Elsevier

Biological Psychiatry

Volume 69, Issue 3, 1 February 2011, Pages 208-217
Biological Psychiatry

Archival Report
Sigma Receptor Agonists: Receptor Binding and Effects on Mesolimbic Dopamine Neurotransmission Assessed by Microdialysis

https://doi.org/10.1016/j.biopsych.2010.07.026Get rights and content

Background

Subtypes of sigma (σ) receptors, σ1 and σ2, can be pharmacologically distinguished, and each may be involved in substance-abuse disorders. σ-Receptor antagonists block cocaine place conditioning and σ-receptor agonists are self-administered in rats that previously self-administered cocaine. Self-administration of abused drugs has been related to increased dopamine (DA) neurotransmission, however, σ-receptor agonist effects on mesolimbic DA are not fully characterized.

Methods

Receptor-binding studies assessed affinities of σ-receptor ligands for σ-receptor subtypes and the DA transporter; effects on DA transmission in the rat nucleus accumbens shell were assessed using in vivo microdialysis.

Results

Cocaine (.1–1.0 mg/kg intravenous [IV]), the nonselective σ1/2-receptor agonist DTG (1.0–5.6 mg/kg IV), and the selective σ1-receptor agonist PRE-084 (.32–10 mg/kg IV) dose-dependently increased DA to ∼275%, ∼150%, and ∼160% maxima, respectively. DTG-induced stimulation of DA was antagonized by the nonselective σ1/2-receptor antagonist BD 1008 (10 mg/kg intraperitoneal [IP]) and the preferential σ2-receptor antagonist SN 79 (1–3 mg/kg IP), but not by the preferential σ1-receptor antagonist, BD 1063 (10–30 mg/kg IP). Neither PRE-084 nor cocaine was antagonized by BD 1063 or BD 1008.

Conclusions

σ-Receptor agonists stimulated DA in a brain area critical for reinforcing effects of cocaine. DTG effects on DA appear to be mediated by σ2-receptors rather than σ1-receptors. However, DA stimulation by cocaine or PRE-084 does not likely involve σ-receptors. The relatively low potency on DA transmission of the selective σ1-receptor agonist, PRE-084, and its previously reported potent reinforcing effects, suggest a dopamine-independent reinforcing pathway that may contribute to substance-abuse disorders.

Section snippets

σ1 and σ2 Receptor Binding

Frozen whole guinea pig brains (minus cerebellum) were used and processed as already published (37) (see also Supplement 1 for complete details). The guinea pig brains were preferred over rat brains due to their use as a standard for σ-receptor binding because of the relatively higher density of those receptors in that tissue compared with the rat (38). Ligand binding experiments were conducted for σ1-receptor studies with 3 nmol/L [3H](+)-pentazocine (specific activity 28 Ci/mmol) and 8.0 mg

In Vitro Binding Experiments

As has been previously reported (47, 48), DTG and PRE-084 had high affinity for σ-receptors. The homologous competition of DTG modeled better for two than one binding site (Table 1). The high affinity binding Kd value of 21.9 nmol/L is comparable with that reported previously for σ2-receptors in the papers cited above and indicates a twofold to threefold selectivity for σ2 over σ1-receptors, as also reported previously. In contrast, PRE-084 had a high affinity for σ1-receptors (53.2 nmol/L) and

Discussion

A recent study with rodents on self-administration of the σ-receptor agonists DTG and PRE-084 (26) prompted the present study of the effects of these drugs on DA levels in the NAc shell. The goal of the present study was to assess whether the effectiveness of DTG and PRE-084 in maintaining self-administration behavior would correspond with an increase in DA neurotransmission in the NAc shell after acute administration. This correspondence has been found with most drugs abused by humans (28, 29,

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