Convulsant Effects Of Cocaine Research Articles

Benzimidazolone-based selective σ2 receptor ligands: Synthesis and pharmacological evaluation

Sigma receptors (σRs) are considered to be a significant and valid target for developing new medications to address several diseases. Their potential involvement in numerous central nervous system disorders, neuropathic pain, addiction, and cancer has been extensively reported. In particular, the σ2R has been identified as potential target for the development of pharmaceutical agents intended to treat the negative effects associated with drugs of abuse. As a continuation of our previous efforts to develop new selective σ2R ligands, a series of benzimidazolone derivatives were designed, synthesized, and characterized. The newly synthesized ligands were evaluated through in vitro radioligand binding assays to determine their affinity and selectivity towards both σ1 and σ2 receptors. Several derivatives displayed high affinity for the σ2R (Ki = 0.66–68.5 nM) and varied from preferring to selective, compared to σ1R (σ1/σ2 = 5.8–1139). Among them, compound 1-{4-[4-(4-fluorophenyl)piperazin-1-yl]butyl}-3-propyl-1,3-dihydrobenzimidazol-2-one dihydrochloride (14) displayed the ability to produce a dose-dependent reduction in the convulsive effects of cocaine in a rodent model after injecting 10 mg/kg (i.p.). These preliminary results support the use of selective σ2R ligands in the development of useful pharmacological tools or potential pharmacotherapies for cocaine toxicity.

Anticonvulsant and convulsant effects of cocaine in genetically epilepsy‐prone rats

Cocaine produces dose‐dependent increases in locomotor activity which can manifest as seizures at high doses. Cocaine is a local anesthetic that also blocks the uptake of norepinephrine (NE), dopamine (DA) and serotonin (5‐HT). Antidepressants that block the uptake of NE and/or 5‐HT produce anticonvulsant effects in genetically epilepsy‐prone rats (GEPRs) at doses below doses producing seizures. The purpose of this study was to determine if cocaine was capable of producing anticonvulsant effects against sound‐induced seizures in the GEPR. Procaine (local anesthetic) imipramine (NE and 5‐HT uptake blockade) and bupropion (DA uptake blockade) effects were also characterized. Anticonvulsant and convulsant dose response curves were determined in moderate seizure (GEPR‐3s) and severe seizure (GEPR‐9s) GEPRs. Effective dose‐50s for anticonvulsant effects and convulsant dose‐50s were determined for all 4 drugs. Cocaine, procaine, imipramine and bupropion all produced anticonvulsant effects in GEPR‐3s and GEPR‐9s at doses lower than doses producing convulsions. These results suggest that cocaine produces anticonvulsant effects at low doses and convulsant effects at high doses through its local anesthetic and NE, DA and 5‐HT uptake blockade mechanisms.

Citalopram enhances cocaine's subjective effects in rats

Serotonin-selective reuptake inhibitors (SSRIs) have been shown to enhance the locomotor stimulatory, discriminative-stimulus, and convulsive effects of cocaine in rodents. A pharmacokinetic mechanism for the interaction is supported by increases in the brain levels of cocaine by fluoxetine treatment. Furthermore, the locomotor-stimulant effects of cocaine in rodents are enhanced by fluoxetine and fluvoxamine, SSRIs known to inhibit cocaine-metabolizing cytochrome P450 enzymes, whereas citalopram, an SSRI that does not inhibit P450 enzymes, does not enhance cocaine's locomotor-stimulant effects. Citalopram, however, attenuated the discriminative-stimulus effects of cocaine in squirrel monkeys trained to discriminate cocaine from saline, though it enhanced the discriminative-stimulus effects of a low dose of cocaine in rats trained to discriminate high and low doses of the drug. This study investigated the effects of citalopram on cocaine's discriminative-stimulus effects in rats trained more simply to discriminate cocaine from saline. Citalopram alone produced predominantly saline-appropriate responding, but when administered before cocaine, citalopram dose-dependently shifted the cocaine dose-response curve leftward. The present findings suggest that enhancement of cocaine's discriminative-stimulus effects may occur through a mechanism different from that underlying enhancement of cocaine's locomotor effects or that another action of citalopram selectively blocks locomotor enhancement.

Pharmacological modulation of GABA(B) receptors affects cocaine-induced seizures in mice.

Previous data have demonstrated that the convulsant effects of cocaine can be modulated by compounds that increase levels of endogenous gamma-aminobutyric acid (GABA) or that directly stimulate GABA(A) receptors. To determine whether the convulsant effects of cocaine can be modulated by ligands selective for GABA(B) receptors in mice. Effects of the GABA(B) receptor agonist ((+/-)-baclofen), antagonist (phaclofen), and their combination were tested against clonic seizures induced by cocaine (75 mg/kg). Enantiomers of baclofen were used to confirm stereospecificity of (+/-)-baclofen's effects. Pharmacological specificity of (+/-)-baclofen's effects was tested by comparison against seizures induced by GBR 12909 (monoamine transporter inhibitor), pentylenetetrazole (GABA(A) antagonist), N-methyl-D-aspartate (NMDA agonist), and aminophylline (A1/A2 adenosine antagonist). Additionally, effects of (+/-)-baclofen on kindled seizures induced by repeated administration of cocaine (60 mg/kg every 24 h for 6 days) were evaluated. The inverted screen test was used to assess behavioral side effects of baclofen. (+/-)-Baclofen dose-dependently inhibited acute (ED50=4.1 mg/kg) and kindled (6.4 mg/kg) seizures induced by cocaine at doses somewhat lower than those producing behavioral side effects (11.5 mg/kg), and these effects were stereospecific. (+/-)-Baclofen suppressed seizures induced by GBR 12909 but not by pentylenetetrazole, NMDA, and aminophylline, suggesting selectivity of its anticonvulsant effects for monoamine-related mechanisms. Finally, phaclofen dose-dependently enhanced the convulsant effects of a threshold dose of cocaine (60 mg/kg). Modulation of GABA(B) receptors can affect seizures induced by cocaine. This molecular mechanism may be involved in seizures induced by cocaine or, alternatively, may function as an independent inhibitory mechanism against seizures arising from blockade of monoamine uptake.

Attenuation of the stimulant and convulsant effects of cocaine by 17-substituted-3-hydroxy and 3-alkoxy derivatives of dextromethorphan

Pharmacological evidence has suggested a role for both sigma and N-methyl- d-aspartate (NMDA) receptors in the behavioral stimulant effects of cocaine and its convulsant effects observed at higher doses. A series of dextromethorphan (DM) analogs with a range of affinities for sigma-1 binding sites and for the NMDA receptor ion channel were used to explore the contribution of these two mechanisms in controlling the stimulant and convulsant effects of cocaine. These compounds were potent and efficacious blockers of both stimulant and convulsant effects produced by acute cocaine administration in mice (cocaine 10 or 75 mg/kg ip for locomotor activity or convulsions, respectively). Generally, the DM analogs blocked these effects of cocaine at doses that did not display ataxic and sedative side effects as measured in the inverted screen test. In contrast to the high-affinity NMDA blockers, (+)-MK-801 (dizocilpine) and dextrorphan (DX), DM and analogs did not stimulate locomotor activity. There was no significant correlation between the affinities of the DM analogs for the sigma-1 or the phencyclidine (PCP) binding site and their potencies to produce behavioral effects on their own or to attenuate the behavioral or toxic effects of cocaine. The present study has identified a series of agents that have cocaine-blocking effects that appear to be distinct from that of classical sigma-1 receptor ligands and that of traditional uncompetitive NMDA receptor antagonists. These findings point to potentially novel pharmacological strategies for blocking cocaine stimulant and toxic effects.

Effects of AMPA/kainate glutamate receptor antagonists on cocaine-induced convulsions and lethality in mice

Prior studies demonstrate that NMDA receptor antagonists attenuate cocaine-induced convulsions and lethality. Since glutamate is the primary neurotransmitter for NMDA receptors, pharmacological interventions to lower glutamatergic activity through non-NMDA ionotropic receptor-mediated mechanisms were evaluated for their ability to prevent the convulsive and lethal effects of cocaine. Pre-treatment of male, Swiss Webster mice with the α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA)/kainate receptor antagonists 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[ f]quinoxaline-7-sulfonamide (NBQX; 10–80 mg/kg, i.p.) or 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5 H-2,3-benzodiazepine hydrochloride (GYKI 52466; 10–20 mg/kg, i.p.) failed to significantly attenuate cocaine-induced convulsions or lethality. Although ineffective when administered alone, NBQX enhanced the protective effects of 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA-1021), an NMDA/glycine site antagonist, when administered in combination. The mixed NMDA/non-NMDA receptor competitive antagonist 5-chloro-7-trifluoromethyl-1,2,3,4-tetrahydroquinoxaline-2,3-dione (ACEA-1011) also protected against the convulsive effects of cocaine. The data suggest that AMPA/kainate receptors indirectly influence the pathophysiological changes that occur after a cocaine overdose through modulation of NMDA receptors.

Cocaine Sensitivity in Borna Disease Virus-Infected Rats

Borna disease virus (BDV) is a neurotropic RNA virus that infects warm-blooded animals to cause disturbances of movement and behavior. Studies in infected rats have demonstrated behavioral sensitivity to direct and indirect dopamine (DA) agonists; however, behavioral responses to an indirect DA agonist with a pure presynaptic effect have not been analyzed. Rats infected with BDV had an enhanced response to the locomotor, behavioral, and convulsant effects of cocaine at intraperitoneal doses of 7.5, 15, and 30 mg/kg. The basis for this sensitivity was examined by striatal DA uptake site and D 1 and D 2 receptor autoradiography. DA uptake sites, labeled with [ 3H] mazindol, were reduced in medial caudate-putamen (CP), and binding of [ 3H] raclopride to D 2 sites was reduced in medial and ventral striatal areas. The topography of DA uptake and D 2 site loss corresponds to the distribution of BDV viral nucleic acids in CP and overlays the medial striatal areas that function in conditioned reward. The BDV-infected rat provides a model of cocaine sensitivity based on viral central nervous system infection and may have relevance for studies of cocaine abuse in the context of other viral encephalopathies, such as those associated with HIV infection.

Effects of ifenprodil on stimulatory, discriminative stimulus, and convulsant effects of cocaine

Ifenprodil, like cocaine, binds to the dopamine transporter and blocks uptake of dopamine. In this study, the ability of ifenprodil to mimic, enhance or block behavioral and toxic effects of cocaine was evaluated. Fixed-interval responding maintained by food presentation in rats was increased by cocaine but decreased by ifenprodil. Low rates of responding during timeout periods were also increased by cocaine but not ifenprodil. Ifenprodil neither increased locomotor activity nor augmented the stimulatory effect of cocaine; however, ifenprodil attenuated the stimulant effects of cocaine at doses 0.5 log unit lower than those required to reduce spontaneous activity when given alone. Ifenprodil neither substituted for nor augmented the discriminative stimulus effects of cocaine in rats discriminating 10mg/kg cocaine from saline. In contrast to cocaine, ifenprodil did not produce convulsions or signs of proconvulsant activity, and ifenprodil reduced the percentage of mice convulsing in the presence of cocaine. These results suggest that pharmacological actions in addition to blockade of dopamine uptake or novel interactions with the dopamine transporter may contribute to the non-stimulant behavioral profile and cocaine-blocking actions of ifenprodil.

Prenatal cocaine: Seizure susceptibility in rat offspring

Proconvulsant and convulsant effects of cocaine have been described in various experimental models of epilepsy. We have studied the susceptibility to bicuculline and pentylenetetrazol-induced seizures in developing 10-, 20- and 30-day old rats, gestationally exposed to cocaine. Incidence and latency of appearance of the epileptic manifestations, their evolution toward status epilepticus and successive recovery or death, have been evaluated and compared to the same parameters obtained in control animals of the same ages. Results have demonstrated that 10-day-old rats that had been exposed to cocaine are significantly less sensitive than control animals to the convulsant action of both bicuculline and pentylenetetrazole while no substantial differences between the two groups have been found at the successive ages. It is possible that modifications of various neurotransmitter systems caused by prenatal cocaine exposure modify neuronal excitability at least at early stages of development.

Evaluation of ADCI against convulsant and locomotor stimulant effects of cocaine: Comparison with structural analogs dizocilpine and carbamazepine

Both the antiepileptic, carbamazepine, and the N- methyl- D- aspartate receptor antagonist, dizocilpine, have shown preclinical efficacy against behavioral and toxic effects of cocaine. Nonetheless, side effects or toxicity of these compounds eitherr alone or in conjunction with cocaine are problematic. 5-Aminocarbonyl-10,11-dihydro-5h-dibenzo[a,d] cyclohepten-5,10-imine (ADCI), a molecular hybrid of these compounds, has been shown to have a broad anticonvulsant profile with a good protective index (behavioral TD 50/anticonvulsant ED 50). In male Swiss Webster mice, ADCI and dizocilpine produced dose-dependent protection against the convulsant effects of cocaine that were insensitive to carbamazepine. However, in contrast to dizocilpine, ADCI did not produce behavioral impairment on the inverted screen test demonstrating a protective index of greater than 15; the protective index for dizocilpine was 1.2. All three compounds attenuated the locomotor stimulant effects of cocaine without significantly decreasing locomotor activity on their own, although the cocaine antagonism was not always dose dependent. Only dizocilpine increased spontaneous locomotor activity when given alone and augmented the locomotor stimulant effects of cocaine. The results confirm the novel anticonvulsant activity of ADCI and its lack of phencyclidine-like behavioral side effects. The data also suggest a modest blocking action of these compounds against the locomotor stimulatory effects of cocaine.

Mazindol may potentiate the convulsant effects of cocaine

Mazindol may potentiate the convulsant effects of cocaine