Noradrenergic mechanisms appear not to be involved in cocaine-induced seizures and lethality

Jackson, Helen C.; Ball, Dough; Nutt, David

doi:10.1016/0024-3205(90)90594-h

Cited by 12 publications

(5 citation statements)

References 11 publications

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“…These results are consistent with previous studies examining possible noradrenergic influence on cocaineinduced convulsions (Derlet and Albertson 1990a;Jackson et al 1990). …”

Section: Discussionsupporting

confidence: 94%

Cocaine-induced convulsions: pharmacological antagonism at serotonergic, muscarinic and sigma receptors

Ritz¹,

George²

1997

Psychopharmacology

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The concurrent influence of multiple neurotransmitter systems in mediating cocaine-induced convulsions is predicted by the results of previous receptor binding studies. The present results demonstrate that pharmacological manipulations of these predicted neurotransmitter systems alters the occurrence of cocaine-induced convulsions. The 5-HT reuptake inhibitor fluoxetine enhanced the occurrence and severity of convulsions produced by 100 mg/kg (-) cocaine, while the 5-HT2 receptor antagonists cinanserin, ketanserin and pirenperone antagonized cocaine-induced convulsions in a dose-dependent manner. Further, the M1 receptor antagonist pirenzepine antagonized cocaine-induced convulsions, but atropine did not. In addition, both the (+) and (-) stereoisomers of the sigma ligand SKF 10047 significantly attenuated cocaine-induced convulsions. (+)SKF 10047 was more potent than (-)SKF 10047 in this effect, suggesting a stereoselective effect at sigma receptor sites. In constrast, DA and NE neurotransmission do not appear to modulate the proconvulsant effects of cocaine in a specific, dose-dependent manner. Thus, of the CNS binding sites with which cocaine is known to interact, the results are consistent with the conclusion that 5-HT transporters and 5-HT2 receptor sites appear to be direct and primary sites related to cocaine-induced convulsions, while M1 and sigma binding sites appear to play important but secondary and modulatory roles in this response.

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“…These results are consistent with previous studies examining possible noradrenergic influence on cocaineinduced convulsions (Derlet and Albertson 1990a;Jackson et al 1990). …”

Section: Discussionsupporting

confidence: 94%

Cocaine-induced convulsions: pharmacological antagonism at serotonergic, muscarinic and sigma receptors

Ritz¹,

George²

1997

Psychopharmacology

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“…Competition experiments were designed to measure drug inhibition of ligand binding at cocaine-binding sites that have been previously demonstrated to mediate cocaine-induced toxicity (i.e., dopamine and 5-HT transporters, as well as sigma and M 1 and M 2 receptors). Although cocaine has well-established effects on norepinephrine uptake, this site was not included in our binding analysis because much research has demonstrated that norepinephrine neurotransmission does not appear to mediate cocaine-induced toxicity (Jackson, Ball, & Nutt, 1990; Ritz & George 1993; 1997a). Although radiolabeled cocaine has been used as the binding ligand in several studies, we have used other ligands that bind with higher affinities and specificities to particular receptors and provide better specific-to-nonspecific binding ratios.…”

Section: Methodsmentioning

confidence: 99%

“…However, desipramine shifted the cocaine convulsion dose-response curve to the left in a noncornpetitive fashion (p < .005), suggesting that the effects of this compound on cocaine-induced convulsions do not occur through a single neural mechanism. Despite the high affinity of desipramine for norepinephrine uptake, noradrenergic mechanisms do not likely play a role in mediating cocaine-induced lethality given the previous research suggesting that norepinephrine does not appear to play a role in mediating this toxic effect of cocaine (Jackson et al, 1990;Ritz & George, 1993). The ability of desipramine to facilitate cocaine-induced lethality is more likely related to nonselective effects of this compound that alter several other neurotransmitter systems.…”

Section: Effects Of Antidepressant Administration On Cocaine-induced ...mentioning

confidence: 96%

Antidepressant drugs appear to enhance cocaine-induced toxicity.

O’Dell¹,

George²,

Ritz³

2000

Experimental and Clinical Psychopharmacology

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It has been shown that cocaine-induced convulsions and lethality appear to be mediated by serotonin and dopamine neurotransmission, respectively. However, many antidepressants considered for treatment of cocaine addiction target these monoamine systems and may thus amplify these toxic effects during relapse. In this study, the authors assessed whether pretreatment with antidepressants influences cocaine-induced toxicity in mice as well as the potency of these medications at cocaine-binding sites previously shown to be associated with cocaine toxicity. Overall, selective serotonin reuptake inhibitors (SSRIs) facilitated cocaine-induced convulsions but not lethality. Dopamine uptake inhibition facilitated cocaine-induced lethality, but not convulsion. The SSRI sertraline enhanced neither convulsions nor lethality and may be unique due to its high affinity for sigma receptors. These results have important implications for safe and effective addiction treatments.

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“…Thus, repeated previous inhibition of norepinephrine uptake produced plastic changes that lead to increased susceptibility to local anesthetic-induced convulsions. Previously, Jackson et al [17] reported that acute treatments with a norepinephrine uptake inhibitor and α 2 adrenoceptor-antagonists, both of which increase noradrenergic synaptic activity, neither increased nor decreased cocaine-induced convulsions, concluding that no noradrenergic mechanism is involved in the cocaine-induced convulsion.…”

Section: Discussionmentioning

confidence: 99%

Chronic inhibition of the norepinephrine transporter in the brain participates in seizure sensitization to cocaine and local anesthetics

Arai

Morita²,

Kitayama³

et al. 2003

Brain Research

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The involvement of chronic inhibition of monoamine transporters (MAT) in the brain with respect to sensitization to cocaine- and local anesthetic-induced seizures was studied in mice. Repeated administration of subconvulsive doses of meprylcaine as well as cocaine, both of which inhibit MAT, but not lidocaine, which does not inhibit MAT, increased seizure activity and produced sensitization to other local anesthetics. The effects of five daily treatments of monoamine transporter inhibitors on lidocaine-induced convulsions were examined 2 or 3 days after the last dose of the inhibitors. Daily treatments of GBR 12935, a specific inhibitor of dopamine uptake, significantly increased the incidence and the intensity of lidocaine-induced convulsions at 20 mg/kg and decreased the threshold of the convulsions. Daily treatments of desipramine and maprotiline, selective norepinephrine uptake inhibitors, markedly increased the incidence and intensity of lidocaine-induced convulsions, and decreased the threshold in a dose-dependent manner at between 5 and 20 mg/kg. Daily treatments of citalopram, a selective serotonin uptake inhibitor, at 10 and 20 mg/kg, produced no significant increase in the incidence or intensity of lidocaine-induced convulsions, but decreased the threshold of the convulsions. These results suggest that the chronic intermittent inhibition of monoamine uptake increases susceptibility to cocaine- and local anesthetic-induced seizures, and the norepinephrine transporter is an integral component of this sensitization.

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Noradrenergic mechanisms appear not to be involved in cocaine-induced seizures and lethality

Cited by 12 publications

References 11 publications

Cocaine-induced convulsions: pharmacological antagonism at serotonergic, muscarinic and sigma receptors

Cocaine-induced convulsions: pharmacological antagonism at serotonergic, muscarinic and sigma receptors

Antidepressant drugs appear to enhance cocaine-induced toxicity.

Chronic inhibition of the norepinephrine transporter in the brain participates in seizure sensitization to cocaine and local anesthetics

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