Cocaine-induced Seizures Research Articles

Acupuncture in the treatment of cocaine addiction: how does it work?

Cocaine is a frequently abused and highly addictive drug that damages brain health and imposes substantial social and economic costs. Acupuncture has been used in the treatment of cocaine addiction and has been shown to improve abnormal mental and motor states. This article mainly focuses on the neurobiological mechanisms involving the central nervous system (CNS) and peripheral nervous system (PNS) that underlie the effects of acupuncture in the treatment of cocaine addiction. The central dopamine system is a key player in acupuncture treatment of cocaine addiction; the ventral tegmental area (VTA)-nucleus accumbens (NAc) signaling pathway, which has a modulatory influence on behavior and psychology after chronic use of cocaine, is a significant target of acupuncture action. Moreover, acupuncture alleviates cocaine-induced seizures or acute psychomotor responses through the paraventricular thalamus and the lateral habenula (LHb)-rostromedial tegmental (RMTg) nucleus circuits. The data suggest that acupuncture can impact various cocaine-induced issues via stimulation of diverse brain areas; nevertheless, the interconnection of these brain regions and the PNS mechanisms involved remain unknown. In this review, we also discuss the effects of specific acupuncture protocols on cocaine addiction and note that variations in needling modalities, current intensities and traditional acupuncture point locations have led to different experimental results. Therefore, standardized acupuncture protocols (with respect to stimulation methods, point locations and number of sessions) may become particularly important in future studies.

Ibrutinib as a potential therapeutic for cocaine use disorder

Cocaine use presents a worldwide public health problem with high socioeconomic cost. No current pharmacologic treatments are available for cocaine use disorder (CUD) or cocaine toxicity. To explore pharmaceutical treatments for tthis disorder and its sequelae we analyzed gene expression data from post-mortem brain tissue of individuals with CUD who died from cocaine-related causes with matched cocaine-free controls (n = 71, Mage = 39.9, 100% male, 49% with CUD, 3 samples/brain regions). To match molecular signatures from brain pathology with potential therapeutics, we leveraged the L1000 database honing in on neuronal mRNA profiles of 825 repurposable compounds (e.g., FDA approved). We identified 16 compounds that were negatively associated with CUD gene expression patterns across all brain regions (padj < 0.05), all of which outperformed current targets undergoing clinical trials for CUD (all padj > 0.05). An additional 43 compounds were positively associated with CUD expression. We performed an in silico follow-up potential therapeutics using independent transcriptome-wide in vitro (neuronal cocaine exposure; n = 18) and in vivo (mouse cocaine self-administration; n = 12–15) datasets to prioritize candidates for experimental validation. Among these medications, ibrutinib was consistently linked with the molecular profiles of both neuronal cocaine exposure and mouse cocaine self-administration. We assessed the therapeutic efficacy of ibrutinib using the Drosophila melanogaster model. Ibrutinib reduced cocaine-induced startle response and cocaine-induced seizures (n = 61–142 per group; sex: 51% female), despite increasing cocaine consumption. Our results suggest that ibrutinib could be used for the treatment of cocaine use disorder.

Cocaine vaccine dAd5GNE protects against moderate daily and high-dose "binge" cocaine use.

The cocaine vaccine dAd5GNE is comprised of a disrupted serotype 5 adenovirus gene therapy vector covalently conjugated to the cocaine analog GNE. The vaccine evokes a high titer of circulating anti-cocaine antibodies that prevent cocaine from reaching its cognate receptors in the central nervous system. Prior studies have demonstrated the efficacy of dAd5GNE in models of occasional, moderate cocaine use. However, previous studies have not sufficiently evaluated the efficacy of dAd5GNE in models of the repetitive and high-dose “binge” use patterns common in human addicts. In the present study, we evaluated the capacity of dAd5GNE vaccination to protect against “binge” cocaine use and circumstances where vaccinated addicts attempt to override the vaccine. We modeled repetitive daily cocaine use in vaccinated Balb/c mice and African green monkeys, and evaluated high-dose “binge” scenarios in Balb/c mice. In each model of daily use the dAd5GNE vaccine prevented cocaine from reaching the central nervous system. In the high-dose “binge” model, vaccination decreased cocaine-induced hyperactivity and reduced the number of cocaine-induced seizures. Based on this data and our prior data in rodents and nonhuman primates, we have initiated a clinical trial evaluating the dAd5GNE anti-cocaine vaccine as a potential therapy for cocaine addicts who wish to stop cocaine use. If dAd5GNE vaccination is safe and produces high anti-cocaine antibody titers in the clinic, we hypothesize that the vaccine will restrict the access of cocaine to the central nervous system and inhibit cocaine-induced “highs” even in the context of moderate daily and high-dose “binge” use that might otherwise cause a drug-induced overdose.

Cannabinoids Rescue Cocaine-Induced Seizures by Restoring Brain Glycine Receptor Dysfunction

Cannabinoids are reported to rescue cocaine-induced seizures (CISs), a severe complication in cocaine users. However, the molecular targets for cannabinoid therapy of CISs remain unclear. Here, we report that the systemic administration of cannabinoids alleviates CISs in a CB1/CB2-receptor-independent manner. In HEK293 cells and cortical neurons, cocaine-induced dysfunction of the glycine receptor (GlyR) is restored by cannabinoids. Such restoration is blocked by GlyRα1S296A mutation. Consistently, the therapeutic effects of cannabinoids on CISs are also eliminated in GlyRα1S296A mutant mice. Based on molecular dynamic simulation, the hydrogen-bonding interaction between cocaine and the GlyR is weakened by cannabinoid docking. Without altering cocaine distribution across the brain, cannabinoids significantly suppress cocaine-exaggerated neuronal excitability in the prefrontal cortex (PFC) and hippocampus by rehabilitating extra-synaptic GlyR function. Microinjection of cannabinoids into the PFC and hippocampus restores cocaine-puzzled neural activity and alleviates CISs. These findings suggest that using GlyR-hypersensitive cannabinoids may represent a potential therapeutic strategy for treating CISs.

Cannabidiol, a Cannabis sativa constituent, inhibits cocaine-induced seizures in mice: Possible role of the mTOR pathway and reduction in glutamate release

Cannabidiol (CBD), a major non-psychotomimetic constituent of Cannabis sativa, has therapeutic potential for certain psychiatric and neurological disorders. Studies in laboratory animals and limited human trials indicate that CBD has anticonvulsant and neuroprotective properties. Its effects against cocaine neurotoxicity, however, have remained unclear. Thus, the present study tested the hypothesis that CBD protects against cocaine-induced seizures and investigated the underlying mechanisms. CBD (30mg/kg) pre-treatment increased the latency and reduced the duration of cocaine (75mg/kg)-induced seizures in mice. The CB1 receptor antagonist, AM251 (1 and 3mg/kg), and the CB2 receptor antagonist, AM630 (2 and 4mg/kg), failed to reverse this protective effect, suggesting that alternative mechanisms are involved. Synaptosome studies with the hippocampus of drug-treated animals revealed that cocaine increases glutamate release, whereas CBD induces the opposite effect. Finally, the protective effect of this cannabinoid against cocaine-induced seizure was reversed by rapamycin (1 and 5mg/kg), an inhibitor of the mammalian target of rapamycin (mTOR) intracellular pathway. In conclusion, CBD protects against seizures in a model of cocaine intoxication. These effects possibly occur through activation of mTOR with subsequent reduction in glutamate release. CBD should be further investigated as a strategy for alleviating psychostimulant toxicity.

A Comparison of Dexmedetomidine, Moxonidine and Alpha-Methyldopa Effects on Acute, Lethal Cocaine Toxicity.

Background:The treatment of cocaine toxicity is an important subject for emergency physicians. We investigated the effects of dexmedetomidine, moxonidine and alpha-methyldopa on acute cocaine toxicity in mice.Objectives:The aim of this study was to evaluate the effects of dexmedetomidine, moxonidine and alpha-methyldopa in a mouse model of acute cocaine toxicity.Materials and Methods:We performed an experiment consisting of four groups (n = 25 each). The first group received normal saline solution, the second group received 40 µg/kg of dexmedetomidine, the third group received 0.1 mg/kg of moxonidine and the fourth group received 200 mg/kg of alpha-methyldopa, all of which were intraperitoneally administered 10 minutes before cocaine hydrochloride (105 mg/kg). All animals were observed for seizures (popcorn jumping, tonic-clonic activity, or a loss of the righting reflex) and lethality over the 30 minutes following cocaine treatment.Results:The ratio of animals with convulsions was lower in all treated groups when compared to the control (P < 0.001). Furthermore, 68% (n = 17) of animals in the dexmedetomidine group, 84% (n = 21) of the alpha-methyldopa group, 92% (n = 23) of the moxonidine group and 100% (n = 25) of the control group showed evidence of seizure activity (P = 0.009). Cocaine-induced lethality was observed in 12% (n = 3) of the dexmedetomidine group, 48% (n = 12) of the alpha-methyldopa group, 52% (n = 13) of the moxonidine group, and 72% (n = 18) of the control group (P < 0.001). All treatments prolonged the time to seizure, which was longest in the dexmedetomidine group (P > 0.05). In addition, the time to lethality was also longer in the same group (P < 0.001).Conclusions:The present study provides the first experimental evidence in support of dexmedetomidine treatment for cocaine-induced seizures. Premedication with dexmedetomidine reduces seizure activity in a mouse model of acute cocaine toxicity. In addition, while dexmedetomidine may be effective, moxonidine and alpha-methyldopa did not effectively prevent cocaine-induced lethality.

Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB1 receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB1 receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity.

Cannabidiol rescues acute hepatic toxicity and seizure induced by cocaine.

Cocaine is a commonly abused illicit drug that causes significant morbidity and mortality. The most severe and common complications are seizures, ischemic strokes, myocardial infarction, and acute liver injury. Here, we demonstrated that acute cocaine intoxication promoted seizure along with acute liver damage in mice, with intense inflammatory infiltrate. Considering the protective role of the endocannabinoid system against cell toxicity, we hypothesized that treatment with an anandamide hydrolysis inhibitor, URB597, or with a phytocannabinoid, cannabidiol (CBD), protects against cocaine toxicity. URB597 (1.0 mg/kg) abolished cocaine-induced seizure, yet it did not protect against acute liver injury. Using confocal liver intravital microscopy, we observed that CBD (30 mg/kg) reduced acute liver inflammation and damage induced by cocaine and prevented associated seizure. Additionally, we showed that previous liver damage induced by another hepatotoxic drug (acetaminophen) increased seizure and lethality induced by cocaine intoxication, linking hepatotoxicity to seizure dynamics. These findings suggest that activation of cannabinoid system may have protective actions on both liver and brain induced by cocaine, minimizing inflammatory injury promoted by cocaine, supporting its further clinical application in the treatment of cocaine abuse.

Abstracts and Commentaries on Key Articles in the Literature

Abstracts and Commentaries on Key Articles in the Literature

Effects of an epilepsy-causing mutation in the SCN1A sodium channel gene on cocaine-induced seizure susceptibility in mice

High doses of cocaine can elicit seizures in humans and in laboratory animals. Several mechanisms have been proposed for the induction of seizures by cocaine, including enhanced monoaminergic signaling, blockade of ion channels, and alterations in GABA and glutamate transmission. Mutations in the SCN1A gene, which encodes the central nervous system (CNS) voltage-gated sodium channel (VGSC) Nav1.1, are responsible for several human epilepsy disorders including Dravet syndrome and genetic (generalized) epilepsy with febrile seizures plus (GEFS+). Mice heterozygous for the R1648H GEFS+ mutation (RH mice) exhibit reduced interneuron excitability, spontaneous seizures, and lower thresholds to flurothyl- and hyperthermia-induced seizures. However, it is unknown whether impaired CNS VGSC function or a genetic predisposition to epilepsy increases susceptibility to cocaine-induced seizures. Our primary goal was to determine whether Scn1a dysfunction caused by the RH mutation alters sensitivity to cocaine-induced behavioral and electrographic (EEG) seizures. We also tested novelty- and cocaine-induced locomotor activity and assessed the expression of Nav1.1 in midbrain dopaminergic neurons. We found that RH mice had a profound increase in cocaine-induced behavioral seizure susceptibility compared to wild-type (WT) controls, which was confirmed with cortical EEG recordings. By contrast, although the RH mice were hyperactive in novel environments, cocaine-induced locomotor activity was comparable between the mutants and WT littermates. Finally, immunofluorescence experiments revealed a lack of Nav1.1 immunoreactivity in dopaminergic neurons. These data indicate that a disease-causing CNS VGSC mutation confers susceptibility to the proconvulsant, but not motoric, effects of cocaine.

Electroacupuncture Reduces Cocaine-Induced Seizures and Mortality in Mice

The aims of this study were to characterize the protective profile of electroacupuncture (EA) on cocaine-induced seizures and mortality in mice. Mice were treated with EA (2 Hz, 50 Hz, and 100 Hz), or they underwent needle insertion without anesthesia at the Dazhui (GV14) and Baihui (GV20) acupoints before cocaine administration. EA at 50 Hz applied to GV14 and GV20 significantly reduced the seizure severity induced by a single dose of cocaine (75 mg/kg; i.p.). Furthermore, needle insertion into GV14 and GV20 and EA at 2 Hz and 50 Hz at both acupoints significantly reduced the mortality rate induced by a single lethal dose of cocaine (125 mg/kg; i.p.). In the sham control group, EA at 50 Hz applied to bilateral Tianzong (SI11) acupoints had no protective effects against cocaine. In addition, EA at 50 Hz applied to GV14 and GV20 failed to reduce the incidence of seizures and mortality induced by the local anesthetic procaine. In an immunohistochemistry study, EA (50 Hz) pretreatment at GV14 and GV20 decreased cocaine (75 mg/kg; i.p.)-induced c-Fos expression in the paraventricular thalamus. While the dopamine D3 receptor antagonist, SB-277011-A (30 mg/kg; s.c), did not by itself affect cocaine-induced seizure severity, it prevented the effects of EA on cocaine-induced seizures. These results suggest that EA alleviates cocaine-induced seizures and mortality and that the dopamine D3 receptor is involved, at least in part, in the anticonvulsant effects of EA in mice.

Effects of pretreatment with etomidate, ketamine, phenytoin, and phenytoin/midazolam on acute, lethal cocaine toxicity

Objective: To evaluate the effects of etomidate, ketamine, phenytoin, and phenytoin/midazolam in a mouse model of acute cocaine toxicity.Methods: We performed a randomized controlled study consisting of five groups (n = 25 each) of rats that received intraperitoneal injections of normal saline solution, 5 mg/kg ketamine, 7·5 mg/kg etomidate, 40 mg/kg phenytoin, and 40 mg/kg phenytoin and 2 mg/kg midazolam 10 minutes before cocaine hydrochloride (105 mg/kg). Following cocaine administration, a blinded observer watched the animals for 30 minutes to assess seizures (popcorn jumping, tonic-clonic activity, or loss of righting reflex), and lethality for 30 minutes.Results: The number of animals with seizures was lower in the etomidate (60%), phenytoin (40%), and phenytoin/midazolam (40%) groups (P<0·001). The etomidate (24%) and phenytoin/midazolam (16%) treatments were most effective in preventing lethality (P<0·001). Conversely, compared to the vehicle group (72%), cocaine-induced lethality was higher in the ketamine (84%) and phenytoin (92%) groups. All treatments prolonged the time to seizure, but this effect was most pronounced in the etomidate and phenytoin/midazolam groups, which also had the longest average time to lethality.Discussion: The present study provides the first experimental evidence supporting the use of etomidate to treat cocaine-induced seizures. Notably, ketamine and phenytoin were ineffective. Our findings suggest that premedication with etomidate, phenytoin, and phenytoin/midazolam reduced seizure activity in an acute cocaine toxicity mouse model.

Assessment of propofol, midazolam and ziprasidone, or the combinations for the prevention of acute cocaine toxicity in a mouse model

Study objectiveTo evaluate the effects of pretreatment, midazolam (M), propofol (P), ziprasidone (Z), and two combinations of [(midazolam plus propofol (MP); midazolam plus ziprasidone (MZ)] in mice models in the prevention of seizures, and death due to acute cocaine toxicity. Methods180 male CF-1 mice were randomized to 6 groups (30/group) in this experimental study. The animals were administered intraperitoneal injections of M (2mg/kg), P (25mg/kg), Z (4mg/kg), MP (2mg/kg and 25mg/kg) and MZ (2mg/kg and 4mg/kg) or saline (S) as a pretreatment. 10min later, the mice were administered intraperitoneal injections of 105mg/kg cocaine. The groups were observed for cocaine-induced seizure and lethality. ResultsThe MP and MZ combinations showed the highest protective effect in terms of seizure and lethality relative to P and S (p<0.001). M and Z were found effective compared to P and S (p<0.001). There were no significant differences among MP and MZ, however there were significant differences between MP and Z in terms of lethality (p=0.05). There were no significant differences among MP, MZ, M and Z groups in terms of seizure (p>0.05). No death was observed in the MP combination group. Seizure rate was observed o be least in the MZ group with respect to the other groups. ConclusionAccording to our particular mouse model, this study suggests that MP and MZ combinations may be more effective than M or Z only for the prevention of cocaine-induced seizure and lethality. However, P alone does not prevent cocaine-induced seizure and lethality.

Shared vulnerability between seizures and psychosis in cocaine addiction?

Cocaine-induced seizures (CIS) and cocaine-induced psychosis (CIP) may be complications of acute cocaine intoxication. CIS could result from a kindling process, involving the glutamate NMDA receptor (NMDAR) phosphorylation state, which is enhanced by activation of the dopamine D1 receptor (D1R). CIP is considered to be more specifically associated with the activity of the dopamine D2 receptor (D2R). The authors describe the case of a 21-year-old woman who presented with recurrent CIP during a period of increased cocaine abuse that ended in two consecutive CIS. This case report may illustrate a possible overlap in the mechanisms underlying CIS and CIP, disclosing some subtle interactions occurring between dopaminergic and glutamatergic receptors during cocaine chronic intoxication. Chronic cocaine exposure usually induces the formation of a NMDAR–D2R complex, which seems to be linked to the usual clinical effects of the drug, but also causes complex formation not to occur in both D2R-based CIP and D1R-based CIS. To explain the case of this patient, we propose a pharmacological hypothesis based on a literature review and implying the lack of formation of this complex, which triggers CIP and CIS. On a more practical level, this case report also encourages practitioners to be aware of the possible co-occurrence of CIP and CIS in cocaine abusers, especially with respect to antipsychotic medications that could be administered in such situations.

Gastrodia Elata Bl Attenuates Cocaine-Induced Conditioned Place Preference and Convulsion, but not Behavioral Sensitization in Mice: Importance of GABAA Receptors

It has been suggested that GABAergic neurotransmission can modulate cocaine dependence and seizure activity. Since Gastrodia elata Bl (GE), an oriental herb agent, has been shown to enhance GABAergic transmission, we examined whether GE affects cocaine-induced seizures, conditioned place preference (CPP), and behavioral sensitization in mice. Treatment with GE (500 or 1000 mg/kg, p.o.) significantly delayed seizure onset time and significantly shortened seizure duration induced by cocaine (90 mg/kg, i.p.). In addition, cocaine (15 mg/kg, i.p.)-induced CPP was significantly attenuated by GE in a dose-dependent manner. However, GE did not significantly alter behavioral sensitization induced by cocaine (15 mg/kg, i.p.). In order to understand whether GABAergic receptors are implicated in GE-mediated pharmacological action in response to cocaine, GABAA receptor antagonist bicuculline and GABAB receptor antagonist SCH 50911 were employed in the present study. GE-mediated attenuations on the cocaine-induced seizures and CPP were significantly reversed by bicuculline (0.25 or 0.5 mg/kg, i.p.), but not by SCH 50911 (1.5 or 3.0 mg/kg, i.p.). Therefore, our results suggest that GE attenuates cocaine-induced seizures and CPP via, at least in part, GABAA receptor activation.

Protective effects of cannabinoid receptor agonists against cocaine and other convulsant-induced toxic behavioural symptoms.

Based on the previously reported co-localization and relationship between cannabinoid and dopamine receptors, the effects of cannabinoid receptor agonists against cocaine-induced toxic behavioural symptoms, including convulsive seizures, were examined in mice. The anticonvulsant effect of several cannabimimetics against seizures induced by other convulsants was also compared. The cannabinoid receptor agonists CP 55940 ((-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)-cyclohexanol) and WIN 55212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone), and the endogenous cannabinoid anandamide were co-administered intraperitoneally with cocaine (75 mg kg(-1)) or other convulsants such as bicuculline, methyl 6,7-dimethoxy-4-ethyl-beta-carboline-carboxylate (DMCM), L-glutamic acid and N-methyl-D-aspartate (NMDA). CP 55940 (2.5 mg kg(-1)) and anandamide (15 mg kg(-1)) significantly antagonized cocaine-induced lethality, and CP 55940 and WIN 55212-2 (2.5 mg kg(-1)) significantly attenuated the severity of cocaine-induced convulsive seizures. Furthermore, ataxic hyperactivity, which was observed only in the cocaine-treated group of mice and could be evaluated by their activity counts, was also depressed in the groups of mice co-treated with each of the three cannabinoid agonists. However, none of these agonists protected against bicuculline- or DMCM-induced lethality or convulsive seizures. In contrast, all of the cannabinoid agonists, most notably anandamide, antagonized both L-glutamic acid (2 g kg(-1))- and NMDA (200 mg kg(-1))-induced convulsive seizures. These data support the previously reported close correlation between dopamine and cannabinoid receptors, and between cannabinoid agonists, especially anandamide, and glutamate (NMDA) receptors. Furthermore, these results suggest a potential therapeutic role for cannabinoid agonists against cocaine- and other-convulsant-induced toxicities.

Lack of effect of sildenafil on cocaine-induced convulsions in mice

The convulsant action of cocaine and the proconvulsant effects of sildenafil, a drug which is widely used in the treatment of erectile dysfunction, have been documented both in humans and mice. Since it was reported that sildenafil alone, and in conjunction with cocaine, is used recreationally, the present study was performed to examine the influence of sildenafil on cocaine-induced seizures in mice. We showed that administration of sildenafil (5–20mg/kg, ip) did not affect latency to clonic seizures induced by ip administration of cocaine at a dose of 85mg/kg, nor did it influence seizure incidence and mortality. We conclude that sildenafil does not significantly increase the risk of seizures when co-administered with cocaine.

The Dopamine D3/D2 Agonist (+)-PD-128,907 [(R-(+)-trans-3,4a,10b-Tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] Protects against Acute and Cocaine-Kindled Seizures in Mice: Further Evidence for the Involvement of D3 Receptors

Previous findings have demonstrated a protective role for dopamine D(3)/D(2) receptor agonists in the convulsant and lethal effects of acutely administered cocaine. Data are provided here to establish that the protection occurs through a D(3)-linked mechanism and that protection is extended to seizure kindling. The D(3) antagonist SB-277011-A [4-quinolinecarboxamide,N-[trans-4-[2-(6-cyano-3,4-dihydro-2(1H)-isoquinolinyl)ethyl]-cyclohexyl]-(9CI)] prevented the anticonvulsant effect of the D(3)/D(2) receptor agonist (+)-PD-128,907 [(R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] on cocaine-induced seizures. The protection afforded by the D(3)/D(2) agonist, (+)-PD-128,907, was eliminated in D(3) receptor-deficient mice. In D(2) receptor knockout mice, the anticonvulsant effects of (+)-PD-128,907 were preserved. (+)-PD-128,907 also prevented the acquisition and expression of cocaine-kindled seizures engendered by repeated daily dosing with 60 mg/kg cocaine. (+)-PD-128,907 also blocked the seizures induced in mice fully seizure kindled to cocaine. Although repeated dosing with cocaine increased the potency of cocaine to produce seizures and lethality (decreased ED(50) values), daily coadministration of (+)-PD-128,907 significantly prevented this potency shift. In mice treated daily with cocaine and (+)-PD-128,907, the density, but not the affinity, of D(3) receptors was increased. The specificity with which (+)-PD-128,907 acts upon this cocaine-driven process was demonstrated by the lack of a significant effect of (+)-PD-128,907 on seizure kindling to a GABA(A) receptor antagonist, pentylenetetrazol. Taken together and with literature findings, the data indicate that dopamine D(3) receptors function in the initiation of a dampening mechanism against the toxic effects of cocaine, a finding that might have relevance to psychiatric disorders of drug dependence, schizophrenia, and bipolar depression.

Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures

The antialcoholism drug disulfiram has shown recent promise as a pharmacotherapy for treating cocaine dependence, probably via inhibition of dopamine β-hydroxylase (DBH), the enzyme that catalyzes the conversion of dopamine (DA) to norepinephrine (NE). We previously showed that DBH knockout ( Dbh −/−) mice, which lack NE, are susceptible to seizures and are hypersensitive to the psychomotor, rewarding, and aversive effects of cocaine, suggesting that disulfiram might exacerbate cocaine-induced seizures (CIS) by inhibiting DBH. To test this, we examined CIS in wild-type and Dbh −/− mice following administration of disulfiram or the selective DBH inhibitor nepicastat. We found that Dbh genotype had no effect on CIS probability or frequency, whereas disulfiram, but not nepicastat, increased the probability of having CIS in both wild-type and Dbh −/− mice. Both disulfiram and nepicastat increased CIS frequency in wild-type but not Dbh −/− mice. There were no genotype or treatment effects on serum cocaine levels, except for an increase in disulfiram-treated Dbh −/− mice at the highest dose of cocaine. These results suggest that disulfiram enhances CIS via two distinct mechanisms: it both increases CIS frequency by inhibiting DBH and increases CIS frequency in a DBH-independent manner.

85: Cocaine-Associated Seizures and Incidence of Status Epilepticus

Methods: We performed a retrospective multi-center study of patients with seizures resulting from cocaine use. We identified study subjects at 15 hospitals by record review and conducted a computer-assisted records search to identify patients with seizures for each institution over a fouryear period. We selected subjects from this group on the basis of cocaine use and determined the occurrence of status epilepticus among them. Data were collected on each subject using a standardized data collection form. Results: We evaluated 43 patients in the ED for cocaine-associated seizures. Their age range was 17 to 54, with a mean age was 31 years; 53% were male. Of 43 patients, 42 experienced a single tonic-clonic seizure and one developed status epilepticus. All patients had either a history of cocaine use or positive urine drug screen for cocaine. Conclusion: Despite reported cases of status epilepticus with cocaine-induced seizures, the incidence of this complication was unclear based on prior literature. This study shows that most cocaine-associated seizures are self-limited. [West J Emerg Med. 2010; 11(2):157-160.]