Structural plasticity in mesencephalic dopaminergic neurons produced by drugs of abuse: critical role of BDNF and dopamine

While midbrain dopamine (DA) neuronal circuits are central to motivated behaviors, much remains unknown about our knowledge of how these circuits are modified over time by experience to facilitate selective aspects of experience-dependent plasticity. Most studies of the DA system in drug addiction focus on the role of the mesolimbic DA pathway from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) in facilitating drug-associated reward. In contrast, less is known about how midbrain DA cells and associated circuits contribute to negative affective states including anxiety that emerge during protracted withdrawal from drug administration. Here, we demonstrate the selective role of a midbrain DA projection to the amygdala (VTADA-Amygdala) for anxiety that develops during protracted withdrawal from cocaine administration but does not participate in cocaine reward or sensitization. Our rabies virus-mediated circuit mapping approach revealed a persistent elevation in spontaneous and task-related activity of GABAergic cells from the bed nucleus of the stria terminals (BNST) and downstream VTADA-Amygdala cells that could be detected even after a single cocaine exposure. Activity in BNSTGABA cells was related to cocaine-induced anxiety but not reward or sensitization, and silencing the projection from these cells to the midbrain was sufficient to prevent the development of anxiety during protracted withdrawal following cocaine administration. We observed that VTADA-Amygdala cells, but not other midbrain DA cells, were strongly activated after a challenge exposure to cocaine, and found that activity in these cells was necessary for the expression of reinstatement of cocaine place preference. Lastly, the importance of activity in VTADA-Amygdala cells extends beyond cocaine, as these cells mediate the development of anxiety states triggered by morphine and a predator odor. Our results provide an exemplar for how to identify key circuit substrates that contribute to behavioral adaptations and reveal a critical role for BNSTGABA-VTADA-Amygdala pathway in anxiety states induced by drugs of abuse or natural experiences as well as cocaine-primed reinstatement of conditioned place preference.

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Addiction (Oxford Psychiatry Library)

10.1093/med/9780198797746.001.0001 ◽

2018 ◽

Author(s):

David J. Nutt ◽

Liam J. Nestor

Keyword(s):

Drugs Of Abuse ◽

Critical Role ◽

Brain Disorder ◽

Comprehensive Overview ◽

Brain Science ◽

Pharmacological Targets ◽

Variable Nature ◽

Reward Dependence ◽

The Brain

Part of the Oxford Psychiatry Library series, this resource is a clear and comprehensive overview of the brain science underpinning addiction that helps explain the current and future therapeutics for the range of addictions, using full colour images to enhance understanding. It focuses on the nature of addiction as a brain disorder that includes a range of different behavioural traits such as impulsivity and reward dependence, and discusses the critical role of kinetic and pharmacological factors. The also explains how the primary pharmacological targets of drugs of abuse are now understood, the relation to the variable nature of addiction to different substances, and how this may lead to new approaches to treatment.

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Targeted Ablation of Primary Cilia in Differentiated Dopaminergic Neurons Reduces Striatal Dopamine and Responsiveness to Metabolic Stress

Antioxidants ◽

10.3390/antiox10081284 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1284

Author(s):

Rasem Mustafa ◽

Chahinaz Rawas ◽

Nadja Mannal ◽

Grzegorz Kreiner ◽

Björn Spittau ◽

...

Keyword(s):

Dopaminergic Neurons ◽

Primary Cilia ◽

Critical Role ◽

Metabolic Stress ◽

Relative Number ◽

Dopamine System ◽

Adult Mice ◽

Metabolic Conditions ◽

Molecular Signals

Primary cilia (PC) are microtubule-based protrusions of the cell membrane transducing molecular signals during brain development. Here, we report that PC are required for maintenance of Substantia nigra (SN) dopaminergic (DA) neurons highly vulnerable in Parkinson’s disease (PD). Targeted blockage of ciliogenesis in differentiated DA neurons impaired striato-nigral integrity in adult mice. The relative number of SN DA neurons displaying a typical auto-inhibition of spontaneous activity in response to dopamine was elevated under control metabolic conditions, but not under metabolic stress. Strikingly, in the absence of PC, the remaining SN DA neurons were less vulnerable to the PD neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP). Our data indicate conserved PC-dependent neuroadaptive responses to DA lesions in the striatum. Moreover, PC control the integrity and dopamine response of a subtype of SN DA neurons. These results reinforce the critical role of PC as sensors of metabolic stress in PD and other disorders of the dopamine system.

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Contribution of the mesolimbic dopamine system in mediating the effects of leptin and ghrelin on feeding

Proceedings of The Nutrition Society ◽

10.1017/s0029665112000614 ◽

2012 ◽

Vol 71 (4) ◽

pp. 435-445 ◽

Cited By ~ 40

Author(s):

R. van Zessen ◽

G. van der Plasse ◽

R. A. H. Adan

Keyword(s):

Energy Balance ◽

Dopaminergic Neurons ◽

Drugs Of Abuse ◽

Neural Circuit ◽

Direct Effects ◽

Mesolimbic Dopamine ◽

Dopamine System ◽

Mesolimbic Dopamine System ◽

Brain Circuits

Feeding behaviour is crucial for the survival of an organism and is regulated by different brain circuits. Among these circuits the mesolimbic dopamine (DA) system is implicated in the anticipation and motivation for food rewards. This system consists of the dopaminergic neurons in the ventral tegmental area (VTA), and their projections to different cortico-limbic structures such as the nucleus accumbens and medial prefrontal cortex. While the importance of this system in motivational drive for different rewards, including drugs of abuse, has been clearly established, its role in energy balance remains largely unexplored. Evidence suggests that peripheral hormones such as leptin and ghrelin are involved in the anticipation and motivation for food and this might be partially mediated through their effects on the VTA. Yet, it remains to be determined whether these effects are direct effects of ghrelin and leptin onto VTA DA neurons, and to what extent indirect effects through other brain areas contribute. Elucidation of the role of leptin and ghrelin signalling on VTA DA neurons in relation to disruptions of energy balance might provide important insights into the role of this neural circuit in obesity and anorexia nervosa.

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Ketamine and rapidly acting antidepressants: Breaking the speed of sound or light?

Australian & New Zealand Journal of Psychiatry ◽

10.1177/0004867418783567 ◽

2018 ◽

Vol 52 (11) ◽

pp. 1026-1029 ◽

Cited By ~ 5

Author(s):

Michael Berk ◽

Collen Loo ◽

Christopher G Davey ◽

Brian H Harvey

Keyword(s):

Drugs Of Abuse ◽

Critical Role ◽

Rapid Onset ◽

Onset Of Action ◽

Delayed Onset ◽

Adaptive Mechanisms ◽

Psychotropic Agents ◽

Current Therapies ◽

Psychotropic Effects

There is an urgent need for rapidly acting antidepressants. Current therapies share a delayed onset of action, contrasting with drugs of abuse that have rapid psychotropic effects but cause tolerance and dependence. A key uncertainty is whether there is a finite speed limit imposed by the critical role of homeostatic adaptive mechanisms that underpin the efficacy and onset of available psychotropic agents and whether this is mutable with emerging agents with potential rapid onset, in particular ketamine.

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The Role of the SLP in Autism Spectrum Disorder Screening and Assessment

Perspectives on Language Learning and Education ◽

10.1044/lle15.2.50 ◽

2008 ◽

Vol 15 (2) ◽

pp. 50-59 ◽

Cited By ~ 1

Author(s):

Amy Philofsky

Keyword(s):

Language Development ◽

Critical Role ◽

Children With Autism ◽

Autism Spectrum ◽

Children With Asd ◽

Prevalence Estimates ◽

Notable Increase ◽

Screening Assessment ◽

Critical Components

AbstractRecent prevalence estimates for autism have been alarming as a function of the notable increase. Speech-language pathologists play a critical role in screening, assessment and intervention for children with autism. This article reviews signs that may be indicative of autism at different stages of language development, and discusses the importance of several psychometric properties—sensitivity and specificity—in utilizing screening measures for children with autism. Critical components of assessment for children with autism are reviewed. This article concludes with examples of intervention targets for children with ASD at various levels of language development.

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