JL13, a pyridobenzoxazepine compound with potential atypical antipsychotic activity, increases extracellular dopamine in the prefrontal cortex, but not in the striatum and the nucleus accumbens of rats

Invernizzi, Roberto William; Garavaglia, C; Samanin, R.

doi:10.1007/s002109900195

Cited by 10 publications

(11 citation statements)

References 37 publications

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“…Selected dose of JL 13 is behaviorally, neurochemically, and molecularly active in rats (Invernizzi et al 2000;Ellenbroek and Liégeois 2003;Moran-Gates et al 2006). After 4 weeks of treatment, residual drug solution in each minipump implanted in control-and drug-treated rats was <5% of the original volume, indicating vehicle and JL 13 were adequately delivered.…”

Section: Drug Treatment and Tissue Preparationmentioning

confidence: 99%

“…Neurochemical studies reported that JL 13 shared similar neurochemical actions with clozapine and other atypical antipsychotics, in terms of their ability to selectively increase dopamine levels in prefrontal cortex in a dosedependent fashion without altering concentrations of dopamine or its metabolites in caudate-putamen (CPu) (Invernizzi et al 2000). Behavioral studies suggested that JL 13 might possess antipsychotic activity, evidenced by its ability to reverse amphetamine-induced disruption of prepulse inhibition (Ellenbroek et al 2001) and to antagonize apomorphine-induced climbing.…”

Section: Introductionmentioning

confidence: 98%

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Long-term Effects of JL 13, a Potential Atypical Antipsychotic, on Ionotropic Glutamate Receptors

et al. 2007

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Changes in ionotropic glutamate (Glu) N-methyl-d-aspartic acid (NMDA), and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in rat forebrain regions were autoradiographically quantified after continuous infusion of JL 13 [(5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine fumarate] for 28 days using osmotic minipumps, and compared to the effects of representative typical (haloperidol) and atypical (clozapine, olanzapine, and risperidone) antipsychotic drugs from previous studies. Similar to other atypical and not typical antipsychotics, JL 13 decreased labeling of NMDA receptors in medial and lateral caudate-putamen (CPu; by 40%). These findings indicate that down-regulation of NMDA receptors by JL 13 and other atypical antipsychotic agents in CPu may contribute to their low risk of extrapyramidal side effects. In addition, and similar to olanzapine and risperidone, JL 13 increased AMPA receptor binding in CPu (by 42%). Changes in AMPA receptors may contribute to psychopharmacological properties of JL 13 and other atypical agents. Similar to clozapine, JL 13 did not alter levels of NMDA and AMPA receptors in hippocampus and entorhinal cortex. Long-term effects of JL 13 on ionotropic Glu receptors, as well as on other dopamine and serotonin receptors, support the atypical antipsychotic profile of this novel agent.

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Section: Drug Treatment and Tissue Preparationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Long-term Effects of JL 13, a Potential Atypical Antipsychotic, on Ionotropic Glutamate Receptors

et al. 2007

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“…In support of this hypothesis, a recent study found that other antipsychotics with low 5‐HT 1A receptor affinity, such as olanzapine and risperidone, can increase cortical release of DA through a 5‐HT 1A ‐sensitive mechanism that results indirectly from combined blockade of D 2 and 5‐HT 2A receptors and not from direct 5‐HT 1A receptor activation (Ichikawa et al2001). It remains to be determined whether JL 13‐induced increases in cortical DA levels (Invernizzi et al,2000) follow similar or independent mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…In nonhuman primates, the compound was well tolerated, with low incidence of adverse side effects (Casey et al,2001). Neurochemical studies reported that JL 13, similar to clozapine and few other atypical antipsychotics, selectively increased DA levels in prefrontal cortex in a dose‐dependent fashion, without altering concentrations of DA or its metabolites in striatum (Invernizzi et al,2000). Moreover, JL 13 is less sensitive to oxidation than clozapine (Liégeois et al,1997).…”

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confidence: 99%

Long‐term effects of JL 13, a potential atypical antipsychotic, on rat dopamine and serotonin receptor subtypes

Moran-Gates

Massari

Graulich

et al. 2006

J of Neuroscience Research

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Changes in dopamine (DA) D(1), D(2), D(3), and D(4) receptors and serotonin 5-HT(1A) and 5-HT(2A) receptors in rat forebrain regions were autoradiographically quantified after continuous infusion of JL 13 [(5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine fumarate] for 28 days with osmotic minipumps and compared with the effects of other typical (fluphenazine) and atypical (clozapine, olanzapine, and risperidone) antipsychotic drugs from previous studies. Similar to other typical and atypical antipsychotics, JL 13 increased labeling of D(2) receptors in medial prefrontal cortex (MPC) and hippocampus (HIP) and D(4) receptors in nucleus accumbens (NAc), caudate-putamen (CPu), and HIP. In addition, JL 13 increased 5-HT(1A) and decreased 5-HT(2A) receptors in MPC and dorsolateral frontal cortex (DFC), an effect shared by atypical antipsychotics, and may contribute to their psychopharmacological properties. Clozapine and JL 13, but not other antipsychotics, spared D(2) receptors in CPu, which may reflect their ability to induce minimal extrapyramidal side effects. In addition, JL 13 but not other typical and atypical antipsychotic drugs increased abundance of D(1) receptors in CPu and NAc. JL 13 as well as other antipsychotic agents did not alter levels of forebrain D(3) receptors. An atypical-like profile of JL 13 on DA and 5-HT receptor subtypes should encourage further development of this compound as a novel atypical antipsychotic drug.

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“…At 20 and 40 mg/kg i.p., JL 13 dose-dependently increased the extracellular dopamine concentration in PFC, 234 and 434% of basal levels at peak, respectively (35). Extracellular concentrations of metabolites (DOPAC, HVA) were also raised in the PFC of rats given 40 mg/kg.…”

Section: Microdialysis Approachesmentioning

confidence: 95%

JL 13, An Atypical Antipsychotic: A Preclinical Review

Ellenbroek

Liégeois

2003

CNS Drug Reviews

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The extensive pharmacological evaluation of JL 13 as an atypical antipsychotic drug has revealed a close similarity to clozapine, however with some major advantages. JL 13 was characterized as a weak D 2 antagonist, both in vitro and in vivo, with a strong affinity for the D 4 and the 5-HT 2A receptors. It has no affinity for the 5-HT 2C receptor. In vivo microdialysis experiments in rat showed that JL 13, like clozapine, preferentially increased extracellular dopamine concentrations in the prefrontal cortex compared to nucleus accumbens or striatum.Behavioral studies showed that JL 13, like clozapine, has the profile of an atypical antipsychotic. Thus, JL 13 did not antagonize apomorphine-induced stereotypy nor did it produce catalepsy, but it antagonized apomorphine-induced climbing in rodents. It was inactive against d-amphetamine-induced stereotypy but antagonized d-amphetamine-induced hyperactivity in the mouse. Likewise, in the paw test, it was more effective in prolonging hindlimb retraction time than prolonging forelimb retraction time. Like other antipsychotic drugs, JL 13 reversed the apomorphine-and amphetamine-induced disruption of prepulse inhibition. In a complex temporal regulation schedule in the dog, JL 13 showed a high resemblance with clozapine without inducing sialorrhea, palpebral ptosis or any significant motor side effects. In rats and squirrel monkeys JL 13 induced a high degree of generalization (70%) to clozapine.Regarding behavioral toxicology, JL 13 did not produce dystonia or Parkinsonian symptoms in haloperidol-sensitized monkeys. After acute administration, again like clozapine, JL 13 induced only a transient increase in circulating prolactin. Last but not the least, regarding a possible hematological toxicity, unlike clozapine, JL 13 did not present sensitivity to peroxidase-induced oxidation. Moreover, its electrooxidation potential was close to that of loxapine and far from that of clozapine. Taking all these preclinical data into account, it appears that JL 13 is a promising atypical antipsychotic drug.

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JL13, a pyridobenzoxazepine compound with potential atypical antipsychotic activity, increases extracellular dopamine in the prefrontal cortex, but not in the striatum and the nucleus accumbens of rats

Cited by 10 publications

References 37 publications

Long-term Effects of JL 13, a Potential Atypical Antipsychotic, on Ionotropic Glutamate Receptors

Long-term Effects of JL 13, a Potential Atypical Antipsychotic, on Ionotropic Glutamate Receptors

Long‐term effects of JL 13, a potential atypical antipsychotic, on rat dopamine and serotonin receptor subtypes

JL 13, An Atypical Antipsychotic: A Preclinical Review

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