Potential serotonergic and noradrenergic involvement in the discriminative stimulus effects of the selective imidazoline I2-site ligand 2-BFI

MacInnes, Nicholas; Handley, Sheila L.

doi:10.1016/s0091-3057(03)00136-9

Cited by 17 publications

(16 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because MAO-A plays an essential role in monoamine synthesis and because microdialysis studies show increased extracellular level of monoamines in the brain after I 2 receptor ligands treatment (Hudson et al, 1999), it is reasonable to predict that the modulation of monoamines may contribute to the discriminative stimulus effects of I 2 receptor ligands. Indeed, the monoamine-releasing agents amphetamine and fenfluramine dose-dependently substituted for 2-BFI, while norepinephrine (desipramine, reboxetine) and serotonin (clomipramine, citalopram) reuptake inhibitors all partially substituted for 2-BFI (MacInnes & Handley, 2003). These results suggest that the discriminative stimulus effects of 2-BFI may involve noradrenergic and serotonergic components.…”

Section: Neuropharmacology Of Imidazoline I2 Receptor Ligandsmentioning

confidence: 99%

Imidazoline I 2 receptors: An update

2017

Pharmacology & Therapeutics

View full text Add to dashboard Cite

Since first introduced more than two decades ago, the research in imidazoline I2 receptors has been steadily increasing. This review provides an update on the current status of I2 receptor pharmacology. Imidazoline I2 receptors or I2 binding sites refer to several (at least four) different proteins that bind to [3H]-idazoxan and [3H]-2-BFI with high affinity. The molecular identities of the proteins remain elusive. One of the proteins (45 kD) seems to be consistent with the identity of brain creatine kinase. The biological functions of I2 receptors have been primarily unveiled by the studies of selective I2 receptor ligands. Accumulating evidence suggests that I2 receptor ligands are effective analgesics for persistent and chronic painful conditions such as inflammatory, neuropathic and postoperative pain. One selective I2 receptor ligand, CR4056, has been advanced to phase II clinical trial with the therapeutic indication of chronic inflammatory pain (osteoarthritis). The expansion to the treatment of other chronic pain conditions should be expected if CR4056 could eventually be approved as a new drug. I2 receptor ligands also demonstrate robust discriminative stimulus activity and induce a characteristic discriminative cue in animals. Biochemical and preclinical in vivo investigations also suggest that I2 receptor ligands have neuroprotective activity and modulate body temperature. The emerging discrepancies of a range of purported selective I2 receptor ligands suggest different pharmacological effects mediated by discrete I2 receptor components which likely attribute to the I2 receptor-related proteins. It is proposed that the I2 receptors represent an emerging drug target for the treatment of neurological disorders such as pain and stroke, and deserve more research attention to translate preclinical findings to pharmacotherapies.

show abstract

Section: Neuropharmacology Of Imidazoline I2 Receptor Ligandsmentioning

confidence: 99%

Imidazoline I 2 receptors: An update

2017

Pharmacology & Therapeutics

View full text Add to dashboard Cite

show abstract

“…For example, 2-BFI (2-(2-Benzofuranyl)-2-imidazoline hydrochloride), a widely used selective I 2 receptor ligand, exerts robust discriminative stimulus effects in rats, which is probably partially mediated through reversible inhibition of monoamine oxidase (MAO) A (Jordan et al, 1996; MacInnes and Handley, 2002, 2003). We recently reported that a new selective I 2 receptor ligand CR4056 also can serve as a discriminative stimulus in rats (Qiu et al, 2014a).…”

Section: Introductionmentioning

confidence: 99%

Discriminative stimulus effects of the imidazoline I2 receptor ligands BU224 and phenyzoline in rats

Qiu

Zhang

2015

European Journal of Pharmacology

View full text Add to dashboard Cite

Although imidazoline I2 receptor ligands have been used as discriminative stimuli, the role of efficacy of I2 receptor ligands as a critical determinant in drug discrimination has not been explored. This study characterized the discriminative stimulus effects of selective imidazoline I2 receptor ligands BU224 (a low-efficacy I2 receptor ligand) and phenyzoline (a higher efficacy I2 receptor ligand) in rats. Two groups of male Sprague-Dawley rats were trained to discriminate 5.6 mg/kg BU224 or 32 mg/kg phenyzoline (i.p.) from their vehicle in a two-lever food-reinforced drug discrimination procedure, respectively. All rats acquired the discriminations after an average of 18 (BU224) and 56 (phenyzoline) training sessions, respectively. BU224 and phenyzoline completely substituted for one another symmetrically. Several I2 receptor ligands (tracizoline, CR4056, RS45041, and idazoxan) all occasioned > 80% drug-associated lever responding in both discriminations. The I2 receptor ligand 2-BFI and a monoamine oxidase inhibitor harmane occasioned > 80% drug-associated lever responding in rats discriminating BU224. Other drugs that occasioned partial or less substitution to BU224 cue included clonidine, methamphetamine, ketamine, morphine, methadone and agmatine. Clonidine, methamphetamine and morphine also only produced partial substitution to phenyzoline cue. Naltrexone, dopamine D2 receptor antagonist haloperidol and serotonin (5-HT) 2A receptor antagonist MDL100907 failed to alter the discriminative stimulus effects of BU224 or phenyzoline. Combined, these results are the first to demonstrate that BU224 and phenyzoline can serve as discriminative stimuli and that the low-efficacy I2 receptor ligand BU224 shares similar discriminative stimulus effects with higher-efficacy I2 receptor ligands such as phenyzoline and 2-BFI.

show abstract

“…In rats with lesions in the nigrostriatal tract, 2-BFI increases the rotational behaviors (MacInnes and Duty, 2004). Rats also discriminate 2-BFI and this assay has high pharmacological selectivity such that only drugs with high imidazoline I 2 receptor binding affinity and positive efficacy produce responding on the 2-BFI-associated lever (Jordan et al, 1996; MacInnes and Handley, 2002, 2003). 2-BFI produces antinociceptive effects in a rat writhing test which are antagonized by idazoxan (Li et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Behavioral effects of the imidazoline I2 receptor ligand BU99006 in rats

Qiu

Thorn²,

Zhang³

et al. 2014

Behavioural Pharmacology

View full text Add to dashboard Cite

The imidazoline I2 receptor ligand BU99006 binds to and attenuates effects mediated by I2 receptors in vitro, although its effects in vivo have not been studied. This study examined the effects of BU99006 in two behavioral assays in rats: hypothermia and 2-BFI discrimination. BU99006 (3.2 – 15 mg/kg, i.p.) produced a dose-dependent hypothermic effect (rectal temperature), which was antagonized by the I2 receptor antagonist idazoxan. BU99006 (3.2 or 10 mg/kg given 10 min or 2 hr before the session, respectively) did not significantly alter hypothermia produced by I2 receptor agonist 2-BFI (10 mg/kg). In rats discriminating 5.6 mg/kg 2-BFI, BU99006 (1.78 – 17.8 mg/kg, i.p.) produced 40% and 82% responding on the 2-BFI-associated lever when it was administered immediately or 2 hrs prior to the test sessions, respectively. BU99006 enhanced the discriminative stimulus and rate-suppressing effects of 2-BFI. Collectively, these data suggest that BU99006 is an imidazoline I2 receptor agonist with no evidence of I2 receptor antagonism in rats.

show abstract

Potential serotonergic and noradrenergic involvement in the discriminative stimulus effects of the selective imidazoline I2-site ligand 2-BFI

Cited by 17 publications

References 38 publications

Imidazoline I 2 receptors: An update

Imidazoline I 2 receptors: An update

Discriminative stimulus effects of the imidazoline I2 receptor ligands BU224 and phenyzoline in rats

Behavioral effects of the imidazoline I2 receptor ligand BU99006 in rats

Contact Info

Product

Resources

About