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Shared vulnerability between seizures and psychosis in cocaine addiction?
Abstract
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.
... In addition, there is evidence of a relationship between cocaine use and a special mechanism that ostensibly creates a secondary seizure focus called "kindling," a progressive sensitization to the seizurogenic effects of cocaine (Meehan and Schechter, 1996). This cocaine-induced sensitization is produced when a constant dose of cocaine is intermittently and repeatedly administered over time; "kindling" is the mechanism that could explain the possible increase in convulsions associated with chronic cocaine consumption, as has been described in human cases (Rolland et al., 2011). ...
... Both the cases of accidental massive cocaine overdose involving seizures in body-packers (Gomez et al., 1998;Hoffman et al., 1990;Klein et al., 2000) and the experimentation with high doses in animals (Hayase et al., 2006;Kaminski et al., 2007; might suggest a cause-effect relationship at high doses. However, we cannot infer from this that such a relationship exists at lower doses, or that a pattern of prolonged chronic use will produce it, although the consequences and physiopathologic mechanisms of "kindling" should be further investigated (Meehan and Schechter, 1996;Rolland et al., 2011). ...
Institutional monographs/medical textbooks mention seizures as a neurological complication of cocaine, but no systematic reviews (SRs) have been published on this issue. We aimed to conduct a SR of the literature on the relationship between cocaine use and seizures and to summarize the biological plausibility of that relationship.
The pathophysiological mechanisms that may underlie an association between cocaine and seizures were summarized; a SR was then performed using three databases (EMBASE, Medline, PsycINFO) and the Cochrane-library to search for published papers (1980-2012) aimed at quantifying the associations between cocaine use and seizures. The inclusion criteria for selection were: articles based on clinical trials, cohort, case-control (CC) or cross-sectional (CS) studies, participants ≥14 years old and not pregnant, and use of cocaine in the last 72h. Information was extracted, evaluated and cross-checked independently by two researchers.
Of the 1243 potentially relevant articles initially identified; one CC and 22 CS studies were finally selected. The CC study did not find cocaine use to be a risk-factor for seizures. In addition to the limitations of the CS design, these studies had important methodological weaknesses and biases.
Despite its biological plausibility, no rigorous scientific evidence supports a causal relationship between cocaine use and seizures. The misinterpretation of the role of cocaine may have important implications in medical services. Well-conducted studies are urgently needed.
... Although the duration of neuronal [Ca 2+ ] i response to cocaine with NIF pretreatment was significantly diminished (t > 17 min in Fig. 1D), the peak for the normalized neuronal [Ca 2+ ] i increase did not differ from that of the VEH (t ≤ 17 min, Fig. 1D). Lack of a peak effect suggests that NIF did not interfere with cocaine-induced activation of NMDARs or their phosphorylation, which increases [Ca 2+ ] i influx [52][53][54]. It could also indicate that NIF did not block the initial increase in intracellular Ca 2+ release from the endoplasmic reticulum [55]. ...
Cocaine profoundly affects both cerebral blood vessels and neuronal activity in the brain. The vasoconstrictive effects of cocaine, concurrently with its effects on neuronal [Ca ²⁺ ] i accumulation are likely to jeopardize neuronal tissue that in the prefrontal cortex (PFC) could contribute to impaired self-regulation and compulsive cocaine consumption. Here we used optical imaging to study the cerebrovascular and neuronal effects of acute cocaine (1 mg/kg i.v.) and to examine whether selective blockade of L-type Ca ²⁺ channels by Nifedipine (NIF) (0.5 mg/kg i.v.) would alleviate cocaine’s effects on hemodynamics (measured with cerebral blood volume, HbT), oxygenation (measured with oxygenated hemoglobin, HbO 2 ) and neuronal [Ca ²⁺ ] i , which were concomitantly measured in the PFC of naive rats. Our results show that in the PFC acute cocaine significantly reduced flow delivery (HbT), increased neuronal [Ca ²⁺ ] i accumulation and profoundly reduced tissue oxygenation (HbO 2 ) and these effects were significantly attenuated by NIF pretreatment. They also show that cocaine-induced vasoconstriction is distinct from its increase of neuronal [Ca ²⁺ ] i accumulation though both of them contribute to hypoxemia and both effects were attenuated by NIF. These results provide evidence that blockade of voltage-gated L-type Ca ²⁺ channels might be beneficial in preventing vasoconstriction and neurotoxic effects of cocaine and give support for further clinical investigations to determine their value in reducing cocaine’s neurotoxicity in cocaine use disorders.
... Cocaine kindling is postulated to be secondary to modified NDMA receptor expression with repeated exposure, resulting in increased glutamate activity in the brain. 12,23 The underlying mechanism behind seizures after SAH remains unclear and is possibly multifactorial. Potential contributing factors include direct toxicity of the blood itself, inflammation, increased intracranial pressure, vasospasm, and cortical spreading depolarization. ...
OBJECT
Seizures are relatively common after aneurysmal subarachnoid hemorrhage (aSAH). Seizure prophylaxis is controversial and is often based on risk stratification; middle cerebral artery (MCA) aneurysms, associated intracerebral hemorrhage (ICH), poor neurological grade, increased clot thickness, and cerebral infarction are considered highest risk for seizures. The purpose of this study was to evaluate the impact of recent cocaine use on seizure incidence following aSAH.
METHODS
Prospectively collected data from aSAH patients admitted to 2 institutional neuroscience critical care units between 1991 and 2009 were reviewed. The authors analyzed factors that potentially affected the incidence of seizures, including patient demographic characteristics, poor clinical grade (Hunt and Hess Grade IV or V), medical comorbidities, associated ICH, intraventricular hemorrhage (IVH), hydrocephalus, aneurysm location, surgical clipping and cocaine use. They further studied the impact of these factors on “early” and “late” seizures (defined, respectively, as occurring before and after clipping/coiling).
RESULTS
Of 1134 aSAH patients studied, 182 (16%) had seizures; 81 patients (7.1%) had early and 127 (11.2%) late seizures, with 26 having both. The seizure rate was significantly higher in cocaine users (37 [26%] of 142 patients) than in non-cocaine users (151 [15.2%] of 992 patients, p = 0.001). Eighteen cocaine-positive patients (12.7%) had early seizures compared with 6.6% of cocaine-negative patients (p = 0.003); 27 cocaine users (19%) had late seizures compared with 10.5% non-cocaine users (p = 0.001). Factors that showed a significant association with increased risk for seizure (early or late) on univariate analysis included younger age (< 40 years) (p = 0.009), poor clinical grade (p = 0.029), associated ICH (p = 0.007), and MCA aneurysm location (p < 0.001); surgical clipping was associated with late seizures (p = 0.004). Following multivariate analysis, age < 40 years (OR 2.04, 95% CI 1.355–3.058, p = 0.001), poor clinical grade (OR 1.62, 95% CI 1.124–2.336, p = 0.01), ICH (OR 1.95, 95% CI 1.164–3.273, p = 0.011), MCA aneurysm location (OR 3.3, 95% CI 2.237–4.854, p < 0.001), and cocaine use (OR 2.06, 95% CI 1.330–3.175, p = 0.001) independently predicted seizures.
CONCLUSIONS
Cocaine use confers a higher seizure risk following aSAH and should be considered during risk stratification for seizure prophylaxis and close neuromonitoring.
Background
Early-life stressful events affect the neurobiological maturation of cerebral circuitries including the endogenous opioid system and the effects elicited by adolescent cocaine exposure on this system have been poorly investigated. Here, we evaluated whether cocaine exposure during adolescence causes short- or long-term alterations in mRNAs codifying for selected elements belonging to the opioid system. Moreover, since brain-derived neurotrophic factor (BDNF) may undergo simultaneous alterations with the opioid peptide dynorphin, we also evaluated its signaling pathway as well.
Methods
Adolescent male rats were exposed to cocaine (20 mg/kg/day) from post-natal day (PND) 28 to PND42, approximately corresponding to human adolescence. After short- (PND45) or long-term (PND90) abstinence, prodynorphin-κ-opioid receptor (pDYN-KOP) and pronociceptin-nociceptin receptor (pN/OFQ-NOP) gene expression were evaluated in the nucleus accumbens (NAc) and hippocampus (Hip) together with the analysis of BDNF signaling pathways.
Results
In the NAc of PND45 rats, pDYN mRNA levels were up-regulated, an effect paralled by increased BDNF signaling. Differently from NAc, pDYN mRNA levels were down-regulated in the Hip of PND45 rats without significant changes of BDNF pathway. At variance from PND45 rats, we did not find any significant alteration of the investigated parameters either in NAc and Hip of PND90 rats.
Conclusions
Our results indicate that the short-term withdrawal from adolescent cocaine exposure is characterized by a parallel pDYN mRNA and BDNF signaling increase in the NAc. Given the depressive-like state experienced during short abstinence in humans, we hypothesize that such changes may contribute to promote the risk of cocaine abuse escalation and relapse.
La cocaïne se situe au deuxième rang des produits illicites les plus consommés en France après le cannabis. Elle est absorbée essentiellement par voie sniffée (sous forme chlorhydrate) ou fumée (sous forme base). Elle est fortement métabolisée dans l’organisme, ses principaux métabolites étant la benzoylecgonine (BZE) et l’ecgonine methylester (EME). Les méthodes de dosage reposent sur des techniques séparatives, soit liquide, soit gazeuse, couplées à une détection par spectrométrie de masse. Il est fortement conseillé de doser la cocaïne ainsi que la BZE et l’EME. En effet, la cocaïne est relativement instable in vitro, et peut se dégrader en ses métabolites sous l’action d’estérases érythrocytaires et plasmatiques. Un prélèvement sur fluorure de sodium à 2,5 % permet de diminuer cette instabilité. Pour les mêmes raisons, la conservation des prélèvements doit se faire à –20 °C plutôt qu’à +4 °C, température à laquelle apparaît une dégradation après 48 heures. Dans le cadre de la circulation routière, certains pays quantifient dans le sang total, d’autres ont choisi le plasma ou le sérum. Dans des conditions optimales de conservation, la cocaïne va persister environ 3 à 8 heures dans le sang, et jusqu’à 24 heures dans les urines. Ces délais peuvent être prolongés chez les consommateurs chroniques. La BZE est retrouvée classiquement jusqu’à 24 heures dans le sang et entre 40 et 60 heures dans les urines. Les seuils limites appliqués sont variables en fonction des pays, correspondant à des seuils analytiques et non de dangerosité. Certains pays ont un seuil imposé uniquement pour la cocaïne, comme la France (50 μg/L), alors que d’autres ont également un seuil imposé pour la BZE, comme la Belgique ou la Finlande. Il est actuellement admis que la cocaïne perturbe la capacité de conduite automobile, mais il ne ressort pas clairement de seuil de dangerosité de l’étude de la littérature. Des experts de différentes nationalités ont proposé des seuils sanguins au-delà duquel le risque d’avoir un accident ou une conduite perturbée est significativement augmenté, variant de 2 à 50 μg/L, associé ou non à des valeurs seuils pour la BZE. En France, la SFTA a proposé un seuil de 10 μg/L pour la cocaïne. Dans la plupart des études, les concentrations salivaires de cocaïne sont plus élevées que dans le sang, mais il n’existe pas de corrélation entre ces deux milieux. Les effets de la cocaïne dépendent de la quantité consommée, de la voie d’administration, de la sensibilité du sujet et des substances associées. Le craving est une composante majeure de l’addiction. Les complications peuvent être nombreuses, essentiellement de type cardiovasculaire, mais également pulmonaire, ORL, neurologique et psychiatrique.
Objective:
This study aimed to determine whether the association between antidepressant (AD) and anticonvulsant effects of electroconvulsive therapy constitutes a necessary, causal relationship.
Methods:
The rats received corneal kindling to induce an epileptic focus, whereas electroconvulsive shock (ECS) was given antagonistically. The forced swim test (FST; a model of AD efficacy), cumulative kindling scores (indexing epileptogenesis), and clonus duration (measuring anticonvulsant effects) were used to assess the effects of ECS. Intensity and route of administration (corneal vs pinnate) of ECS were varied within or across 2 experiments.
Results:
Under various conditions, an increase in mobility in the FST (an index of AD properties) was observed in the absence of any retardation of kindling; under other conditions, an antiepileptogenic effect occurred in the absence of any change in immobility in the FST. In addition, 2 forms of ECS treatment had equal AD properties, whereas only 1 of the 2 treatments reduced clonus time (suggesting an elevated seizure threshold).
Conclusions:
In a rat model, putative AD effects of ECS are dissociable from its antiepileptogenic and anticonvulsant effects, suggesting different stimulus thresholds for the various effects of corneal ECS: the antiepileptogenic effect required a lower current dose than the behavioral effect in the FST, whereas the anticonvulsant effect required the highest stimulation level. With transpinnate ECS, the threshold for the behavioral effect in the FST and the antiepileptogenic threshold were reversed.
Activation of dopamine D1 receptors (D1Rs) has been shown to induce epileptiform activity. We studied the molecular changes occurring in the hippocampus in response to the administration of the D1-type receptor agonist, SKF 81297. SKF 81297 at 2.5 and 5.0 mg/kg induced behavioural seizures. Electrophysiological recordings in the dentate gyrus revealed the presence of epileptiform discharges peaking at 30-45 min post-injection and declining by 60 min. Seizures were prevented by the D1-type receptor antagonist, SCH 23390, or the cannabinoid CB1 receptor agonist, CP 55,940. The effect of SKF 81297 was accompanied by increased phosphorylation of the extracellular signal-regulated protein kinases 1 and 2 (ERK), in the granule cells of the dentate gyrus. This effect was also observed in response to administration of other D1-type receptor agonists, such as SKF83822 and SKF83959. In addition, SKF 81297 increased the phosphorylation of the ribosomal protein S6 and histone H3, two downstream targets of ERK. These effects were prevented by genetic inactivation of D1Rs, or by pharmacological inhibition of ERK. SKF 81297 was also able to enhance the levels of Zif268 and Arc/Arg3.1, two immediate early genes involved in transcriptional regulation and synaptic plasticity. These changes may be involved in forms of activity-dependent plasticity linked to the manifestation of seizures and to the ability of dopamine to affect learning and memory.
In the present study we examined the effects of cocaine seizure kindling on the expression of NMDA receptors and levels of extracellular glutamate in mouse brain. Quantitative autoradiography did not reveal any changes in binding of [³H] MK-801 to NMDA receptors in several brain regions. Likewise, in situ hybridization and Western blotting revealed no alteration in expression of the NMDA receptor subunits, NR1 and NR2B. Basal overflow of glutamate in the ventral hippocampus determined by microdialysis in freely moving animals also did not differ between cocaine-kindled and control groups. Perfusion with the selective excitatory amino acid transporter inhibitor, pyrrolidine-2,4-dicarboxylic acid (tPDC, 0.6 mM), increased glutamate overflow confirming transport inhibition. Importantly, KCl-evoked glutamate overflow under tPDC perfusion was significantly higher in cocaine-kindled mice than in control mice. These data suggest that enhancement of depolarization stimulated glutamate release may be one of the mechanisms underlying the development of increased seizure susceptibility after cocaine kindling.
Clozapine produces EEG abnormalities and dose-dependent risk of epileptic seizures. Much less is known about EEG effects of newer antipsychotics. The present study therefore examined the risk of EEG abnormalities associated with various antipsychotic drugs.
EEG recordings from 323 hospitalized psychiatric patients (293 treated with antipsychotics, 30 who did not receive any antipsychotic treatment) were graded blind to diagnosis and treatment for type and severity of EEG abnormalities. Drug type, dose, and clinical factors were evaluated for association with EEG abnormalities by multivariate logistic regression.
EEG abnormalities occurred in 56 subjects (19.1%) treated and four (13.3%) not treated with antipsychotics. EEG abnormality risk among antipsychotic agents varied greatly (clozapine=47.1%, olanzapine=38.5%, risperidone=28.0%, typical neuroleptics=14.5%, quetiapine=0.0%). Significant risk factors in order of influence were hypertension, use of an atypical antipsychotic, bipolar diagnosis, and older age; benzodiazepine cotreatment lowered risk. Unassociated with risk were sex, treatment response, length of hospital stay, drug potency, daily dose (in mg or mg/kg), drug exposure time, or cotreatments.
EEG abnormality risk varied widely among specific antipsychotics. Risk was particularly high with clozapine and olanzapine, moderate with risperidone and typical neuroleptics, and low with quetiapine. Comorbid hypertension, bipolarity, and older age-but not dose or clinical response-were associated with risk.
Pharmacological blockade of NR2B-containing N-methyl-d-aspartate receptors (NMDARs) during epileptogenesis reduces neurodegeneration provoked in the rodent hippocampus by status epilepticus. The functional consequences of NMDAR activation are crucially influenced by their synaptic vs extrasynaptic localization, and both NMDAR function and localization are dependent on the presence of the NR2B subunit and its phosphorylation state. We investigated whether changes in NR2B subunit phosphorylation, and alterations in its neuronal membrane localization and cellular expression occur during epileptogenesis, and if these changes are involved in neuronal cell loss. We also explored NR2B subunit changes both in the acute phase of status epilepticus and in the chronic phase of spontaneous seizures which encompass the epileptogenesis phase. Levels of Tyr1472 phosphorylated NR2B subunit decreased in the post-synaptic membranes from rat hippocampus during epileptogenesis induced by electrical status epilepticus. This effect was concomitant with a reduced interaction between NR2B and post-synaptic density (PSD)-95 protein, and was associated with decreased CREB phosphorylation. This evidence suggests an extra-synaptic localization of NR2B subunit in epileptogenesis. Accordingly, electron microscopy showed increased NR2B both in extra-synaptic and pre-synaptic neuronal compartments, and a concomitant decrease of this subunit in PSD, thus indicating a shift in NR2B membrane localization. De novo expression of NR2B in activated astrocytes was also found in epileptogenesis indicating ectopic receptor expression in glia. The NR2B phosphorylation changes detected at completion of status epilepticus, and interictally in the chronic phase of spontaneous seizures, are predictive of receptor translocation from synaptic to extrasynaptic sites. Pharmacological blockade of NR2B-containing NMDARs by ifenprodil administration during epileptogenesis significantly reduced pyramidal cell loss in the hippocampus, showing that the observed post-translational and cellular changes of NR2B subunit contribute to excitotoxicity. Therefore, pharmacological targeting of misplaced NR2B-containing NMDARs, or prevention of these NMDAR changes, should be considered to block excitotoxicity which develops after various pro-epileptogenic brain injuries.
Cocaine addiction is a chronic disease marked by relapses, co-morbidities and the importance of psychosocial consequences. The etiology of cocaine addiction is complex and involves three types of factors: environmental factors, factors linked to the specific effects of cocaine and genetic factors. The latter could explain 40–60% of the risk for developing an addiction. Several studies have looked for a link between cocaine addiction and the genes of the dopaminergic system: the genes DRD2, COMT, SLC6A3 (coding for the dopamine transporter DAT) and DBH (coding for the dopamine beta hydroxylase) but unfortunately very few well established results. Pharmacogenetic approach could be an interesting opportunity for the future.
The dopamine D2 receptor is the common target for antipsychotics, and the antipsychotic clinical doses correlate with their affinities for this receptor. Antipsychotics quickly enter the brain to occupy 60-80% of brain D2 receptors in patients (the agonist aripiprazole occupies up to 90%), with most clinical improvement occurring within a few days. The D2 receptor can exist in a state of high-affinity (D2(High) ) or in a state of low-affinity for dopamine (D2Low).
The present aim is to review why individuals with schizophrenia are generally supersensitive to dopamine-like drugs such as amphetamine or methyphenidate, and whether the D2(High) state is a common basis for dopamine supersensitivity in the animal models of schizophrenia.
All animal models of schizophrenia reveal elevations in D2(High) receptors. These models include brain lesions, sensitization by drugs (amphetamine, phencyclidine, cocaine, corticosterone), birth injury, social isolation, and gene deletions in pathways for NMDA, dopamine, GABA, acetylcholine, and norepinephrine.
These multiple abnormal pathways converge to a final common pathway of dopamine supersensitivity and elevated D2(High) receptors, presumably responsible for psychotic symptoms. Although antipsychotics alleviate psychosis and reverse the elevation of D2(High) receptors, long-term antipsychotics can further enhance dopamine supersensitivity in patients. Therefore, switching from a traditional antipsychotic to an agonist antipsychotic (aripiprazole) can result in psychotic signs and symptoms. Clozapine and quetiapine do not elicit parkinsonism or tardive dyskinesia because they are released from D2 within 12 to 24 h. Traditional antipsychotics remain attached to D2 receptors for days, preventing relapse, but allowing accumulation that can lead to tardive dyskinesia. Future goals include imaging D2(High) receptors and desensitizing them in early-stage psychosis.
Preclinical and uncontrolled human studies have suggested the possible efficacy of second-generation antipsychotics, particularly olanzapine, in treating cocaine dependence. We conducted a randomized, double-blind, placebo-controlled trial in which 48 cocaine-dependent subjects received olanzapine or identical-appearing placebo for 16 weeks. The primary outcome measure was the proportion of cocaine-negative weekly urine screens during treatment. Secondary measures included scores on a Craving Questionnaire, Addiction Severity Index subscales, and extrapyramidal symptom scales. Olanzapine and placebo did not differ on any outcome measure. Both olanzapine and placebo subjects frequently reported side effects, but no unexpected ones. We conclude that olanzapine appears ineffective for cocaine dependence.
Kindling has been suggested as a possible mechanism for cocaine-induced seizures in chronic cocaine abusers, even though no convincing examples have been reported. We report a 37-year-old woman who initially experienced generalized tonic-clonic seizures (GTC) only immediately after “crack” use. She had a normal examination, negative family or past history for seizures, and normal cranial computed tomography and EEG. After she had abused cocaine almost daily for 2 years, her EEG demonstrated bitemporal slowing with independent spikes, and seizures were no longer temporally associated with acute cocaine use. Thereafter, despite complete abstinence from cocaine and treatment with phenytoin, she continued to experience four to six GTC a month. In light of the lack of other predisposing factors for epilepsy, this case may represent an example of cocaine-induced kindling in humans.
A pesar de que no se han publicado ejemplos convincentes se ha sugerido que un proceso de condicionamiento (kindling) po-dría ser el mecanismo de los ataques inducidos por la cocaina en adictos a esta droga. Publicamos una mujer de 37 años que, inicialmente, experimentó ataques generalizados tónico-clónicos (GTC) solo inmediatamente después de usar “crack.” La exploratión clinica era normal y la historia familiar o personal negativa para ataques con un CT y un EEG normales. Tras 2 años de abuso casi diario de cocaina el EEG demostró una lentificación bitemporal con puntas independientes en el EEG. Los ataques ya no se asociaban temporalmente al uso agudo de cocaina. Después, y a pesar de una abstinencia completa y con un trat-amiento con fenitoina, continuó con 4–6 GTC al mes. Al no existir otros factores que predisponen a padecer epilepsía, este caso puede representar un ejemplo de “kindling” (condicionamiento) por cocaina en humanos.
The behavioral effects of amphetamine and cocaine are generally considered to be the result of their indirect dopaminergic activity. Recent reports, however, suggest that the activity of the psychomotor stimulants involves not only the dopaminergic but also the glutamatergic system. In the present study the role of the glutamate system in the action of the stimulants was investigated in mice with the use of glutamatergic agonists and antagonists administered either intraperitoneally or intracranially into the striatum. CPP, an NMDA-type glutamate antagonist, given systemically or intrastriatally, blocked stereotypy induced by either amphetamine or cocaine. These results represent pharmacological evidence that the glutamate system is an essential component in the expression of the stereotypic effect of the psychomotor stimulants, and that a locus of this action of glutamate is in the striatum. These conclusions were supported further by the observation that NMDLA administered focally into the striatum caused stereotypy which was indistinguishable from that produced by either amphetamine or dopamine. Stereotypy induced by amphetamine injected into the striatum was blocked by CPP or sulpiride administered either systemically or directly into the striatum; in contrast, stereotypy induced by NMDLA given into the striatum was blocked by CPP but not by sulpiride, regardless of whether the antagonists were presented systemically or into the striatum. The data suggest that stereotypy induced by amphetamine or cocaine is mediated by a dopaminergic activation of a glutamatergic system within the striatum.
The present study was undertaken to examine the role of the benzodiazepine/GABA and N-methyl-d-aspartate (NMDA) systems in the convulsive effect of cocaine in mice. When cocaine (3.5 mg/ml) solution was infused into the tail vein at a rate of 0.3 ml/min, mice showed clonic and tonic convulsions. These seizures were not affected by low doses of bicuculline or picrotoxin, a GABAA receptor antagonist and a Cl ion channel blocker, respectively. Aminooxyacetic acid (AOAA), a GABA deaminase inhibitor, and phenobarbital, a Cl ion channel activator, and baclofen, a GABAB receptor agonist, also had no effect on these convulsions. Benzodiazepine inverse agonist beta-DMCM, at a dose which by itself had no convulsive effect lowered the convulsive threshold of cocaine. This lowered convulsive threshold was reversed by flumazenil, a benzodiazepine inverse antagonist, and diazepam, a benzodiazepine full agonist, which by themselves did not inhibit cocaine seizure. It is likely that cocaine seizure involves a benzodiazepine (beta-carboline) recognition site other than the benzodiazepine/GABAA receptor-Cl ionophore complex system. CPP and MK-801, competitive and noncompetitive NMDA receptor antagonists, respectively, inhibited cocaine seizures. The inhibitory effects of CPP on cocaine convulsion were reversed by a low dose of NMDA, which by itself did not induce seizure. A dopamine D1 receptor agonist SKF38393 enhanced both clonic and tonic convulsions, while a dopamine D2 receptor agonist bromocriptine inhibited these convulsions. These stimulatory and inhibitory effects were reversed by the D1 and D2 receptor antagonists, SCH23390 and haloperidol, respectively. These results suggest that the cocaine-induced convulsion may involve an activation of the NMDA-Ca ionophore complex system, which is mediated by the dopaminergic system, and a beta-carboline recognition site other than the benzodiazepine/GABAA receptor-Cl ionophore complex system.
The aim of this article is to review the literature on the effects of psychostimulants in epileptic subjects in order to reach a consensus statement regarding the use or abuse of these substances.
Psychostimulant substances have been considered the drugs that share the ability to produce excitation of the CNS leading to convulsions. The stimulation may be at cortical, brainstem, or spinal levels. In this article, the following cortical stimulants are analyzed and discussed: cocaine, amphetamine and related agents, caffeine, cannabinoids, and psychedelic drugs. This review is based on research done using pharmacological textbooks and Medline.
The use of cocaine is associated with the occurrence of seizures. The reported frequency varies from 1% to 40% of addicted subjects, based on the typology of the considered study. Amphetamines and related drugs rarely induce epileptic seizures at therapeutic doses, but seizures may occur after the first dosing. Caffeine at high doses may induce epileptic seizures because of its adenosine receptor-antagonizing properties. Marijuana, at variance with other psychostimulants, owing to its serotonin-mediated anticonvulsant action, could have a medical use for the treatment of epilepsy. Psychedelic compounds rarely induce epileptic seizures, but the most common clinical CNS complication after ingestion of ecstasy is the occurrence of seizures.
The use of psychostimulants, except for marijuana, can induce single or multiple seizures in healthy subjects.
Drug addiction is a chronic disease characterized by compulsive drug use despite the severe negative consequences associated with it. Repeated exposure to drugs of abuse results in molecular adaptations in neuronal signaling pathways, which eventually manifest in the complex behavioral alterations that characterize addiction. These include tolerance, sensitization, dependence, drug craving, and relapse. In this Review, we focus on recent studies highlighting signaling cascades initiated by cocaine, as a representative of a drug of abuse with a defined site of action, and alcohol, as a drug with an undefined primary site of action. Specifically, we describe recent studies that emphasize the role of protein-protein interactions, phosphorylation, and compartmentalization in the molecular mechanisms that result in the cellular and behavioral adaptations that underlie addiction. Signaling cascades that contribute to addiction, as well as those that protect or delay the development of addiction, are presented.
Dopamine-glutamate interactions in the neostriatum determine psychostimulant action, but the underlying molecular mechanisms remain elusive. Here we found that dopamine stimulation by cocaine enhances a heteroreceptor complex formation between dopamine D2 receptors (D2R) and NMDA receptor NR2B subunits in the neostriatum in vivo. The D2R-NR2B interaction is direct and occurs in the confined postsynaptic density microdomain of excitatory synapses. The enhanced D2R-NR2B interaction disrupts the association of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) with NR2B, reduces NR2B phosphorylation at a CaMKII-sensitive site (Ser1303), and inhibits NMDA receptor-mediated currents in medium-sized striatal neurons. Furthermore, the regulated D2R-NR2B interaction is critical for constructing behavioral responsiveness to cocaine. Our findings here uncover a direct and dynamic D2R-NR2B interaction in striatal neurons in vivo. This type of dopamine-glutamate integration at the receptor level may be responsible for synergistically inhibiting the D2R-mediated circuits in the basal ganglia and fulfilling the stimulative effect of psychostimulants.
Comorbidity between drug abuse and mental illness is very common, but the association of such comorbidity with specific responses to drugs of abuse remains obscure. The current study examined the relationship between the presence of non-psychotic Axis I psychiatric diagnoses and the frequency and severity of cocaine-induced psychosis. We interviewed 243 unrelated cocaine-dependent adults [37% European American (EA), 52.3% African American (AA); 58.8% male] using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) to establish DSM-IV diagnoses, and two instruments for the identification of cocaine-induced paranoia, the Cocaine Experience Questionnaire (CEQ) and the Scale for Assessment of Positive Symptoms for Cocaine-Induced Psychosis (SAPS-CIP). Comorbid substance use and psychiatric disorders were common in this cocaine-dependent sample. Ninety percent of subjects met criteria for substance use disorders other than cocaine dependence; common non-substance-use disorders included antisocial personality disorder (ASPD), adult ASPD, major depression, and attention deficit-hyperactivity disorder (ADHD). Comorbid opioid dependence was more common in EA subjects than in AA participants. After correction for multiple comparisons, a lifetime diagnosis of ADHD was associated with the categorical presence of CIP (p = 0.007), as well as significantly more severe CIP symptoms. Comorbid substance use and psychiatric disorders are very common among individuals with cocaine dependence. Comorbid ADHD increases the odds of an individual endorsing CIP, suggesting some common basis for these phenomena.
The monaminergic properties of second generation antipsychotics are prompting research on their use to treat cocaine dependence, with inconclusive results to date. In preliminary reports, the atypical antipsychotic quetiapine has shown promise for the treatment of substance abuse disorders. The primary objective of the current study was to assess the efficacy of quetiapine in reducing cocaine cravings and use in nonpsychotic subjects with cocaine dependence over 6 weeks of open-label treatment. Twenty-two cocaine-dependent, nonpsychotic men were initiated to open-label treatment with quetiapine (300-600 mg/d). The primary outcome measure was weekly self-report of cocaine cravings as assessed with the Brief Substance Craving Scale. Cocaine use was captured with a self-report Timeline Follow-back calendar, administered every 2 weeks. Side effect monitoring was conducted weekly, and movement disorders were assessed every 2 weeks. Intent-to-treat regression analyses (n = 22) indicated that the Brief Substance Craving Scale total score decreased significantly overtime (P < 0.001). Self-reports also suggested decreased cocaine use. There was no treatment-related increase in movement disorders, and most side effects were mild. However, all subjects did experience sedation, and several subjects dropped out because of it. What is more, weight increased significantly over time (P < 0.001). Open-label quetiapine treatment reduced cravings and improved some aspects of cocaine dependence in nonpsychotic individuals. Additional research is needed to confirm the current findings and to further delineate the role quetiapine may play in the treatment of cocaine use disorders.