RESUMEN
Nonconvulsive seizures (NCSs) after traumatic and ischemic brain injury are often refractory to antiepileptic drug therapy and are associated with a decline in patient outcome. We recently characterized an in vivo rat model of focal brain ischemia-induced NCS and here sought to evaluate potential pharmacological treatments. Electroencephalographic activity was recorded continuously for 24 h in freely behaving rats subjected to permanent middle cerebral artery occlusion (MCAo). Rats were treated with an antiepileptic drug from one of seven different drug classes at ED(50) and 2x ED(50) doses (as reported in other rat seizure models), delivered as a single i.v. injection 20 min post-MCAo. Vehicle-treated rats (n = 9) had an 89% incidence of NCS with an average number of NCS of 8.6 +/- 1.9. The latency to onset of NCS was 32.5 +/- 3.4 min post-MCAo with an average duration of 49.1 +/- 8.2 s/event. The high doses of ethosuximide, gabapentin, fos-phenytoin, and valproate significantly reduced the incidence of NCS (11, 14, 14, and 38%, respectively), whereas midazolam, phenobarbital, and dextromethorphan had no significant effect at either dose. Across treatment groups, there was a low but significant correlation between the number of NCS events per animal and volume of brain infarction (r = 0.352). Antiepileptic drug therapy that prevented the occurrence of NCS also reduced mortality from 26 to 7%. Based on combined effects on NCS, infarction, neurological recovery, and mortality, ethosuximide and gabapentin were identified as having the best therapeutic profile.
Asunto(s)
Aminas/uso terapéutico , Anticonvulsivantes/uso terapéutico , Isquemia Encefálica/complicaciones , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Etosuximida/uso terapéutico , Convulsiones/tratamiento farmacológico , Ácido gamma-Aminobutírico/uso terapéutico , Animales , Infarto Encefálico/etiología , Infarto Encefálico/prevención & control , Lesiones Encefálicas/etiología , Lesiones Encefálicas/prevención & control , Modelos Animales de Enfermedad , Electroencefalografía , Gabapentina , Masculino , Ratas , Ratas Sprague-Dawley , Convulsiones/etiologíaRESUMEN
Remifentanil (Ultiva) is a novel, ultra-short-acting opioid which has recently been approved for use as an analgesic during induction and maintenance of general anesthesia. Esmolol is a short-acting beta-blocker used during surgical procedures to reduce heart rate and blood pressure. Both drugs are metabolized by nonspecific esterases in the blood and other tissues and may be administered concomitantly during surgery. The goal of this study was to determine if coadministration of esmolol significantly alters the pharmacokinetics of remifentanil in the rat. Two groups of rats were dosed with remifentanil [25 micrograms/kg/min (n = 8)] and remifentanil plus esmolol [25 and 200 mg/kg/min (n = 7)] for 20 min. Cardiovascular measurements were collected continuously over the course of the study. Serial blood samples (12) were collected over 25 min into test tubes containing 0.5 mL of acetonitrile. Blood samples were extracted (liquid-liquid) with methylene chloride and then analyzed by a validated GC-MS assay. Compartmental data analysis was performed using PCNONLIN. The mean(+/- SD) for Cl and t1/2 observed in treatment I were 390(+/- 98) mL/min/kg and 0.69(+/- 0.27) min and in treatment II were 421(+/- 164) mL/min/kg and 0.56(+/- 0.22) min, respectively. Comparison of clearance, volume of distribution, and terminal half-life between the two groups showed that coadministration of esmolol had no significant (p < 0.05) effect on the pharmacokinetics of remifentanil in the rat.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Analgésicos Opioides/farmacocinética , Piperidinas/farmacocinética , Propanolaminas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Interacciones Farmacológicas , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Modelos Biológicos , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , RemifentaniloRESUMEN
The present study characterized the electroencephalographic (EEG) effects of the neuroprotective kappa opioids enadoline and PD117302 in conscious, freely moving rats with the use of computer-assisted spectral analysis (CASA). Enadoline (25-100 microg/kg) or PD117302 (1.25-5.0 mg/kg) was administered intravenously to rats implanted with cortical EEG electrodes. Although both drugs produced an immediate, mild sedation, there were no signs of head-weaving or ataxia, and there was little visual evidence of opioid-like EEG slow-wave bursts or seizures. Both drugs produced only modest increases in total EEG power that were not dose dependent. In contrast, CASA revealed significant dose-dependent frequency shifts in relative power distributions, thereby identifying distinct kappa opioid alterations in awake EEG activity; EEG power decreased in the 0- to 4-Hz frequency band with concomitant increases in power measured in the 4- to 8-Hz frequency range. The kappa opioids produced a dose-dependent consolidation of the EEG waveform centered about a peak frequency of 5.0 Hz (for enadoline) or 4.8 Hz (for PD117302) and a significant shift in the mean EEG frequency from 6.6 Hz (predrug) to 6.2 Hz (postdrug). Further CASA revealed significant postdrug decreases in the edge frequency, mobility and complexity of the EEG. Both drugs produced moderate increases in the latency to slow-wave sleep (SWS). Overall, enadoline (ED50 = 18 microg/kg) was approximately 94 times more potent than PD117302 (ED50 = 1690 microg/kg) in producing the kappa EEG profile. Because the kappa-induced EEG changes were stereospecific for the (-)-enantiomers and inhibited by norbinaltorphimine (nor-BNI), the EEG "fingerprint" described in this study could be attributed to specific activation of brain kappa opioid receptors.
Asunto(s)
Benzofuranos/farmacología , Electroencefalografía/efectos de los fármacos , Narcóticos/farmacología , Fármacos Neuroprotectores/farmacología , Pirroles/farmacología , Pirrolidinas/farmacología , Receptores Opioides kappa/efectos de los fármacos , Tiofenos/farmacología , Animales , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The effect of neuroprotective sigma ligands possessing a range of relative selectivity for sigma and phencyclidine (PCP) binding sites on N-methyl-D-aspartate (NMDA) and (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD)-stimulated calcium flux was studied in 12-15-day-old primary cultures of rat cortical neurons. In approximately 80% of the neurons tested, NMDA (80 microM) caused a sustained increase in intracellular calcium ([Ca2+]i). With the exception of R-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride ((+)-3-PPP) (previously shown not to be neuroprotective) all of the sigma ligands studied significantly altered NMDA-induced calcium dynamics. The primary effect of dextromethorphan, (+)-pentazocine, (+)-cyclazocine, (+)-SKF10047, carbetapentane, 1,3-di(2-tolyl) guanidine (DTG), and haloperidol was to shift the NMDA response from a sustained, to either a biphasic or a transient, calcium event. In contrast to NMDA, the primary response observed in 62% of the neurons treated with trans-ACPD (100 microM) was a transient elevation in [Ca2+]i. Here, however, only the highly selective neuroprotective sigma ligands (i.e., those lacking substantial PCP binding affinity) significantly decreased the number of transient responses elicited by trans-ACPD whereas the PCP-related sigma ligands such as dextromethorphan, (+)-SKF10047 and (+)-cyclazocine were ineffective. Unexpectedly, (+)-3-PPP potentiated trans-ACPD activity. These results demonstrating attenuating effects of sigma ligands on NMDA-stimulated neuronal calcium responses agree with earlier studies using glutamate and KCl and identify a sigma receptor modulation of functional NMDA responsiveness. Furthermore, the ability of sigma ligands to attenuate NMDA-, trans-ACPD- and KCl-evoked neuronal calcium dynamics indicates that the receptor mechanisms mediating sigma neuroprotection comprise complex interactions involving ionotropic, metabotropic, and even voltage-gated calcium signaling processes.
Asunto(s)
Calcio/fisiología , Cicloleucina/análogos & derivados , N-Metilaspartato/farmacología , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Receptores sigma/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Células Cultivadas , Cicloleucina/antagonistas & inhibidores , Cicloleucina/farmacología , Ligandos , N-Metilaspartato/antagonistas & inhibidores , Ratas/embriología , Ratas Sprague-DawleyRESUMEN
PURPOSE: The goal of this study was to determine if the co-administration of esmolol (ES), a short acting cardioselective beta-blocker, significantly alters the pharmacokinetics and/or pharmacodynamics of remifentanil (REMI), an ultra short-acting opioid, in the rat. METHODS: Sprague-Dawley rats (N = 8, Wt. = 325 +/- 15 g) were surgically implanted with stainless steel cerebrocortical EEG electrodes three days before the study. Each rat was dosed with REMI (15 micrograms/kg/min), and REMI & ES (15 micrograms/kg/min and 600 micrograms/kg/min) for 21 minutes in a random crossover design. Six serial blood samples were collected over 25 minutes into test-tubes containing 0.5 ml acetonitrile. Blood samples were extracted with methylene chloride and analyzed by a validated GC-MS assay. EEG was captured and subjected to power spectral analysis (0.1-50 Hz) for spectral edge (97%). RESULTS: No significant differences (p < 0.05) were found in clearance (REMI = 287 + 73 ml/min/leg vs. REMI & ES = 289 +/- 148 ml/min kg) or Vd (REMI = 286 +/- 49 ml/kg vs REMI & ES = 248 + 40 ml/kg). A linked sigmoid Emax PK-PD model was used and the pharmacodynamic parameters were not statistically different. Mean Emax and EC50 after REMI were 18.0 +/- 6.0 Hz and 32 +/- 12 ng/ml; and after REMI + ES were 19 + 4.8 Hz and 26 + 8.6 ng/ml. CONCLUSIONS: At the doses tested, there is no pharmacokinetic or pharmacodynamic interaction between remifentanil and esmolol in the rat.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Analgésicos Opioides/farmacocinética , Electroencefalografía/efectos de los fármacos , Piperidinas/farmacocinética , Propanolaminas/farmacología , Antagonistas Adrenérgicos beta/administración & dosificación , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Animales , Estudios Cruzados , Interacciones Farmacológicas , Semivida , Infusiones Intravenosas , Masculino , Tasa de Depuración Metabólica , Piperidinas/administración & dosificación , Piperidinas/farmacología , Propanolaminas/administración & dosificación , Ratas , Ratas Sprague-Dawley , RemifentaniloRESUMEN
Since unique calcium dynamics have been reported for toxic (40-80 M) and non-toxic (5-10 microM) concentrations of glutamate, we evaluated the effect of neuroprotective sigma ligands on glutamate and potassium chloride (KCl)-stimulated changes in [Ca2+]i using 12-15 day old primary rat neuronal cortical cultures. In approximately 80% of the neurons tested, 80 microM glutamate caused a sustained calcium flux previously shown to be associated with neurotoxicity. The majority of sigma ligands that were evaluated altered glutamate-induced calcium flux. For example, the primary effect of maximally neuroprotective concentrations of the sigma ligands dextromethorphan, (+)-pentazocine, (+)-cyclazocine, (+)-SKF 10047, carbetapentane and haloperidol was a shift from a sustained, to either a biphasic or a monophasic transient calcium response indicative of neuroprotection. (+)-3-PPP, previously shown not to be neuroprotective in this model system, failed to alter glutamate-induced calcium flux. In contrast to glutamate, KCl (50 mM) produced changes in [Ca2+]i which were not neurotoxic to the neurons as measured by LDH release. The primary response observed in 59% of the neurons treated with 50 mM KCl alone was an initial spike in [Ca2+]i which abruptly declined then plateaued above basal levels throughout the 12 min of analysis (modified sustained response). The highly selective sigma ligands produced a shift from the modified sustained response to a monophasic transient calcium response. Again, (+)-3-PPP had no effect on KCl-induced calcium dynamics. Of the PCP-related sigma ligands only (+)-SKF-10047 consistently attenuated the KCl-induced calcium flux. Collectively, these results indicate that modulation of [Ca2+]i through receptor and voltage-gated calcium channels contributes significantly to sigma mediated neuroprotection.
Asunto(s)
Calcio/fisiología , Corteza Cerebral/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores sigma/fisiología , Animales , Células Cultivadas , Corteza Cerebral/citología , Ácido Glutámico/farmacología , Ligandos , Cloruro de Potasio/farmacología , Ratas , Receptores sigma/efectos de los fármacosRESUMEN
The effects of the selective kappa-opioid, PD117302 ((+/-)-trans-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzo[b]thiophene-4-acetamide), on transient (15 min) global forebrain ischemia, induced by four-vessel occlusion, was evaluated using a multiple fixed-ratio, fixed-interval schedule of food presentation in rats. The schedule produced distinctive patterns of responding in the fixed-ratio and fixed-interval components. Ischemia produced CA1 hippocampal necrosis and prolonged suppression of responding under both schedule components. When responding resumed, the pattern of responding rapidly returned. Response disruption and CA1 hippocampal necrosis were minimal or nonexistent in sham-occluded rats. Behavioral recovery time under both components of the schedule of reinforcement correlated with CA1 necrosis. On average, CA1 necrosis was less, and behavioral recovery time was shorter, in rats treated with PD117302 postocclusion as compared with vehicle-treated rats. The difference, however, did not reach statistical significance. These results demonstrate the utility of schedule-controlled responding for evaluating potentially therapeutic compounds for the treatment of ischemic injury. These results also further characterize the neuroprotective actions of kappa opioids.
Asunto(s)
Condicionamiento Operante/efectos de los fármacos , Ataque Isquémico Transitorio/tratamiento farmacológico , Prosencéfalo/irrigación sanguínea , Pirroles/farmacología , Receptores Opioides kappa/efectos de los fármacos , Tiofenos/farmacología , Animales , Muerte Celular/efectos de los fármacos , Ataque Isquémico Transitorio/psicología , Masculino , Ratas , Ratas Sprague-Dawley , Esquema de RefuerzoRESUMEN
The effect of the selective D1 antagonist, SCH 23390, and the selective D2 antagonist, spiperone, was investigated in rats trained to self-administer intravenous cocaine on a fixed-ratio (FR) 5 schedule of reinforcement. Both SCH 23390 and spiperone pretreatment increased responding up to doses of 10.0 micrograms/kg, and decreased responding at higher doses. Since rate of responding maintained by a drug can be influenced by factors other than its reinforcing efficacy, behavior maintained by cocaine was also investigated under a progressive-ratio schedule. The breaking point obtained under this schedule is used as a measure of the efficacy of the reinforcer and this value is not exclusively determined by response rate. With the progressive-ratio schedule, both SCH 23390 and spiperone produced dose-dependent decreases in the highest ratio completed in rats self-administering cocaine. The results obtained using the FR 5 and progressive-ratio schedules suggest that both D1 and D2 receptors are involved in mediating the reinforcing effects of cocaine.
Asunto(s)
Conducta Animal/efectos de los fármacos , Cocaína/farmacología , Antagonistas de Dopamina , Animales , Benzazepinas/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Endogámicas , Receptores de Dopamina D1 , Receptores de Dopamina D2 , Esquema de Refuerzo , Autoadministración , Espiperona/farmacologíaRESUMEN
Female Sprague-Dawley rats prepared with chronic i.v. cannulas and/or cerebrocortical electrodes were administered sequentially increasing doses of phencyclidine (PCP, 0.1-6.4 mg/kg/injection), (+)-SKF-10,047 [(+)-N-allynormetazocine] (0.4-25.6 mg/kg/injection) or MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine maleate] (0.01-0.64 mg/kg/injection). Effects on overt behavior, cortical EEG power spectra, locomotor activity and rotarod performance were assessed. Quantitative EEG spectral parameters (peak, mean and edge frequency; total and relative power; time domain descriptors mobility and complexity) were analyzed from the global frequency range of 1 to 50 Hz. Increasing doses of each drug produced increases in EEG spectra power from 1 to 50 Hz which was associated with a slowing of the peak frequency. PCP and MK-801 produced decreases in the mean frequency, mobility and edge frequency whereas (+)-SKF-10,047 produced increases in these spectral parameters. Moreover, (+)-SKF-10,047 increased complexity whereas MK-801 decreased complexity and PCP did not change this parameter. Total spectral power from 20 to 50 Hz was increased by (+)-SKF-10,047 and PCP, but was not changed by MK-801. Each drug increased spontaneous locomotor activity. At the highest doses, PCP and MK-801 decreased activity whereas (+)-SKF-10,047 was lethal. Each drug disrupted rotarod performance. The rank order of potency for each effect was: MK-801 greater than PCP greater than (+)-SKF-10,047. The data indicate that subtle differences in the effects of these drugs can be detected using EEG power spectral analysis.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Anticonvulsivantes/farmacología , Dibenzocicloheptenos/farmacología , Electroencefalografía , Actividad Motora/efectos de los fármacos , Fenazocina/análogos & derivados , Fenciclidina/farmacología , Animales , Maleato de Dizocilpina , Femenino , Fenazocina/farmacología , Ratas , Ratas Endogámicas , Receptores de N-Metil-D-Aspartato , Receptores de Neurotransmisores/efectos de los fármacos , Receptores Opioides/efectos de los fármacos , Receptores sigma , Conducta Estereotipada/efectos de los fármacosRESUMEN
Female rats, implanted with cerebrocortical EEG recording electrodes, were trained to self-administer cocaine and then ketamine under a fixed ratio 10 schedule of reinforcement, during limited access sessions. Periodically, a single unit dose of either phencyclidine (0.5 mg/kg), ketamine (4 mg/kg) or 1-(1-phenylcyclohexyl)morpholine (PCM 4 mg/kg) was substituted for ketamine, while the cortical EEG was recorded. Spectrum quantities of samples of EEG, taken immediately before and after each injection, were subjected to a discriminant analysis. For each drug, the preinjection state of the EEG could be classified separately from the postinjection state, using specific EEG spectrum quantities from the global frequency range (0.1-20 Hz). Furthermore, the relevant EEG parameters, which described the change from pre- to postinjection states, were unique for each drug (phencyclidine: total power and complexity; ketamine: peak frequency, relative power and mobility; PCM: all parameters except peak frequency), indicating potential differences in the EEG, occurring with a level of intake of drug which was controlled by the subject. Overall, these data serve to model the changes in the EEG that occur during the self-administration of three phencyclinoids. Furthermore, the combination of EEG spectrum analysis with discriminant analysis is useful in detecting subtle differences in the effects of these three drugs on the EEG.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Electroencefalografía , Fenciclidina/administración & dosificación , Animales , Cocaína/farmacología , Femenino , Ketamina/farmacología , Fenciclidina/análogos & derivados , Ratas , Ratas Endogámicas , Esquema de Refuerzo , AutoadministraciónRESUMEN
Phencyclidine profoundly alters cerebral metabolism in the rat. This study explored whether cerebral metabolic effects of phencyclidine differed when the drug was self-administered by trained rats, compared with when it was given acutely to naive rats. The regional cerebral uptake of 2-deoxy-D-[1-(D14C] glucose (DG) was examined following two injections of phencyclidine (0.5 mg/kg/injection, i.v.) or saline in freely-moving, drug-experienced rats. Naive controls received phencyclidine or saline according to an identical dose regimen. In self-administering and naive rats, phencyclidine produced many of the same effects on uptake of DG, including the following: decreases in the habenula, inferior colliculus, sensory cortical areas and corresponding thalamic relay nuclei; and increases in limbic areas (entorhinal and retrosplenial cortices, subicular areas). Some regions (auditory and motor cortices, medial geniculate body, globus pallidus) showed different effects in self-administering and naive rats. Another study, in which rats were not self-administering phencyclidine, but had histories of treatment with drugs similar to those of the self-administering rats, indicated that chronic exposure to drug accounted for some of the differences. Furthermore, differences between the effects of phencyclidine in self-administering, versus non-self-administering rats with similar histories suggested that activity in some regions of the brain may relate to training in drug self-administration and/or behavior.
Asunto(s)
Química Encefálica/efectos de los fármacos , Desoxiazúcares/metabolismo , Desoxiglucosa/metabolismo , Fenciclidina/farmacología , Animales , Cocaína/farmacología , Femenino , Ketamina/farmacología , Fenciclidina/administración & dosificación , Ratas , Ratas Endogámicas , AutoadministraciónRESUMEN
Female Sprague-Dawley rats were trained to self-administer phencyclidine (PCP; 0.125, 0.25, or 0.5 mg/kg/injection) on a fixed ratio (FR) schedule of reinforcement under limited access conditions (3 h). Initial training began with cocaine, which was later replaced with ketamine and then one of the three unit doses of PCP. Baseline rates of injection were determined at FR 10. The size of the ratio was then incremented geometrically every fifth daily session. Increasing the ratio resulted in a decrease in the number of injections per session. Furthermore, this decrease was greater for the 0.25 mg/kg dose than for the 0.5 mg/kg unit dose. The self-administration of the 0.125 mg/kg dose was variable and rapidly extinguished upon the increase in fixed ratio. The results indicate that PCP is self-administered by rats under the conditions imposed in this study. Furthermore, the relative reinforcing efficacy of the different unit doses of PCP could be discriminated using this type of response cost procedure.
Asunto(s)
Fenciclidina/farmacología , Animales , Cocaína/farmacología , Femenino , Ketamina/farmacología , Fenciclidina/administración & dosificación , Ratas , Ratas Endogámicas , Esquema de Refuerzo , AutoadministraciónRESUMEN
The pharmacology and structure-activity relationship of phencyclidine (PCP)-like drugs (phencyclinoids) were studied using electroencephalographic (EEG), behavioral and receptor binding techniques. The effects of PCP, 1-phenylcyclohexylamine HCl, N-methyl-1-phenycyclohexylamine HCl, N-ethyl-1-phenylcyclohexylamine HCl, N-(s-butyl)-1-phenylcyclohexylamine HCL, 1-(1-phenylcyclo-hexyl)-pyrrolidine HCl, 1-[1-(2-thienyl)cyclohexyl] piperidine HCl, 1-[1-(2-thienyl)cyclohexyl]-pyrrolidine HCl, ketamine and (+/-)-SKF 10047 were evaluated on the direct EEG and EEG spectra after acute i.v. injections (0.1-17.8 mg/kg). Similarities and differences were noted in the EEG dose-response curves. At lower doses of PCP and its analogs, low-amplitude theta waves predominated; however, at higher doses, high-amplitude, lower-frequency waves predominated. Qualitatively, the N-piperidine derivatives were similar to PCP and differed primarily in potency. The benzomorphan (+/-)-SKF 10047 produced only theta activity at doses up to 12.8 mg/kg. These EEG effects occurred in conjunction with overt behaviors including locomotion, stereotypy and ataxia, concurrently assessed via observer-based rating scales. A strong correlation (r = 0.98) was obtained between the EEG and behavioral effects and the IC50 values from [3H]PCP displacement experiments using crude rat brain homogenates.
Asunto(s)
Conducta Animal/efectos de los fármacos , Electroencefalografía , Fenciclidina/análogos & derivados , Fenciclidina/farmacología , Receptores de Neurotransmisores/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Femenino , Inyecciones Intravenosas , Fenciclidina/metabolismo , Ratas , Ratas Endogámicas , Receptores de Neurotransmisores/metabolismo , Receptores de Fenciclidina , TritioRESUMEN
Phencyclidine (1-(1-phenylcyclohexyl)piperidine, PCP) self-administration has been demonstrated in rhesus monkeys, baboons, dogs and rats. Generally, an orderly inverted U-shaped dose-response curve for rates of self-injection has been observed. Total drug intake appears to increase slightly with increases in unit dose; however, this increase is much less than might be expected with other CNS depressants such as barbiturates or morphine. Additionally, several arylcyclohexylamine analogues of PCP and some members of the benzomorphan and dioxolane classes referred to collectively as "phencyclinoids" are self-administered by primates and dogs. New data are presented in this review profiling the self-administration of some of these drugs in rats, as well as a characterization of the self-administration of higher unit doses of PCP than previously reported. Also, preliminary results of the assessment of the reinforcing efficacy of some PCP analogues measured by the progressive ratio procedure are presented.
Asunto(s)
Fenciclidina/administración & dosificación , Autoadministración , Trastornos Relacionados con Sustancias , Animales , Cocaína/administración & dosificación , Condicionamiento Operante , Modelos Animales de Enfermedad , Femenino , Infusiones Intravenosas , Ketamina/administración & dosificación , Fenciclidina/análogos & derivados , Abuso de Fenciclidina/etiología , Ratas , Esquema de Refuerzo , Trastornos Relacionados con Sustancias/etiologíaRESUMEN
The effects of chronic phencyclidine (PCP) or ketamine (KET) on their respective acute behavioral and anticonvulsant actions were investigated. Female rats were treated for 15 days with twice daily i.p. injections of saline, 20 mg/kg PCP or 40 mg/kg KET. Subjects treated chronically with PCP were challenged with either 10 mg/kg or 20 mg/kg i.p. PCP, while subjects treated chronically with KET were challenged with 40 mg/kg i.p. KET only. Neither chronic drug treatment induced tolerance to the acute anticonvulsant effect, nor to hyperlocomotion and stereotypy as measured by automated activity monitors. However, evidence of tolerance to the stereotypy induced by acute KET was obtained when an observer-based rating scale was employed. In addition, tolerance occurred to the ataxia induced by KET and the 10 mg/kg, but not 20 mg/kg, dose of PCP. Thus, tolerance occurs to some of the acute behavioral effects of PCP and KET while the anticonvulsant action of these compounds remains unaffected.
Asunto(s)
Anticonvulsivantes , Ketamina/farmacología , Actividad Motora/efectos de los fármacos , Fenciclidina/farmacología , Animales , Tolerancia a Medicamentos , Electrochoque , Femenino , Ratas , Ratas Endogámicas , Conducta Estereotipada/efectos de los fármacosRESUMEN
The electroencephalogram (EEG), electromyogram (EMG) and behavior were monitored in rats with chronic cerebrocortical and temporalis muscle electrodes. They were injected acutely with 0, 2, 4 and 8 mg/kg of phencyclidine (i.p.). The EEG power spectra correlated in a dose-related manner, with the direct EEG and behavioral effects of phencyclidine. At 2 mg/kg, the EEG consisted primarily of low amplitude theta activity from 6 to 8 Hz, accompanied by behavioral arousal and hyperactivity. At 4 mg/kg, the EEG theta activity persisted and was superimposed on a background of high amplitude slow waves which were associated with the emergence of ataxia. Locomotion and stereotypy intensified at this dose. The power spectra of these changes in the EEG were characterized by two distinct spectral peaks lying between 0-5 and 5-10 Hz. After 8 mg/kg, EEG activity shifted predominantly to lower frequencies between 2 and 3 Hz. This shift produced a large increase in spectral power in the 0-5 Hz band which was accompanied behaviorally by severe ataxia, limited locomotion, and stereotypy of head and forepaw movements. Similarities and differences between these EEG changes induced by phencyclidine and the EEG effects of ketamine and SKF 10047 were obtained.
Asunto(s)
Conducta Animal/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Electroencefalografía , Fenciclidina/farmacología , Animales , Nivel de Alerta/efectos de los fármacos , Femenino , Ketamina/farmacología , Actividad Motora/efectos de los fármacos , Fenazocina/análogos & derivados , Fenazocina/farmacología , Ratas , Ratas Endogámicas , Conducta Estereotipada/efectos de los fármacosRESUMEN
Three groups of female Sprague-Dawley rats (n = 4) were conditioned to drink water during a daily 2 hr session. The water was then changed to a solution of 1.0 mg/ml lithium chloride producing average doses between 62.9 and 72.1 mg/kg/day for Groups I and II. These rats were challenged with 4 mg/kg PCP i.p. before and during lithium treatment. Group I was tested for spontaneous locomotor activity in the open field apparatus. Lithium alone did not affect activity. After 1, 2, and 3 weeks of chronic lithium, PCP-induced activity increased 2.1, 1.7, and 2.8 fold, respectively, relative to PCP-induced activity during limited access to water only. Whole brain homogenates from Group II, after one week of chronic lithium, were used for receptor binding experiments using [3H] PCP; Group III served as water controls. The Kd (nM +/- S.E.M.) was not different in untreated (146.39 +/- 18.95) and lithium-treated (181.22 +/- 14.35) rats. The Bmax (pmole/mg protein +/- S.E.M.), however, was increased 48% (p less than 0.01) from 1.50 +/- 0.08 to 2.22 +/- 0.10 after lithium. These preliminary results suggest that chronic administration of lithium modifies the behavioral effects of PCP possibly via alterations at the receptor level.
Asunto(s)
Conducta Animal/efectos de los fármacos , Litio/farmacología , Fenciclidina/farmacología , Receptores de Neurotransmisores/metabolismo , Animales , Interacciones Farmacológicas , Femenino , Cinética , Litio/sangre , Actividad Motora/efectos de los fármacos , Fenciclidina/metabolismo , Ratas , Ratas Endogámicas , Receptores de Neurotransmisores/efectos de los fármacos , Receptores de FenciclidinaRESUMEN
The pro- and anticonvulsant effects of phencyclidine (1-[1-phenylcyclohexyl]piperidine HCl, PCP), a number of its analogues, and SKF 10047 were investigated in rats. The PCP analogues were compounds produced by substitutions for the phenyl and piperidine rings of PCP and were selected to elucidate the structure-activity relationships existing between PCP and its pro- and/or anticonvulsant effects. All of the compounds, except ketamine, induced convulsions at high (12.8-25.6 mg/kg, i.v.), yet almost always sublethal doses. Ketamine failed to induce convulsions, even at lethal doses (51.2 mg/kg, i.v.). The acute pro- or anticonvulsant actions of PCP were then investigated. Rats were subjected to transorbital electroconvulsive shock subsequent to i.p. injections of saline or 0.625, 2.5, 5.0, 10.0 or 20.0 mg/kg PCP. It was found that PCP induced an acute, dose-dependent anticonvulsant effect. The acute pro- and/or anticonvulsant actions of the remaining compounds were then investigated by administration of electroconvulsive shock subsequent to i.p. injections of saline or one of two doses of each compound. The low and high doses of each compound were selected to be behaviorally equivalent to 2.5 and 10.0 mg/kg PCP i.p., respectively. With one exception, each dose of each drug induced an acute anticonvulsant action, with no difference in efficacy between the compounds tested. However, PCA (produced by substitution of an amine for the piperidine ring of PCP) induced a statistically greater anticonvulsant action at the higher, compared to the lower, dose. In addition, PCA was the only compound to eliminate all motor signs of the electrically induced seizure.(ABSTRACT TRUNCATED AT 250 WORDS)