Activation of D2 autoreceptors alters cocaine-induced locomotion and slows down local field oscillations in the rat ventral tegmental area

Koulchitsky, Stanislav; Delairesse, Charlotte; Beeken, Thomas; Alexandre, Monteforte; Dethier, Jean-Claude; Quertemont, Étienne; Findeisen, Rolf; Bullinger, Eric; Seutin, Vincent

doi:10.1016/j.neuropharm.2016.04.034

Cited by 7 publications

(6 citation statements)

References 45 publications

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“…In each case, autoDrd2-KO mice exhibiting a significantly greater locomotor response to cocaine than littermate controls, as expected ( Bello et al, 2011 ; Koulchitsky et al, 2016 ).…”

Section: Resultssupporting

confidence: 77%

Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice

Linden

James

McDaniel

et al. 2018

eNeuro

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Neuroimaging studies in animal models and human subjects have each revealed that relatively low striatal dopamine D2-like receptor binding potential is associated with poor impulse control and with vulnerability for addiction-related behaviors. These studies cannot, however, disambiguate the roles for various pools of D2 receptors found in the striatum (e.g., those expressed on medium spiny striato-pallidal neurons vs on dopamine-releasing nerve terminals) in these behavioral outcomes. To clarify the role of the latter pool, namely, D2 autoreceptors, we studied mice carrying a conditional DRD2 gene, with or without Cre-recombinase expressed under the transcriptional control of the dopamine transporter gene locus (autoDrd2-KO, n = 19 and controls, n = 21). These mice were tested for locomotor response to cocaine, and spatial reversal learning was assessed in operant conditioning chambers. As predicted, compared to control mice, autoDrd2-KO animals demonstrated heightened sensitivity to the locomotor stimulating effect of cocaine (10 mg/kg, i.p.), confirming previous research using a similar genetic model. In the spatial reversal learning task, autoDrd2-KO mice were slower to reach a learning criterion and had difficulty sustaining a prolonged nose poke response, measurements conceptually related to impaired response inhibition. Rate of learning of the initial discrimination and latencies to collect rewards, to initiate trials and to produce a response were unaffected by genetic deletion of D2 autoreceptors, discarding possible motor and motivational factors. Together, these findings confirm the role of D2 autoreceptors in reversal learning and suggest a broader involvement in behavioral inhibition mechanisms.

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“…In each case, autoDrd2-KO mice exhibiting a significantly greater locomotor response to cocaine than littermate controls, as expected ( Bello et al, 2011 ; Koulchitsky et al, 2016 ).…”

Section: Resultssupporting

confidence: 77%

Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice

Linden

James

McDaniel

et al. 2018

eNeuro

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“… 39 A recent study indicated that the beta oscillation was more relevant for long-range synchronization involving long transmission delays, 40 whereas the gamma oscillation was more evident in the communication of close-by areas. 41 Cocaine was reported to significantly increase VTA theta band oscillations in free-moving rats, 42 indicating delta and theta oscillations in VTA corresponded to motivation. The present study found that SNI increased the LFP power in delta, theta, and beta oscillations, but GBP significantly decreased the theta oscillation, indicating that chronic GBP treatment reduced theta band oscillation to reverse the depression-like behaviors at the level of LFP.…”

Section: Discussionmentioning

confidence: 99%

Gabapentin regulates dopaminergic neuron firing and theta oscillation in the ventral tegmental area to reverse depression-like behavior in chronic neuropathic pain state

Wen

Wang

et al. 2018

JPR

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PurposeVentral tegmental area (VTA) dopamine system plays an important role in depression and is also involved in pain experience. In this study, we investigated the VTA dopaminergic (DA) neuron firing and local field potential (LFP) in pain-related depression, and we try to explore the underlying relationship between pain and depression.Materials and methodsWe used neuropathic pain model [spare nerve injury (SNI)] to induce pain-related depression. The Dixon up–down method was used to test mechanical hypersensitivity. Behavioral changes like open field test, sucrose preference test, and forced swim test were used to test depression-like behaviors. Gabapentin (GBP) was used to explore the chronic analgesic treatment that could reverse pain-related depression. To investigate the in vivo variations of VTA DA neuron firing and LFP, multichannel acquisition processor system was used.ResultsWe used SNI to induce depression-like behaviors. Repeated GBP treatment reversed these behaviors after 14 days of injection. An in vivo electrophysiological analysis of the firing characteristics of VTA DA neurons and LFP revealed that SNI increased the firing rate of DA neurons, but not the burst firing activity. Surprisingly, chronic GBP reversed the firing rate of DA neurons and reduced the burst firing activity. Moreover, SNI increased the LFP power in delta and theta oscillation and decreased it in beta oscillation. Repeated administration of GBP significantly suppressed theta oscillation. Above all, chronic GBP altered these characteristics to reverse depression-like behaviors.ConclusionThe present study confirmed that the tonic firing activity of VTA DA neurons, but not the burst firing activity, was the key factor in peripheral neuropathy–induced depression. Chronic GBP regulated the firing pattern of DA neurons and decreased theta oscillation in VTA to treat pain-related depression. This variation tendency of electrophysiological characteristics of VTA DA neurons and theta oscillation in VTA might represent an attempt to cope with pain-related negative mood disorder.

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“…Pharmacological and genetic approaches have implicated GABA B R and D 2 R-dependent signaling in the VTA in drug-induced behaviors. For example, pharmacological activation of D 2 R in the VTA suppressed cocaine-induced activity ( Koulchitsky et al, 2016 ) and cocaine-reinstated drug seeking behavior ( Xue et al, 2011 ), while pharmacological inhibition of D 2 R in the VTA increased psychostimulant-induced locomotor activity ( Chen and Reith, 1994 ; Tanabe et al, 2004 ). Similarly, intra-VTA infusion of the GABA B R agonist baclofen blocked the locomotor-stimulatory effect of psychostimulants and opioids ( Kalivas et al, 1990 ; Steketee and Kalivas, 1991 ; Chen and Reith, 1994 ; Leite-Morris et al, 2002 , 2004 ) and attenuated self-administration of cocaine, opioids, and other drugs of abuse ( Xi and Stein, 1999 ; Brebner et al, 2000 ; Leite-Morris et al, 2004 ; Backes and Hemby, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

Differential Impact of Inhibitory G-Protein Signaling Pathways in Ventral Tegmental Area Dopamine Neurons on Behavioral Sensitivity to Cocaine and Morphine

DeBaker

Velasco

McCall

et al. 2021

eNeuro

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Drugs of abuse engage overlapping but distinct molecular and cellular mechanisms to enhance dopamine (DA) signaling in the mesocorticolimbic circuitry. DA neurons of the ventral tegmental area (VTA) are key substrates of drugs of abuse and have been implicated in addiction-related behaviors. Enhanced VTA DA neurotransmission evoked by drugs of abuse can engage inhibitory G protein-dependent feedback pathways, mediated by GABA B receptors (GABA B Rs) and D 2 DA receptors (D 2 Rs). Chemogenetic inhibition of VTA DA neurons potently suppressed baseline motor activity, as well as the motor-stimulatory effect of cocaine and morphine, confirming the critical influence of VTA DA neurons and inhibitory G protein signaling in these neurons on this addictionrelated behavior. To resolve the relative influence of GABA B R-and D 2 R-dependent signaling pathways in VTA DA neurons on behavioral sensitivity to drugs of abuse, we developed a neuron-specific viral CRISPR/Cas9 approach to ablate D 2 R and GABA B R in VTA DA neurons. Ablation of GABA B R or D 2 R did not impact baseline physiological properties or excitability of VTA DA neurons, but it did preclude the direct somatodendritic inhibitory influence of GABA B R or D 2 R activation. D 2 R ablation potentiated the motor-stimulatory effect of cocaine in male and female mice, whereas GABA B R ablation selectively potentiated cocaine-induced activity in male subjects only. Neither D 2 R nor GABA B R ablation impacted morphine-induced motor activity. Collectively, our data show that cocaine and morphine differ in the extent to which they engage inhibitory G protein-dependent feedback pathways in VTA DA neurons and highlight key sex differences that may impact susceptibility to various facets of addiction. SIGNIFICANCE STATEMENT Although inhibitory G protein-dependent signaling involving the GABA B (GABA B R) and D 2 dopamine receptor (D 2 R) in VTA DA neurons is thought to limit DA neurotransmission evoked by drugs of abuse, their relative impact on behavioral sensitivity to such drugs is unclear. Using a neuron-specific viral CRISPR/Cas9 approach, we show that that loss of D 2 R in VTA DA neurons enhances behavioral sensitivity to systemic administration of cocaine in male and female mice, whereas loss of GABA B R enhances cocaine sensitivity only in males. Neither GABA B R nor D 2 R ablation impacted behavioral sensitivity to morphine. Thus, differential engagement of inhibitory feedback pathways in VTA DA neurons likely contributes to drug-specific neurophysiological and behavioral effects and may underlie sex differences associated 84 with some facets of addiction.

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Activation of D2 autoreceptors alters cocaine-induced locomotion and slows down local field oscillations in the rat ventral tegmental area

Cited by 7 publications

References 45 publications

Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice

Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice

Gabapentin regulates dopaminergic neuron firing and theta oscillation in the ventral tegmental area to reverse depression-like behavior in chronic neuropathic pain state

Differential Impact of Inhibitory G-Protein Signaling Pathways in Ventral Tegmental Area Dopamine Neurons on Behavioral Sensitivity to Cocaine and Morphine

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