The Pharmacology of the Novel and Selective Sigma Ligand, PD 144418

Akunne, Hyacinth C.; Whetzel, Steven Z.; Wiley, J N; Corbin, A; Ninteman, F.W.; Tecle, Haile; Pei, Yanxi; Pugsley, Thomas A.; Heffner, Thomas G.

doi:10.1016/s0028-3908(96)00161-x

Cited by 42 publications

(35 citation statements)

References 36 publications

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“…Unexpectedly, cocaine was able to induce ERK1/2 phosphorylation per se, although this effect depended on the presence of both the D 1 R and σ 1 R. As these particular effects were reproduced by the selective σ 1 R agonist (17) and counteracted by the putative σ 1 R antagonist PD144.418 (22), these results indicate that cocaine acts as a σ 1 R agonist. In living cells, cocaine-induced ERK1/2 phosphorylation was seen at short times of cocaine exposure (10 min); but the maximum effect was reached at 30 min, suggesting an involvement of cocaine-induced translocation of σ 1 R to the plasma membrane, with a consequent increase in cell surface σ 1 R-D 1 R heteromers.…”

Section: Discussionmentioning

confidence: 81%

Direct involvement of σ-1 receptors in the dopamine D ₁ receptor-mediated effects of cocaine

Navarro

Moreno

Aymerich

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

153

158

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It is well known that cocaine blocks the dopamine transporter. This mechanism should lead to a general increase in dopaminergic neurotransmission, and yet dopamine D 1 receptors (D 1 Rs) play a more significant role in the behavioral effects of cocaine than the other dopamine receptor subtypes. Cocaine also binds to σ-1 receptors, the physiological role of which is largely unknown. In the present study, D 1 R and σ 1 R were found to heteromerize in transfected cells, where cocaine robustly potentiated D 1 R-mediated adenylyl cyclase activation, induced MAPK activation per se and counteracted MAPK activation induced by D 1 R stimulation in a dopamine transporterindependent and σ 1 R-dependent manner. Some of these effects were also demonstrated in murine striatal slices and were absent in σ 1 R KO mice, providing evidence for the existence of σ 1 R-D 1 R heteromers in the brain. Therefore, these results provide a molecular explanation for which D 1 R plays a more significant role in the behavioral effects of cocaine, through σ 1 R-D 1 R heteromerization, and provide a unique perspective toward understanding the molecular basis of cocaine addiction.receptor heteromer | drug addiction A key molecular mechanism contributing to the development of addiction by drugs of abuse consist of the increase of the extracellular levels of dopamine in the striatum, particularly in its ventral portion, the nucleus accumbens (1, 2). Cocaine causes a rapid and strong increase in striatal extracellular dopamine by its ability to bind with high affinity to the dopamine transporter (DAT) and to inhibit its function (3-5). In the striatum, dopamine signaling is mediated mainly by dopamine D 1 and D 2 receptors (D 1 Rs and D 2 Rs, respectively), which are mostly segregated in two phenotypically different subtypes of GABAergic medium-sized spiny neurons (MSNs) (6). Activation of D 1 Rs is an absolute requirement for the induction of many of the cellular and behavioral responses to cocaine, as deduced from studies performed in D 1 R KO mice and from experiments with transgenic mice in which D 1 R-or D 2 R-expressing MSNs are visualized by the expression of fluorescent proteins (7-11).The σ-1 receptor, originally proposed as a subtype of opioid receptors, is now considered to be a nonopioid receptor with two transmembrane domains, one extracellular loop and cytosolic N and C termini (12). The σ 1 R is highly expressed in the brain, including the striatum, and its association with neurons is well established (12, 13). However, its biological function and even its main endogenous neurotransmitter remain enigmatic (12). Cocaine interacts with σ 1 Rs at pharmacologically relevant concentrations (12,14). In fact, reducing brain σ 1 R levels with antisense oligonucleotides attenuates the convulsive and locomotor stimulant actions of cocaine (15, 16), and σ 1 R antagonists mitigate the actions of cocaine in animal models (12,14). A recent study showed that σ 1 R agonists not only potentiate the reinforcing effects of cocaine, but they may be self...

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Section: Discussionmentioning

confidence: 81%

Direct involvement of σ-1 receptors in the dopamine D ₁ receptor-mediated effects of cocaine

Navarro

Moreno

Aymerich

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

153

158

View full text Add to dashboard Cite

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“…10C). Moreover, pretreatment with the 1 R antagonist PD144418 (Akunne et al, 1997) blocked the effect of cocaine, and the negative cross- talk between CRF and orexin-A was still present with preincubation of cocaine and PD144418 (Fig. 10D).…”

Section: Resultsmentioning

confidence: 88%

Orexin–Corticotropin-Releasing Factor Receptor Heteromers in the Ventral Tegmental Area as Targets for Cocaine

et al. 2015

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Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R-OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target sigma(1) receptor (sigma R-1) also associates with the CRF1R-OX1R heteromer. Cocaine binding to the sigma R-1-CRF1R-OX1R complex promotes a long-term disruption of the orexin-A-CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking

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“…However, in a behavioral study, the sigma ligand EMD 57445 did not affect several 5-HT related parameters such as 8-OH-DPATinduced behavioural syndrome, m-chlorophenylpiperazine-induced hypothermia or L-5-hydroxytryptophaninduced head twitches (188). In addition, biochemical studies showed that EMD 57445 and the sigma 1 ligand PD144418 did not induce any change in 5-HT or 5-hydroxyindoleacetic acid (5-HIAA) levels in various brain regions, suggesting that these ligands exert no effects on 5-HT-receptor populations or 5-HT metabolism (188,189). However, EMD 57445 and PD 144415 have been suggested to be a sigma antagonists and therefore may have no effects on their own.…”

Section: Sigma Receptors and Serotonergic Neurotransmissionmentioning

confidence: 99%

The Role of Sigma Receptors in Depression

2005

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Abstract. Behavioral models used to test potential antidepressants have shown that ligands that bind to sigma receptors possess "antidepressant-like" properties. The focus of this review is to discuss the literature concerning sigma receptors and their ligands, with respect to their antidepressants properties. In addition to the behavioral data, we discuss electrophysiological and biochemical models demonstrating sigma receptors' ability to modulate important factors in the pathophysiology of depression and / or the mechanisms of action of antidepressants such as the serotonergic neurotransmission in the dorsal raphe nucleus (DRN) and the glutamatergic transmission in the hippocampus. We also discuss the significance of these two systems in the mechanism of action of antidepressants. Sigma ligands have potential as antidepressant medications with a fast onset of action as they produce a rapid modulation of the serotonergic system in the DRN and the glutamatergic transmission in the hippocampus. As these effects of sigma ligands may produce antidepressant properties by completely novel mechanisms of action, they may provide an alternative to the antidepressants currently available and may prove to be beneficial for treatment-resistant depressed patients.

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The Pharmacology of the Novel and Selective Sigma Ligand, PD 144418

Cited by 42 publications

References 36 publications

Direct involvement of σ-1 receptors in the dopamine D ₁ receptor-mediated effects of cocaine

Direct involvement of σ-1 receptors in the dopamine D ₁ receptor-mediated effects of cocaine

Orexin–Corticotropin-Releasing Factor Receptor Heteromers in the Ventral Tegmental Area as Targets for Cocaine

The Role of Sigma Receptors in Depression

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The Pharmacology of the Novel and Selective Sigma Ligand, PD 144418

Cited by 42 publications

References 36 publications

Direct involvement of σ-1 receptors in the dopamine D 1 receptor-mediated effects of cocaine

Direct involvement of σ-1 receptors in the dopamine D 1 receptor-mediated effects of cocaine

Orexin–Corticotropin-Releasing Factor Receptor Heteromers in the Ventral Tegmental Area as Targets for Cocaine

The Role of Sigma Receptors in Depression

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Direct involvement of σ-1 receptors in the dopamine D ₁ receptor-mediated effects of cocaine

Direct involvement of σ-1 receptors in the dopamine D ₁ receptor-mediated effects of cocaine