Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors
TL;DR: This work found that midbrain DA neurons from mice deficient in D2 autoreceptors lacked DA-mediated somatodendritic synaptic responses and inhibition of DA release, and displayed elevated DA synthesis and release, hyperlocomotion and supersensitivity to the psychomotor effects of cocaine.
Abstract: Dopamine (DA) D2 receptors expressed in DA neurons (D2 autoreceptors) exert a negative feedback regulation that reduces DA neuron firing, DA synthesis and DA release. As D2 receptors are mostly expressed in postsynaptic neurons, pharmacological and genetic approaches have been unable to definitively address the in vivo contribution of D2 autoreceptors to DA-mediated behaviors. We found that midbrain DA neurons from mice deficient in D2 autoreceptors (Drd2(loxP/loxP); Dat(+/IRES-cre), referred to as autoDrd2KO mice) lacked DA-mediated somatodendritic synaptic responses and inhibition of DA release. AutoDrd2KO mice displayed elevated DA synthesis and release, hyperlocomotion and supersensitivity to the psychomotor effects of cocaine. The mice also exhibited increased place preference for cocaine and enhanced motivation for food reward. Our results highlight the importance of D2 autoreceptors in the regulation of DA neurotransmission and demonstrate that D2 autoreceptors are important for normal motor function, food-seeking behavior, and sensitivity to the locomotor and rewarding properties of cocaine.
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TL;DR: Molecular genetic studies have identified transduction and transcription factors that act in neurocircuitry associated with the development and maintenance of addiction that might mediate initial vulnerability, maintenance, and relapse associated with addiction.
1,985 citations
TL;DR: The circuit- and cell-level mechanisms of addiction are discussed and interventions designed to mitigate or even reverse them would be beneficial for the treatment of addiction.
926 citations
Cites background from "Cocaine supersensitivity and enhanc..."
...the DA increases triggered by cocaine, and presumably other drugs, activate D2R auto-receptors inhibiting DA cell firing and DA release (Bello et al., 2011), which is perhaps why the intensity of the cocaine ‘‘high’’ is reduced with subsequent...
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...…Inc. the DA increases triggered by cocaine, and presumably other drugs, activate D2R auto-receptors inhibiting DA cell firing and DA release (Bello et al., 2011), which is perhaps why the intensity of the cocaine ‘‘high’’ is reduced with subsequent Mesocorticolimbic brain areas where there…...
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TL;DR: The role of the DA system in drug addiction and food motivation is focused on, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.
Abstract: Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DAmesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural rewards such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.
408 citations
Cites background from "Cocaine supersensitivity and enhanc..."
...…exhibited increased place preference for cocaine, as well as enhanced motivation for food reward, perhaps owing to the absence of presynaptic inhibition by autoreceptors that further elevates extracellular DA and maximizes the stimulation of postsynaptic DA receptors (Bello et al., 2011)....
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TL;DR: It is demonstrated that inactivation of the Fto gene, encoding a nucleic acid demethylase, impairs dopamine receptor type 2 (D2R) and type 3 (D3R) (collectively, 'D2-like receptor')-dependent control of neuronal activity and behavioral responses.
Abstract: Dopaminergic (DA) signaling governs the control of complex behaviors, and its deregulation has been implicated in a wide range of diseases. Here we demonstrate that inactivation of the Fto gene, encoding a nucleic acid demethylase, impairs dopamine receptor type 2 (D2R) and type 3 (D3R) (collectively, 'D2-like receptor')-dependent control of neuronal activity and behavioral responses. Conventional and DA neuron-specific Fto knockout mice show attenuated activation of G protein-coupled inwardly-rectifying potassium (GIRK) channel conductance by cocaine and quinpirole. Impaired D2-like receptor-mediated autoinhibition results in attenuated quinpirole-mediated reduction of locomotion and an enhanced sensitivity to the locomotor- and reward-stimulatory actions of cocaine. Analysis of global N(6)-methyladenosine (m(6)A) modification of mRNAs using methylated RNA immunoprecipitation coupled with next-generation sequencing in the midbrain and striatum of Fto-deficient mice revealed increased adenosine methylation in a subset of mRNAs important for neuronal signaling, including many in the DA signaling pathway. Several proteins encoded by these mRNAs had altered expression levels. Collectively, FTO regulates the demethylation of specific mRNAs in vivo, and this activity relates to the control of DA transmission.
402 citations
TL;DR: An update of the current knowledge regarding the complex biology, signalling, physiology and pharmacology of dopamine receptors is provided.
Abstract: The variety of physiological functions controlled by dopamine in the brain and periphery is mediated by the D1, D2, D3, D4 and D5 dopamine GPCRs. Drugs acting on dopamine receptors are significant tools for the management of several neuropsychiatric disorders including schizophrenia, bipolar disorder, depression and Parkinson's disease. Recent investigations of dopamine receptor signalling have shown that dopamine receptors, apart from their canonical action on cAMP-mediated signalling, can regulate a myriad of cellular responses to fine-tune the expression of dopamine-associated behaviours and functions. Such signalling mechanisms may involve alternate G protein coupling or non-G protein mechanisms involving ion channels, receptor tyrosine kinases or proteins such as β-arrestins that are classically involved in GPCR desensitization. Another level of complexity is the growing appreciation of the physiological roles played by dopamine receptor heteromers. Applications of new in vivo techniques have significantly furthered the understanding of the physiological functions played by dopamine receptors. Here we provide an update of the current knowledge regarding the complex biology, signalling, physiology and pharmacology of dopamine receptors.
400 citations
Cites background from "Cocaine supersensitivity and enhanc..."
...…the direct modulation of the DAT function by D2 receptors might occur (Chen et al., 2013) and this interaction has physiological or pathological relevance (Bowton et al., 2010; Owens et al., 2012); however, no alterations in DAT function were found in D2 autoreceptor KO mice (Bello et al., 2011)....
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...Interestingly, while the role of presynaptic D2 receptors in autoreceptor regulation of dopamine neuron firing rate, as well as dopamine synthesis and release is well established (Bello et al., 2011), a recent study involving cell-specific KO mice has shown a significant contribution of postsynaptic D2 receptors in the local feedback regulation of dopaminergic transmission in the dorsal striatum as well (Anzalone et al....
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...…presynaptic D2 receptors in autoreceptor regulation of dopamine neuron firing rate, as well as dopamine synthesis and release is well established (Bello et al., 2011), a recent study involving cell-specific KO mice has shown a significant contribution of postsynaptic D2 receptors in the local…...
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..., 2012); however, no alterations in DAT function were found in D2 autoreceptor KO mice (Bello et al., 2011)....
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References
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TL;DR: In homozygote mice, dopamine persists at least 100 times longer in the extracellular space, explaining the biochemical basis of the hyperdopaminergic phenotype and demonstrating the critical role of the transporter in regulating neurotransmission.
Abstract: Disruption of the mouse dopamine transporter gene results in spontaneous hyperlocomotion despite major adaptive changes, such as decreases in neurotransmitter and receptor levels. In homozygote mice, dopamine persists at least 100 times longer in the extracellular space, explaining the biochemical basis of the hyperdopaminergic phenotype and demonstrating the critical role of the transporter in regulating neurotransmission. The dopamine transporter is an obligatory target of cocaine and amphetamine, as these psychostimulants have no effect on locomotor activity or dopamine release and uptake in mice lacking the transporter.
2,439 citations
TL;DR: Dopamine’s contribution appears to be chiefly to cause ‘wanting’ for hedonic rewards, more than ‘liking’ or learning for those rewards.
Abstract: Introduction
Debate continues over the precise causal contribution made by mesolimbic dopamine systems to reward. There are three competing explanatory categories: ‘liking’, learning, and ‘wanting’. Does dopamine mostly mediate the hedonic impact of reward (‘liking’)? Does it instead mediate learned predictions of future reward, prediction error teaching signals and stamp in associative links (learning)? Or does dopamine motivate the pursuit of rewards by attributing incentive salience to reward-related stimuli (‘wanting’)? Each hypothesis is evaluated here, and it is suggested that the incentive salience or ‘wanting’ hypothesis of dopamine function may be consistent with more evidence than either learning or ‘liking’. In brief, recent evidence indicates that dopamine is neither necessary nor sufficient to mediate changes in hedonic ‘liking’ for sensory pleasures. Other recent evidence indicates that dopamine is not needed for new learning, and not sufficient to directly mediate learning by causing teaching or prediction signals. By contrast, growing evidence indicates that dopamine does contribute causally to incentive salience. Dopamine appears necessary for normal ‘wanting’, and dopamine activation can be sufficient to enhance cue-triggered incentive salience. Drugs of abuse that promote dopamine signals short circuit and sensitize dynamic mesolimbic mechanisms that evolved to attribute incentive salience to rewards. Such drugs interact with incentive salience integrations of Pavlovian associative information with physiological state signals. That interaction sets the stage to cause compulsive ‘wanting’ in addiction, but also provides opportunities for experiments to disentangle ‘wanting’, ‘liking’, and learning hypotheses. Results from studies that exploited those opportunities are described here.
2,161 citations
TL;DR: A simple non-radioactive in situ hybridization procedure for tissue sections and cultured cells using digoxigenin-labelled cRNA probes for the detection of various transcripts present at a wide range of expression levels in the central nervous system is developed.
Abstract: We have developed a simple non-radioactive in situ hybridization procedure for tissue sections and cultured cells using digoxigenin-labelled cRNA probes. This protocol can be applied for the detection of various transcripts present at a wide range of expression levels in the central nervous system. Cerebellar hybridization signals for transcripts estimated to be expressed at high (MBP, myelin basic protein), moderate (GluR1, subunit of AMPA/kainate sensitive glutamate receptors) and low (inositol polyphosphate-5-phosphatase) levels of abundance are demonstrated as examples. The sensitivity and cellular resolution were significantly improved by avoiding any ethanol treatment commonly used in other procedures. The localization of a labelled cell with respect to its environment is shown to be more easily assessed by counterstaining of the tissue with the nuclear dye Hoechst 33258. The present protocol can be combined with immunocytochemistry as demonstrated for glial fibrillary acidic protein (GFAP). All steps of the procedure, including preparation and labelling of the cRNA probes, pretreatment of tissue, hybridization and visualization of the labelled transcripts, are described in detail.
1,175 citations
TL;DR: The object-recognition task has been used to study mutant mice, aging deficits, early developmental influences, nootropic manipulations, teratological drug exposure and novelty seeking.
Abstract: Rats and mice have a tendency to interact more with a novel object than with a familiar object. This tendency has been used by behavioral pharmacologists and neuroscientists to study learning and memory. A popular protocol for such research is the object-recognition task. Animals are first placed in an apparatus and allowed to explore an object. After a prescribed interval, the animal is returned to the apparatus, which now contains the familiar object and a novel object. Object recognition is distinguished by more time spent interacting with the novel object. Although the exact processes that underlie this 'recognition memory' requires further elucidation, this method has been used to study mutant mice, aging deficits, early developmental influences, nootropic manipulations, teratological drug exposure and novelty seeking.
1,029 citations
TL;DR: Therapeutic interventions aimed at restoring brain dopaminergic tone and activity of cortical projection regions could improve prefrontal function, enhance inhibitory control and interfere with impulsivity and compulsive drug administration while helping to motivate the addicted person to engage in non-drug related behaviors.
883 citations