Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.99.3 (PRE)
 1,923 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Sigma receptors were first described in 1976 as opiate receptors but were later determined to be a distinct class of receptors with two subtypes, sigma(1) and sigma(2). Although the endogenous ligand is yet to be elucidated, the sigma(1) receptor has recently been cloned. 2. Behavioural models used to test potential antidepressants have shown sigma ligands to produce antidepressant effects but their mechanism of action is unknown. 3. The goal of the present study was to assess the effects of various sigma(1) ligands on the firing activity of serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN) using extracellular in vivo recordings in anaesthetized rats. 4. The sigma(1) ligands (+)-pentazocine and 4-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP) (2 mg kg(-1) day(-1)) increased markedly 5-HT firing activity after 2 days of treatment and maintained the same increased firing rate after long-term (21 days) treatments. Furthermore, the increased firing rate produced by 2 and 21 day treatments with (+)-pentazocine was prevented by the co-administration of N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)-thylamine (NE-100) (10 mg kg(-1) day(-1)) a selective sigma(1) antagonist, confirming the sigma(1) receptor's modulation of these effects. In contrast, the sigma(1) ligands (+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-1-ethyl-but-3-en-1-ylamine hydrochloride (JO-1784) and 2-(4-morpholinoethyl 1-phenyl-cyclohexane-1-carboxylate hydrochloride (PRE-084) had no effect. 5. Following a 21-day treatment with (+)-pentazocine there was a marked reduction in the number of neurons found per track. This decrease was not seen after chronic treatment with 4-IBP and may represent a depolarization block. 6. These results suggest a modulation of serotonergic neurotransmission by some sigma receptors and provide a potential mechanism for the 'antidepressant effects' reported and provide evidence toward sigma(1) ligands as potential antidepressants with a rapid onset of action.
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PMID:Modulation of serotonergic neurotransmission by short- and long-term treatments with sigma ligands. 1158 25

The involvement of the sigma(1) receptor on the rewarding effects of cocaine was examined using the conditioned place preference (CPP) procedure in C57BL/6 mice. Acquisition or expression of cocaine (20 mg/kg i.p.)-induced CPP was significantly decreased by pre-treatment with the selective sigma(1) receptor antagonists N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine (NE-100) or N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047), 1-10 mg/kg, i.p. The sigma(1) receptor agonists igmesine or 2-(4-morpholinoethyl-1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084) failed to induce CPP when injected alone. Moreover, the CPP induced by N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine (BTCP), a selective dopamine reuptake inhibitor, was blocked by treatments with the sigma(1) receptor antagonists as was similarly observed with cocaine. In addition, the repetitive treatment with cocaine during conditioning increased sigma(1) receptor mRNA expression in the nucleus accumbens, but not in the caudate putamen, prefrontal cortex or cerebellum. These data show that the sigma(1) receptor is not only necessary for acquisition of the cocaine-induced CPP, but that it is also implicated in its expression, confirming that activation of the sigma(1) receptor is induced during cocaine's early effects. The sigma(1) receptor is activated consequently to dopamine reuptake blockade and is not sufficient to induce CPP by itself. The mechanism of the sigma(1) receptor involvement in CPP and the selectivity toward the CPP-inducing drug remains however to be determined. These results show that strategies targeting the sigma(1) receptor with selective antagonists may allow effective attenuation of cocaine's rewarding properties and, in turn, offer new treatment strategies against drug addiction.
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PMID:Involvement of the sigma(1) receptor in cocaine-induced conditioned place preference: possible dependence on dopamine uptake blockade. 1192 69