Persistent supersensitivity of σ receptors develops during repeated methamphetamine treatment

doi:10.1016/0014-2999(92)90388-K

European Journal of Pharmacology

Volume 211, Issue 3, 18 February 1992, Pages 323-328

https://doi.org/10.1016/0014-2999(92)90388-K Get rights and content

Abstract

Functional changes in σ receptors were examined after behavioral sensitization induced by repeated methamphetamine treatment. Rats received either saline or 4 mg/kg methamphetamine for 14 days. (+)3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), a σ receptor agonist, was given as challenge after various periods of abstinence. (+)-3-PPP at doses greater than 6 mg/kg stimulated several forms of behavior in naive rats. (+)-3-PPP at 12 and 24 mg/kg produced more frequent rearing and more intense stereotyped sniffing and repetitive head movements in rats previously sensitized with methamphetamine than in saline-pretreated rats. The augmented response to (+)-3-PPP in methamphetamine-treated rats was maintained for at least one month. The augmented response to (+)-3-PPP was reversed by the combined administration of 100 mg/kg (±) sulpiride, a D₂ dopamine receptor antagonist, and 30 mg/kg BMY 14802, a σ receptor antagonist. These results suggest that repeated methamphetamine treatment induces persistent supersensitivity in σ receptors and that it may subsequently activate the dopamine system.

References (40)

A. Ceci et al.
Activation of A10 mesolimbic system by the σ-receptor agonist (+)SKF 10,047 can be blocked by rimcazole, a novel putative antipsychotic drug
Eur. J. Pharmacol.
(1988)
B.R. De Costa et al.
Synthesis and evaluation of optically pure [³H]-(+)-pentazocine, a highly potent and selective radioligand for σ receptors
FEBS Lett.
(1989)
R.M. Ferris et al.
Evidence that the potential antipsychotic agent rimcazole (BW 234U) is a specific, competitive antagonist of σ sites in brain
Life Sci.
(1986)
S.W. Koch et al.
Differential effects of the enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) at dopamine receptor sites
Eur. J. Pharmacol.
(1983)
B.L. Largent et al.
Novel antipsychotic drugs share high affinity for σ receptors
Eur. J. Pharmacol.
(1988)
M. Mikuni et al.
Interaction of (+)- and (-)-3-PPP with the dopamine receptor in the anterior pituitary gland
Life Sci.
(1984)
A.H. Mulder et al.
Agonist and antagonist effects of 3-PPP enantiomers on functional dopamine autoreceptors and presynaptic dopamine receptors in vitro
Eur. J. Pharmacol.
(1985)
T.E. Robinson et al.
Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis
Brain Res. Rev.
(1986)
B.S. Starr et al.
Behavioral interactions involving D₁ and D₂ dopamine receptors in non-habituated mice
Neuropharmacology
(1987)
M.S. Starr
D-1/D-2 behavioral interactions in the rat involving striatal dopamine D-1 receptors
Eur. J. Pharmacol.
(1988)

G.F. Steinfels et al.

Selective σ receptor agonist and antagonist dopamine neuronal activity

Eur. J. Pharmacol.

(1989)

A.D. Weissman et al.

Selective loss of cerebral cortical sigma, but not PCP binding sites in schizophrenia

Biol. Psychiat.

(1991)

K. Akiyama et al.

Increased ³H-spiperone binding sites in mesolimbic area related to methamphetamine-induced behavioral sensitization

Biol. Psychiat.

(1982)

B. Angrist

Psychosis induced by central nervous system stimulants and related drugs

J. Arnt et al.

Dopamine receptor agonistic and antagonistic effects of 3-PPP enantiomers

Psychopharmacology

(1983)

G. Chouinard et al.

An early phase II clinical trial of BW234U in the treatment of acute schizohrenia in newly admitted patients

Psychopharmacology

(1984)

J. Davidson et al.

The first clinical study of BW-234U in schizophrenia

Psychopharmacol. Bull.

(1982)

E.H. Ellinwood et al.

Evolving behavior in the clinical and experimental amphetamine (model) psychosis

Am. J. Psychiat.

(1973)

R.M. Ferris et al.

BW234U, (cis-9-[3-(3,5-dimethyl-1-piperazinyl]-carbazole dihydrochloride): a novel antipsychotic agent

J. Pharm. Pharmacol.

(1982)

A.M. Graybiel et al.

Neuroleptic-sensitive binding sites in the nigrostriatal system: Evidence for differential distribution of sigma sites in the substancia nigra, pars compacta of the cat

J. Neurosci.

(1989)

Cited by (46)

The sigma-1 receptor as a regulator of dopamine neurotransmission: A potential therapeutic target for methamphetamine addiction
2018, Pharmacology and Therapeutics
Citation Excerpt :
An early study by Ujike et al. showed that treatment with 3 mg/kg of the σ1/2R agonist (+)-3-PPP acutely decreased rearing, locomotion, sniffing, and head movement but potentiated these behaviors when higher doses were utilized. In rats that received repeated 4 mg/kg METH treatment followed by 5 to 8 days of abstinence, (+)-3-PPP enhanced sensitization to locomotor behavior but decreased sensitization to rearing, sniffing, and head movement (Ujike, Okumura, Zushi, Akiyama, & Otsuki, 1992). Similar to this study, the σ1/2R antagonist BMY 14802 also had no effect on acute stereotypic behavior but decreased stereotypy sensitization (Akiyama, Kanzaki, Tsuchida, & Ujike, 1994).
Methamphetamine (METH) abuse is a major public health issue around the world, yet there are currently no effective pharmacotherapies for the treatment of METH addiction. METH is a potent psychostimulant that increases extracellular dopamine levels by targeting the dopamine transporter (DAT) and alters neuronal activity in the reward centers of the brain. One promising therapeutic target for the treatment of METH addiction is the sigma-1 receptor (σ₁R). The σ₁R is an endoplasmic reticulum-localized chaperone protein that is activated by cellular stress, and, unique to this chaperone, its function can also be induced or inhibited by different ligands. Upon activation of this unique “chaperone receptor”, the σ₁R regulates a variety of cellular functions and possesses neuroprotective activity in the brain. Interestingly, a variety of σ₁R ligands modulate dopamine neurotransmission and reduce the behavioral effects of METH in animal models of addictive behavior, suggesting that the σ₁R may be a viable therapeutic target for the treatment of METH addiction. In this review, we provide background on METH and the σ₁R as well as a literature review regarding the role of σ₁Rs in modulating both dopamine neurotransmission and the effects of METH. We aim to highlight the complexities of σ₁R pharmacology and function as well as the therapeutic potential of the σ₁R as a target for the treatment of METH addiction.
The SIGMAR1 gene is associated with a risk of schizophrenia and activation of the prefrontal cortex
2011, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
Several studies have suggested that sigma-1 receptor ligands are useful in the treatment of schizophrenia. In animal studies, sigma receptor antagonists such as BMY-14802 and panamesine (EMD57445) improved methamphetamine-induced behavioral sensitization in rats (Ujike et al., 1992a,b) and sigma receptor antagonists such as BMY-14802, haloperidol and NE-100 improved phencyclidine (PCP)-induced behavioral abnormalities (Ogawa et al., 1994; Okuyama et al., 1995; Takahashi et al., 2001). On the other hand, recent studies suggest that donepezil, a sigma-1 receptor agonist, plays a role in memory processing and that fluvoxamine, also a sigma-1 agonist, can improve PCP-induced cognitive deficits in mice (Hashimoto et al., 2007a; Kunitachi et al., 2009).
Several studies have identified the possible involvement of sigma non-opioid intracellular receptor 1 (SIGMAR1) in the pathogenesis of schizophrenia. The Gln2Pro polymorphism in the SIGMAR1 gene has been extensively examined for an association with schizophrenia. However, findings across multiple studies have been inconsistent. We performed a meta-analysis of the association between the functional Gln2Pro polymorphism and schizophrenia using combined samples (1254 patients with schizophrenia and 1574 healthy controls) from previously published studies and our own additional samples (478 patients and 631 controls). We then used near-infrared spectroscopy to analyze the effects of the Gln2Pro genotype, a schizophrenia diagnosis and the interaction between genotype and diagnosis on activation of the prefrontal cortex (PFC) during a verbal fluency task (127 patients and 216 controls). The meta-analysis provided evidence of an association between Gln2Pro and schizophrenia without heterogeneity across studies (odds ratio = 1.12, p = 0.047). Consistent with previous studies, patients with schizophrenia showed lower bilateral activation of the PFC when compared to controls (p < 0.05). We provide evidence that Pro carriers, who are more common among patients with schizophrenia, have significantly lower activation of the right PFC compared to subjects with the Gln/Gln genotype (p = 0.013). These data suggest that the SIGMAR1 polymorphism is associated with an increased risk of schizophrenia and differential activation of the PFC.
The sigma receptor agonist SA4503 both attenuates and enhances the effects of methamphetamine
2011, Drug and Alcohol Dependence
Citation Excerpt :
A role for sigma receptors also has been identified by multiple behavioral studies with subtype-selective ligands. The induction of methamphetamine locomotor sensitization was augmented by the nonselective sigma receptor agonist (+)-3-PPP in rats (Ujike et al., 1992b). Furthermore, BMY 14802, a σ1 sigma receptor antagonist, blocked methamphetamine-induced sensitization in rats (Ujike et al., 1992a).
Methamphetamine's behavioral effects have been attributed to its interaction with monoamine transporters; however, methamphetamine also has affinity for sigma receptors.
The present study investigated the effect of the sigma receptor agonist SA 4503 and the sigma receptor antagonists BD-1047 and BD-1063 on methamphetamine-evoked [³H]dopamine release from preloaded rat striatal slices. The effect of SA 4503 on methamphetamine-induced hyperactivity and on the discriminative stimulus properties of methamphetamine also was determined.
SA 4503 attenuated methamphetamine-evoked [³H]dopamine release in a concentration-dependent manner. BD-1047 and BD-1063 did not affect release. SA 4503 dose-dependently potentiated and attenuated methamphetamine-induced hyperactivity. SA 4503 pretreatment augmented the stimulus properties of methamphetamine.
Our findings indicate that SA 4503 both enhances and inhibits methamphetamine's effects and that sigma receptors are involved in the neurochemical, locomotor stimulatory and discriminative stimulus properties of methamphetamine.
Attenuation of methamphetamine-induced effects through the antagonism of sigma (σ) receptors: Evidence from in vivo and in vitro studies
2008, European Neuropsychopharmacology
Methamphetamine (METH) and many other abused substances interact with σ receptors. σ receptors are found on dopaminergic neurons and can modulate dopaminergic neurotransmission. Antisense knock down of σ receptors also mitigates METH-induced stimulant effects, suggesting that these proteins are viable medication development targets for treating psychostimulant abuse. In the present study, AC927, a σ receptor antagonist, was evaluated for its ability to attenuate METH-induced effects in vivo and in vitro. Radioligand binding studies showed that AC927 had preferential affinity for σ receptors compared to 29 other receptors, transporters and ion channels. Pretreatment of male, Swiss Webster mice with AC927 significantly attenuated METH-induced locomotor stimulation, striatal dopamine depletions, striatal dopamine transporter reductions, and hyperthermia. When the neurotoxicity of METH was further examined in vitro under temperature-controlled conditions, co-incubation with AC927 mitigated METH-induced cytotoxicity. Together, the results demonstrate that AC927 protects against METH-induced effects, and suggests a new strategy for treating psychostimulant abuse.
An unambiguous assay for the cloned human sigma<inf>1</inf> receptor reveals high affinity interactions with dopamine D<inf>4</inf> receptor selective compounds and a distinct structure-affinity relationship for butyrophenones
2008, European Journal of Pharmacology
The ability of the sigma₁ receptor to interact with a huge range of drug structural classes coupled with its wide distribution in the body has contributed to it being implicated as a possible therapeutic target for a broad array of disorders ranging from substance abuse to depression to Alzheimer's disease. Surprisingly, the reported affinity values for some sigma₁ receptor ligands vary more than 50-fold. The potential of the sigma₁ receptor as a pharmacotherapeutic target prompted us to develop an unambiguous assay system for measuring the affinity of ligands to the cloned human sigma₁ receptor. In the course of characterizing this system and determining the true affinity values for almost three dozen compounds, it was discovered that some dopamine D₄ receptor selective compounds bind sigma₁ receptors with high affinity. A systematic analysis of haloperidol-like compounds revealed a clear structure–affinity relationship amongst clinically relevant butyrophenones. The antidepressant fluvoxamine, the drug of abuse methamphetamine, and the neurosteroid progesterone were amongst the many ligands whose interactions with the sigma₁ receptor were confirmed with our screening assay.
Synthesis and evaluation of fluorine-18-labeled SA4503 as a selective sigma<inf>1</inf> receptor ligand for positron emission tomography
2007, Nuclear Medicine and Biology
The [¹⁸F]fluoromethyl analog of the sigma₁ selective ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) ([¹⁸F]FM-SA4503) was prepared and its potential evaluated for the in vivo measurement of sigma₁ receptors with positron emission tomography (PET). FM-SA4503 had selective affinity for the sigma₁ receptor (K_i for sigma₁ receptor, 6.4 nM; K_i for sigma₂ receptor, 250 nM) that was compatible with the affinity of SA4503 (K_i for sigma₁ receptor, 4.4 nM; K_i for sigma₂ receptor, 242 nM). [¹⁸F]FM-SA4503 was synthesized by ¹⁸F-fluoromethylation of O-demethyl SA4503 in the radiochemical yield of 2.9–16.6% at the end of bombardment with a specific activity of 37.8–283 TBq/mmol at the end of synthesis. In mice, the uptake of [¹⁸F]FM-SA4503 in the brain was gradually increased for 30 min after injection, and then decreased. In the blocking study, brain uptake was significantly decreased by co-injection of haloperidol to 32% of control, and FM-SA4503 to 52% of control. In PET study of the monkey brain, high uptake was found in the cerebral cortex, thalamus and striatum. The radioactivity level of [¹⁸F]FM-SA4503 in the brain regions gradually increased over a period of 120 min after injection, followed by a stable plateau phase until 180 min after injection. In pretreatment with haloperidol measurement of the monkey brain, the radioactivity level was 22–32% and 11–25% of the baseline at 60 and 180 min, respectively, after injection, suggesting high receptor-specific binding. [¹⁸F]FM-SA4503 showed specific binding to sigma₁ receptors in mice and monkeys; therefore, [¹⁸F]FM-SA4503 has the potential for mapping sigma₁ receptors in the brain.

View all citing articles on Scopus

View full text

Persistent supersensitivity of σ receptors develops during repeated methamphetamine treatment

Abstract

Eur. J. Pharmacol.

FEBS Lett.

Life Sci.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Life Sci.

Eur. J. Pharmacol.

Brain Res. Rev.

Neuropharmacology

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Biol. Psychiat.

Increased 3H-spiperone binding sites in mesolimbic area related to methamphetamine-induced behavioral sensitization

Biol. Psychiat.

Psychosis induced by central nervous system stimulants and related drugs

Dopamine receptor agonistic and antagonistic effects of 3-PPP enantiomers

Psychopharmacology

An early phase II clinical trial of BW234U in the treatment of acute schizohrenia in newly admitted patients

Psychopharmacology

The first clinical study of BW-234U in schizophrenia

Psychopharmacol. Bull.

Evolving behavior in the clinical and experimental amphetamine (model) psychosis

Am. J. Psychiat.

BW234U, (cis-9-[3-(3,5-dimethyl-1-piperazinyl]-carbazole dihydrochloride): a novel antipsychotic agent

J. Pharm. Pharmacol.

Neuroleptic-sensitive binding sites in the nigrostriatal system: Evidence for differential distribution of sigma sites in the substancia nigra, pars compacta of the cat

J. Neurosci.

Increased ³H-spiperone binding sites in mesolimbic area related to methamphetamine-induced behavioral sensitization