reduced by the systemic administration of the dopaminergic antagonists alpha-methyltyrosine, haloperidol or spiroperidol. The dopaminergic agonists, apomorphine, dopa, cocaine and methylphenidated, also reduced feeding and these effects were attenuated by low doses of spiroperidol. In larger doses, spiroperidol itself decreased feeding, and this effect was potentiated by alpha-methyltyrosine. The ability of dopaminergic agonists and antagonists to inhibit food intake was also observed in rats treated with 6-hhyroxydopamine so as to produce a selective 83% depletion of dopamine. In these animals, d-amphetamine was found to be less effective as an anorexic agent, whereas dopa, apomorphine, alpha-methyltyrosine and spiroperidol each was more effective in reducing food intake. These alterations in sensitivity may reflect neurochemical changes which occur at residual dopaminergic synapses after subtotal lesions of dopaminergic neurons. We conclude that both increases and decreases in central dopaminergic activity can reduce feeding and propose that some intermediate rate of dopamine release provides an optimal level of neuronal activity for feeding by the hungry animal.

Animals↗
PubMed2025

Multi-Locus Pro-Dopaminergic Restoration of Reward Brain Circuitry in Reward Deficiency Rescinds Mono-Pharmaceutical Targeting.

Dopaminergic dysfunction in reward circuitry is well-documented as a contributor to addictive behaviors. Evidence indicates that changes in synchronous neural activity between brain regions mediating reward and cognitive functions may significantly contribute to substance-related disorders. In this commentary we highlight findings showing that the pro-dopaminergic nutraceutical (KB220) enhances functional connectivity between reward and cognitive brain areas in both animal and human studies. Animal studies demonstrate that KB220 activates important brain reward-related regions, including the nucleus accumbens, anterior cingulate gyrus, anterior thalamic nuclei, hippocampus, and prelimbic and infralimbic loci. Kb220 induced significant functional connectivity, enhanced neuroplasticity, and improved dopaminergic functionality within the brain reward circuitry with effects localized to these regions rather than broader distributed across the brain. In abstinent heroin-dependent individuals, acute KB220 administration significantly induced BOLD activation in caudate-accumbens dopaminergic pathways relative to placebo. Furthermore, data from 36 clinical trials and preclinical studies encompassing over 1,000 subjects, demonstrate that KB220 supports "dopamine homeostasis" across various reward deficiency behaviors. Clinical outcomes and quantitative electroencephalogy (qEEG) results underscore KB220's potential anti-craving/anti-relapse effects in addiction and other psychiatric disorders through direct or indirect dopaminergic modulation. Based on a review of the existing knowledge and further intensive investigation, we propose that instead of relying on mono-pharmaceutical approaches, the scientific community should endorse multi-loci dopaminergic restoration of reward brain circuitry as a fundamental paradigm for addressing mental illness.

Alcohol Use Disorder (AUD)↗
PubMed2026

In Vivo Screen of Parkinson's Disease GWAS Risk Genes Identifies ARIH2 as a Novel Regulator of α-Synuclein Toxicity in Dopaminergic Neurons.

Parkinson's disease (PD) is a late-onset neurodegenerative disease characterized by preferential degeneration of midbrain dopaminergic neurons and α-synuclein-containing Lewy bodies that are found in both familial and sporadic forms. Genome-wide association studies (GWAS) have identified many loci associated with risk of sporadic PD, but their role in PD pathogenesis remains largely unknown. We screened a subset of GWAS genes in Caenorhabditis elegans (C. elegans) as potential modulators of α-synuclein-mediated degeneration of dopaminergic neurons. Loss of ari-2 (human ARIH2), an E3 ubiquitin ligase, was identified as the strongest suppressor of dopaminergic neurodegeneration in C. elegans. Unbiased proteomics analysis in human-induced pluripotent stem cell-derived dopaminergic neurons revealed novel substrates of ARIH2 including TPPP3, a regulator of microtubule dynamics. Importantly, TPPP3 was required for ARIH2's effects on α-synuclein-induced dopaminergic neurodegeneration. Our studies reveal an unexpected genetic interaction between two PD-linked genes, α-synuclein and ARIH2, and suggest that inhibition of ARIH2's enzymatic activity may serve as a potential therapeutic approach in PD.

Animals↗
PubMed1978

Amphetamine- type reinforcement by dopaminergic agonists in the rat.

Intravenous self-administration of d-amphetamine (0.25 mg/kg/injection) decreased in a dose-related fashion after injections of the dopaminergic agonists apomorphine and piribedil. The dopaminergic agonists appear to suppress amphetamine intake in the same way as do 'free' amphetamine injections, by extending drug satiation in a given interresponse period. Clonidine, an alpha noradrenergic agonist, did not have similar effects. Apomorphine and piribedil did not increase 14C-amphetamine levels in rat brains, nor did they retard disappearance of 14C-amphetamine; thus their amphetamine-like effects are not due to alterations of amphetamine metabolism. Rats responding for amphetamine continued to respond for apomorphine or peribedil when the latter drugs were substituted for the former. Rats experienced in amphetamine self-administration readily initiated and maintained responding for apomorphine and piribedil. The dopaminergic blocker (+)-butaclamol disrupted responding for apomorphine and piribedil, although it produced no marked increase in responding for the dopaminergic agonists, as it does for amphetamine. These data add to the evidence that actions in the dopaminergic synapse account for amphetamine's reinforcing properties.

Amphetamine↗
PubMed1977

Amphetamine-haloperidol interactions in rat striatum: failure to correlate behavioral effects with dopaminergic and cholinergic dynamics.

Previous reports have suggested that the hyperactivity and stereotypy produced by amphetamine (AMP) and the catalepsy produced by haloperidol (HAL) are mediated by striatal dopaminergic mechanisms. In the present study, we have measured the behavioral effects of AMP and HAL, and their effects on striatal dopaminergic function, using both an index of pre-synaptic activity (synaptosomal dopamine (DA) synthesis) and a parameter which we suggest will reflect post-synaptic dopaminergic function (sodium-dependent, high affinity choline uptake). Administration of 2 mg/kg AMP produces hyperactivity and causes a decrease in DA biosynthesis, both of which are blocked by 0.75 mg/kg HAL. AMP (5 mg/kg) produces stereotypy, further decreases DA biosynthesis and causes a decrease in choline uptake, consistent with stimulation of DA receptors. However, while pretreatment with 3 mg/kg HAL completely blocked the stereotypy induced by 5 mg/kg AMP it failed to reverse the effects of this dose on either DA biosynthesis or choline uptake. These data suggest that either 5 mg/kg AMP affects straital dopaminergic and cholinergic parameters by a mechanism independent of HAL sensitive receptors, or the stereotypy produced by high doses of AMP are not related to striatal dopaminergic and cholinergic function.

Amphetamine↗
PubMed1979

The effect of dopaminergic modifiers on morphine-induced analgesia and respiratory depression.

The influences of the dopaminergic system on morphine-induced analgesia and respiratory depression were compared using modulators of dopaminergic activity. Blockade of dopaminergic receptors by haloperidol or pimozide produced a potentiation of morphine analgesia, while stimulation of dopaminergic activity by L-dopa methyl ester inhibited morphine analgesia. Morphine-induced depression of respiratory rate was potentiated by haloperidol and inhibited by pimozide or L-dopa methyl ester. These results suggest that the dopaminergic system plays a modulating role in morphine-induced analgesia, but not in morphine-induced respiratory depression.

Analgesics, Opioid↗
PubMed1978

Steric aspects of dopaminergic drugs.

There are a variety of molecule species of dopamine avaialable at physiological pH. The predominant form available at physiological pH is the phenolic ammonium salt. However, at the present time the molecular form that is optimum for producing dopaminergic activity is unknown. In attempting to delineate the conformational requirements of dopaminergic agonists, a variety of conformationally restricted analogs and complex molecules possessing a dopaminergic segment have been investigated. It appears at this time that the trans extended form of dopamine is the optimum form for binding to dopamine receptors. The rotameric forms of dopamine are also important considerations when examining a molecule for dopaminergic agonist activity. A high degree of stereospecificity has been shown in different dopaminergic systems.

Animals↗