Effects of Trace Amine-associated Receptor 1 Agonists on the Expression, Reconsolidation, and Extinction of Cocaine Reward Memory

Liu, Jian-Feng; Thorn, David A.; Zhang, Yanan; Li, Jun-Xu

doi:10.1093/ijnp/pyw009

Cited by 31 publications

(25 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We use a combination of gene disruption technologies, expression of targeted FRET sensors and the introduction of competitive peptides to prevent specific GPCR G-protein αsubunit interactions to determine the origin of and mechanism through which TAAR1 initiates both GTPase and PKA signaling cascades. We observe in cell lines and neurons that when TAAR1 is activated by AMPH within the cell, it couples through a G-protein α subunit, G 13 , commonly associated with RhoA GTPase activation. RhoA signaling is concentrated near the endoplasmic reticulum (ER).…”

Section: Introductionmentioning

confidence: 89%

See 1 more Smart Citation

Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains

et al. 2019

View full text Add to dashboard Cite

The extensive use of amphetamines to treat attention deficit hyperactivity disorders in children provides a compelling rationale for understanding the mechanisms of action of amphetamines and amphetamine-related drugs. We have previously shown that acute amphetamine (AMPH) regulates the trafficking of both dopamine and glutamate transporters in dopamine neurons by increasing activation of the small GTPase RhoA and of protein kinase A. Here we demonstrate that these downstream signaling events depend upon the direct activation of a trace amine-associated receptor, TAAR1, an intracellular G-protein coupled receptor (GPCR) that can be activated by amphetamines, trace amines, and biogenic amine metabolites. Using cell lines and mouse lines in which TAAR1 expression has been disrupted, we demonstrate that TAAR1 mediates the effects of AMPH on both RhoA and cAMP signaling. Inhibition of different Gα signaling pathways in cell lines and in vivo using small cell-permeable peptides confirms that the endogenous intracellular TAAR1 couples to G 13 and to G S α-subunits to increase RhoA and PKA activity, respectively. Results from experiments with RhoA-and PKA-FRET sensors targeted to different subcellular compartments indicate that AMPH-elicited PKA activation occurs throughout the cell, whereas G 13mediated RhoA activation is concentrated near the endoplasmic reticulum. These observations define TAAR1 as an obligate intracellular target for amphetamines in dopamine neurons and support a model in which distinct pools of TAAR1 mediate the activation of signaling pathways in different compartments to regulate excitatory and dopaminergic neurotransmission.

show abstract

Section: Introductionmentioning

confidence: 89%

“…TAAR1 knockout (KO) mice are hypersensitive to AMPH [6], and antagonists of TAAR1 modulate the locomotor activation produced by methamphetamine [7], cocaine [8], and other psychostimulants. The addictive properties of methamphetamine [9,10] and cocaine [11][12][13] also appear to be regulated by the receptor.…”

Section: Introductionmentioning

confidence: 99%

Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Pump durations/injection volumes were adjusted on a daily basis according to body weight in order to deliver 1.0 mg/kg/infusion. The BRG1 inhibitor PFI3 (Tocris, MN) was dissolved in a mixture of 1 part absolute ethanol, 1 part Emulphor-620 (Rhodia of Solvay, S.A., Brussels, Belgium), and 18 parts saline (17) at a concentration of 30 mM, based on a previous study (18). …”

Section: Methodsmentioning

confidence: 99%

BRG1 in the Nucleus Accumbens Regulates Cocaine-Seeking Behavior

Wang

Martin

Mueller

et al. 2016

Biological Psychiatry

Self Cite

View full text Add to dashboard Cite

Background Drug addiction is defined as a chronic disease characterized by compulsive drug seeking and episodes of relapse despite prolonged periods of drug abstinence. Neurobiological adaptations, including transcriptional and epigenetic alterations in the nucleus accumbens, are thought to contribute to this life-long disease state. We previously demonstrated that transcription factor SMAD3 is increased following seven days of withdrawal from cocaine self-administration. However, it is still unknown which additional factors participate in the process of chromatin remodeling and facilitate the binding of SMAD3 to promoter regions of target genes. Here we examined the possible interaction of BRG1—also known as SMARCA4, an ATPase-containing chromatin remodeler—and SMAD3 in response to cocaine exposure. Methods The expression of BRG1, as well as its binding to SMAD3 and target gene promoter regions, was evaluated in the nucleus accumbens and dorsal striatum of rats using Western blotting, co-immunoprecipitation, and chromatin immunoprecipitation techniques, respectively, following withdrawal from cocaine self-administration. Rats were assessed for cocaine-seeking behaviors following either intra-accumbal injections of the BRG1 inhibitor PFI3 or viral-mediated overexpression of BRG1. Results Following withdrawal from cocaine self-administration, BRG1 expression and complex formation with SMAD3 are increased in the nucleus accumbens, resulting in increased binding of BRG1 to the promoter regions of Ctnnb1, Mef2d, and Dbn1. Intra-accumbal infusion of PFI3 attenuated, while viral overexpression of Brg1 enhanced, cocaine-reinstatement behavior. Conclusion BRG1 is a key mediator of the SMAD3-dependent regulation of cellular and behavioral plasticity mediating cocaine seeking following a period of withdrawal.

show abstract

“…According to previous ex vivo electrophysiological studies, the TAAR1 partial agonist RO5263397 and full agonist RO5166017 act oppositely on the dopaminergic neuron in the VTA, with RO5166017 inhibiting while RO5263397 potentiating the firing rate of VTA neurons, respectively [44,45]. However, previous results suggest that TAAR1 full agonists and partial agonists showed similar pharmacological effects in their abilities to affect several different behaviors [15,45]. Such a discrepancy is currently difficult to reconcile because of the lack of sufficient evidence but we believe the most likely interpretation is due to the difference between the simplified ex vivo VTA-containing brain slice microenvironment and the complexity of behavioral determination.…”

Section: Taar1 Activation Attenuates Abuse-related Behaviors Of Nicotinementioning

confidence: 96%

“…that was used in the nicotine discrimination paradigm, all doses of RO5166017 and RO5263397 (3.2, 5.6, and 10 mg/kg, i.p.) were selected based on our previous findings [11,13,15]. Nicotine tartrate was dissolved in 0.9% physiological saline, and the pH was adjusted to 7.2-7.4 prior to injection.…”

Section: Drugsmentioning

confidence: 99%

Role of trace amine-associated receptor 1 in nicotine’s behavioral and neurochemical effects

Liu

Seaman

Siemian

et al. 2018

Neuropsychopharmacol

Self Cite

View full text Add to dashboard Cite

Nicotine addiction and abuse remains a global health issue. To date, the fundamental neurobiological mechanism of nicotine addiction remains incompletely understood. Trace amine-associated receptor 1 (TAAR1) is thought to directly modulate dopaminergic system and are thought to be a neural substrate underlying addictive-like behaviors. We aimed to investigate the role of TAAR1 in nicotine addictive-like behaviors. TAAR1 expression after nicotine treatment was evaluated by western blotting. c-Fos immunofluorescence and in vivo fast-scan cyclic voltammetry were used to examine the activation of brain regions and dopamine release, respectively. We then thoroughly and systematically examined the role of TAAR1 in mediating nicotine-induced sensitization, nicotine discrimination, nicotine self-administration, nicotine demand curve, and the reinstatement of nicotine-seeking. Local pharmacological manipulation was conducted to determine the role of TAAR1 in the nucleus accumbens (NAcs) in the reinstatement of nicotine-seeking. We found that the expression of TAAR1 protein was selectively downregulated in the NAc, with no change in either dorsal striatum or prefrontal cortex. TAAR1 activation was sufficient to block nicotine-induced c-Fos expression in the NAc, while also reducing nicotine-induced dopamine release in the NAc. Systemic administration of TAAR1 agonists attenuated the expression and development of nicotine-induced sensitization, nicotine self-administration, the reinstatement of nicotine-seeking, and increased the elasticity of nicotine demand curve, while intra-NAc infusions of a TAAR1 agonist was sufficient to attenuate nicotine reinstatement. Moreover, TAAR1-knockout rats showed augmented cue-induced and drug-induced reinstatement of nicotine-seeking. These results indicated that modulation of TAAR1 activity regulates nicotine addictive-like behaviors and TAAR1 represents a novel target towards the treatment of nicotine addiction.

show abstract

Effects of Trace Amine-associated Receptor 1 Agonists on the Expression, Reconsolidation, and Extinction of Cocaine Reward Memory

Cited by 31 publications

References 45 publications

Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains

Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains

BRG1 in the Nucleus Accumbens Regulates Cocaine-Seeking Behavior

Role of trace amine-associated receptor 1 in nicotine’s behavioral and neurochemical effects

Contact Info

Product

Resources

About