µ-Opioid receptor–induced synaptic plasticity in dopamine neurons mediates the rewarding properties of anabolic androgenic steroids

Anabolic androgenic steroids (AAS) have medical utility but are often abused, and the effects of AAS on reward circuits in the brain have been suggested to lead to addiction. We investigated the previously reported correlations between AAS and the endogenous μ-opioid system in the rewarding properties of AAS in mice. We found that a single injection of a supraphysiological dose of natural or synthetic AAS strengthened excitatory synaptic transmission in putative ventral tegmental area (VTA) dopaminergic neurons. This effect was associated with the activation of μ-opioid receptors (MORs) and an increase in β-endorphins released into the VTA and the plasma. Irreversible blockade of MORs in the VTA counteracted two drug-seeking behaviors, locomotor activity and place preference. These data suggest that AAS indirectly stimulate a dopaminergic reward center of the brain through activation of endogenous opioid signaling and that this mechanism mediates the addictive effects of AAS.

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Lack of Effects of Anabolic-Androgenic Steroids on Locomotor Activity in Intact Male Mice

Perceptual and Motor Skills ◽

10.2466/pms.1999.88.1.319 ◽

1999 ◽

Vol 88 (1) ◽

pp. 319-328 ◽

Cited By ~ 9

Author(s):

A. Salvador ◽

L. Moya-Albiol ◽

S. Martínez-Sanchis ◽

V. M. Simón

Keyword(s):

Locomotor Activity ◽

Anabolic Androgenic Steroids ◽

Male Mice ◽

Intact Male ◽

Androgenic Steroids

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Pathophysiological mechanisms underlying antipsychotic-induced tardive dyskinesia

Bulletin of Siberian Medicine ◽

10.20538/1682-0363-2019-4-169-184 ◽

2020 ◽

Vol 18 (4) ◽

pp. 169-184

Author(s):

E. E. Vayman ◽

N. A. Shnayder ◽

N. G. Neznanov ◽

R. F. Nasyrova

Keyword(s):

Tardive Dyskinesia ◽

Dopaminergic Neurons ◽

Neurological Complication ◽

Carbonyl Stress ◽

Endogenous Opioid System ◽

Endogenous Opioid ◽

Drug Induced ◽

Pathophysiological Mechanisms ◽

The Brain

Purpose. To analyze the results of classical and modern studies reflecting the pathophysiological mechanisms of antipsychotic-induced tardive dyskinesia.Materials and methods. We searched for full-text publications in Russian and English in the databases of E-Library, PubMed, Web of Science and Springer published over the past decade, using keywords (tardive dyskinesia (TD), drug-induced tardive dyskinesia, antipsychotics (AP), neuroleptics, typical antipsychotics, atypical antipsychotics, pathophysiology, etiology and combinations of these words). In addition, the review included earlier publications of historical interest.Results. The lecture proposed theories of development of AP-induced TD, examining its effect on dopaminergic receptors, dopaminergic neurons, neurons of the basal ganglia, and other theories: activation of estrogen receptors, disorders of melatonin metabolism, disorders of the endogenous opioid system, oxidative stress with predominant oxidation processes, blockade of 5-HT2-receptors, a decrease in the pyridoxine level, genetic predisposition, interaction of AP with the brain trace element – iron, carbonyl stress and immune inflammation and the role of the neurotrophic factor.Conclusion. The disclosure of the mechanisms of AP-induced TD will allow the development of a strategy for personalized prevention and therapy of the considered neurological complication of the AP-therapy for schizophrenia in real clinical practice.

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Kisspeptin-1 regulates forebrain dopaminergic neurons in the zebrafish

Scientific Reports ◽

10.1038/s41598-020-75777-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Nurul M. Abdul Satar ◽

Satoshi Ogawa ◽

Ishwar S. Parhar

Keyword(s):

Neural Activity ◽

Dopaminergic Neurons ◽

Medial Forebrain Bundle ◽

Marker Gene ◽

Dopamine Neurons ◽

Mrna Levels ◽

Median Raphe ◽

Activity Marker ◽

The Brain ◽

Median Raphé

Abstract The habenula is a phylogenetically conserved epithalamic structure, which conveys negative information via inhibition of mesolimbic dopamine neurons. We have previously shown the expression of kisspeptin (Kiss1) in the habenula and its role in the modulation of fear responses in the zebrafish. In this study, to investigate whether habenular Kiss1 regulates fear responses via dopamine neurons in the zebrafish, Kiss1 peptides were intracranially administered close to the habenula, and the expression of dopamine-related genes (th1, th2 and dat) were examined in the brain using real-time PCR and dopamine levels using LC–MS/MS. th1 mRNA levels and dopamine levels were significantly increased in the telencephalon 24-h and 30-min after Kiss1 administration, respectively. In fish administered with Kiss1, expression of neural activity marker gene, npas4a and kiss1 gene were significantly decreased in the ventral habenula. Application of neural tracer into the median raphe, site of habenular Kiss1 neural terminal projections showed tracer-labelled projections in the medial forebrain bundle towards the telencephalon where dopamine neurons reside. These results suggest that Kiss1 negatively regulates its own neuronal activity in the ventral habenula via autocrine action. This, in turn affects neurons of the median raphe via interneurons, which project to the telencephalic dopaminergic neurons.

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Drugs and the Adolescent Brain

Coming of Age ◽

10.1093/oso/9780195314373.003.0008 ◽

2019 ◽

pp. 120-143

Author(s):

Cheryl L. Sisk ◽

Russell D. Romeo

Keyword(s):

Drug Use ◽

Prescription Drugs ◽

Reward Sensitivity ◽

Anabolic Androgenic Steroids ◽

Adolescent Drug Use ◽

Increased Risk ◽

Brain And Behavior ◽

Androgenic Steroids ◽

And Behavior ◽

The Brain

Chapter 8 highlights some of the ways in which drugs can influence the adolescent brain and its development. Drug use typically begins during adolescence, in part because of increased risk-taking and reward sensitivity that characterizes adolescence. Adolescent drug use is concerning because the developing brain is often more vulnerable to many of the adverse consequences of drug use, and it is a predictor of drug abuse in adulthood. The chapter discusses how the commonly used drugs alcohol, nicotine, and marijuana acutely affect the brain and behavior differently during adolescence and in adulthood, as well as the longer-term effects on brain structure, cognitive function, and motivation that adolescent drug use may have. Research on the effects of anabolic androgenic steroids on aggressive behavior and of prescription drugs used to treat depression and ADHD during adolescence is also discussed.

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Dopaminergic neurons establish a distinctive axonal arbor with a majority of non-synaptic terminals

10.1101/2020.05.11.088351 ◽

2020 ◽

Author(s):

Charles Ducrot ◽

Marie-Josée Bourque ◽

Constantin V. L. Delmas ◽

Anne-Sophie Racine ◽

Dainelys Guadarrama Bello ◽

...

Keyword(s):

Dopaminergic Neurons ◽

Synapse Formation ◽

Critical Role ◽

Gabaergic Neurons ◽

Dopamine Neurons ◽

Target Cells ◽

Axon Terminals ◽

Synaptic Terminals ◽

Axonal Arbor ◽

The Brain

ABSTRACTChemical neurotransmission in the brain typically occurs through synapses, which are structurally and functionally defined as sites of close apposition between an axon terminal and a postsynaptic domain. Ultrastructural examinations of axon terminals established by monoamine neurons in the brain often failed to identify a similar tight pre- and postsynaptic coupling, giving rise to the concept of “diffuse” or “volume” transmission. Whether this results from intrinsic properties of such modulatory neurons remains undefined. Using an efficient co-culture model, we find that dopaminergic neurons establish an axonal arbor that is distinctive compared to glutamatergic or GABAergic neurons in both size and propensity of terminals to avoid direct contact with target neurons. Furthermore, while most dopaminergic varicosities express key proteins involved in exocytosis such as synaptotagmin 1, only ~20% of these are synaptic. The active zone protein bassoon was found to be enriched in a subset of dopaminergic terminals that are in proximity to a target cell. Irrespective of their structure, a majority of dopaminergic terminals were found to be active. Finally, we found that the presynaptic protein Nrxn-1αSS4- and the postsynaptic protein NL-1AB, two major components involved in excitatory synapse formation, play a critical role in the formation of synapses by dopamine neurons. Taken together, our findings support the idea that dopamine neurons in the brain are endowed with a distinctive developmental program that leads them to adopt a fundamentally different mode of connectivity, compared to glutamatergic and GABAergic neurons involved in fast point-to-point signaling.SIGNIFICANCE STATEMENTMidbrain dopamine (DA) neurons regulate circuits controlling movement, motivation, and learning. The axonal connectivity of DA neurons is intriguing due to its hyperdense nature, with a particularly large number of release sites, most of which not adopting a classical synaptic structure. In this study, we provide new evidence highlighting the unique ability of DA neurons to establish a large and heterogeneous axonal arbor with terminals that, in striking contrast with glutamate and GABA neurons, actively avoid contact with the target cells. The majority of synaptic and non-synaptic terminals express proteins for exocytosis and are active. Finally, our finding suggests that, NL-1A+B and Nrxn-1αSS4-, play a critical role in the formation of synapses by DA neurons.

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Generation of a DAT-Flp mouse line for intersectional genetic targeting of dopamine neuron subpopulations

10.1101/2020.06.24.167908 ◽

2020 ◽

Author(s):

Daniel J. Kramer ◽

Polina Kosillo ◽

Drew Friedmann ◽

David Stafford ◽

Liqun Luo ◽

...

Keyword(s):

Gene Expression ◽

Dopaminergic Neurons ◽

Single Gene ◽

Dopamine Neurons ◽

Mouse Line ◽

Flp Recombinase ◽

And Function ◽

Genetic Targeting ◽

The Brain ◽

Mouse Lines

AbstractDopamine neurons project to diverse regions throughout the brain to modulate various brain processes and behaviors. It is increasingly appreciated that dopamine neurons are heterogeneous in their gene expression, circuitry, physiology, and function. Current approaches to target dopamine neurons are largely based on single gene drivers, which either label all dopamine neurons, or mark a sub-set but concurrently label non-dopaminergic neurons. Here we establish a novel mouse line in which Flp recombinase is knocked-in to the endogenous Slc6a3 (dopamine active transporter, DAT) locus. DAT-Flp mice can be used with various Cre-expressing mouse lines to efficiently and selectively label dopaminergic subpopulations using Cre/Flp-dependent intersectional strategies. We demonstrate the utility of this approach by crossing DAT-Flp mice with NEX-Cre mice, to specifically label Neurod6-expressing dopamine neurons that project to the nucleus accumbens medial shell. DAT-Flp mice represent a novel tool, which will help parse the diverse functions mediated by dopaminergic circuits.

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