Sigma receptor agonists: receptor binding and effects on mesolimbic dopamine neurotransmission assessed by microdialysis.
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 σ(½)-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 σ(½)-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.
Psychobiology Section, Medication Discovery Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland, USA.
Linda
L
Garcés-Ramírez
Jennifer L
JL
Green
Takato
T
Hiranita
Theresa A
TA
Kopajtic
Maddalena
M
Mereu
Alexandra M
AM
Thomas
Christophe
C
Mesangeau
Sanju
S
Narayanan
Christopher R
CR
McCurdy
Jonathan L
JL
Katz
Gianluigi
G
Tanda
D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005021:Ethylamines / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D006146:Guanidines / Q000032:analysis / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis / Q000379:methods; D009025:Morpholines / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*
C093337:1-(2-(3,4-dichlorophenyl)ethyl)-4-methylpiperazine; C557789:6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo(d)oxazol-2(3H)-one; D001583:Benzoxazoles; D050483:Dopamine Plasma Membrane Transport Proteins; D005021:Ethylamines; D005029:Ethylenediamines; D006146:Guanidines; D009025:Morpholines; D010879:Piperazines; D011759:Pyrrolidines; D017480:Receptors, sigma; C085527:BD 1008; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; D003042:Cocaine; C050232:1,3-ditolylguanidine; D004298:Dopamine