Tolerance to phencyclidine in pigeons: cross-tolerance to ketamine

In order to determine whether tolerance developed to the behavioral effects of phencyclidine, pigeons were trained to respond under a multiple fixed-ratio 30, fixed-interval 600-sec schedule of food presentation. When rates and patterns of responding reached stability, dose-response curves for phencyclidine (0.1-10 mumol/kg i.m.), ketamine (3-56 mumol/kg i.m.) and pentobarbital (1-75 mumol/kg i.m.) were determined. Phencyclidine, ketamine and pentobarbital all decreased fixed-ratio 30 responding in a dose-related manner and increased fixed-internal 600-sec. responding at immediate doses. At higher doses, pentobarbital decreased responding. High doses of phencyclidine and ketamine suppressed responding in the early portions of the session, but when responding returned, it returned at a high rate. After 35 daily injections of phencyclidine (3 mumol/kg/day i.m.), dose-response curves were redetermined for all three drugs. A tolerance was observed for moderate doses of phencyclidine, and a moderate cross-tolerance was observed to ketamine. No tolerance was observed for the total suppression of responding produced by high doses of phencyclidine and ketamine early in the test sessions. No cross-tolerance to pentobarbital was observed. After 215 days of daily phencyclidine administration, no withdrawal signs were observed upon the discontinuation of daily injections.     

The effect of phencyclidine and ketamine on schedule-controlled behavior in the pigeon.

Pigeons were trained under a multiple schedule of food presentation with alternating 30-response fixed-ratio (FR-30) and 10-minute fixed-interval (FI-10) components. Average rates of responding were 2.9 and 0.55 responses/sec, respectively. Both phencyclidine (0.03-3.0 mg/kg i.m.) and ketamine (0.1-30.0 mg/kg i.m.) increased response rates at low doses while decreasing response rates at high doses during the FI-10 component. Only a dose-related decrease in response rates was seen in the FR-30 component with both phencyclidine and ketamine. In individual birds, the maximum rate increases in the FI-10 component ranged from 110% to 163% of the control rate. The rate increases in the FI-10 component depended on the control rate of responding. The effects of phencyclidine and ketamine were qualitatively similar to d-amphetamine (0.1-10 mg/kg i.m.).     

The effects of phencyclidine, ketamine, delta-amphetamine and pentobarbital on schedule-controlled behavior in the mouse.

The response of mice of breaking a light beam onto a photocell was programmed to produce food according to a multiple schedule with alternating 30-response fixed ratio, 300-second fixed interval (FR-30 FI-300 sec) components. Training was standardized for all mice, and stable patterns of responding that were similar to those described for other species and responses under this schedule developed quickly. The effects of pentobaribtal, delta-amphetamine, phencyclidine and ketamine were studied. At some dose, each of the four drugs produced an increase in rate of responding; the increase was proportionately greater at low rates of responding than at higher rates. At some dose range, delta-amphetamine, ketamine and phencyclidine produced dose-related increases in FI average rates were to 1.83, 1.25 and 1.32 times the control rate for delta-amphetamine (1 mg/kg), ketamine (100 mg/kg) and phencyclidine (3 mg/kg), respectively. Phencyclidine and ketamine thus showed some "amphetamine-like" effects in the mouse. Pentobarbital increased (1.25 times the control rate) both the FR and FI response rates at a dose of 3 mg/kg. Higher doses of pentobarbital progressively decreased both FR and FI response rates in a parallel fashion.     

Presynaptic dopaminergic activity of phencyclidine in rat caudate

This study tested the hypothesis that phencyclidine (PCP) is an indirect dopamine (DA) agonist in the caudate nucleus. Single caudate neurons in rats anesthetized with urethane were recorded extracellularly with multibarrel micropipettes. Effects of drug solutions, applied by pressure microejection, were measured as changes in spontaneous and evoked neuronal activity. Caudate neurons were classified according to their latency-to-discharge in response to supramaximal cortical stimulation. PCP inhibited the spontaneous activity of 92% of neurons with latencies less than 13 msec, while DA inhibited 87%. Both drugs inhibited evoked activity significantly less than spontaneous activity (P less than .01). Neurons with latencies greater than 13 msec were excited by DA significantly more often (45%) than by PCP (13%; P less than .05). Receptor stereospecificity is suggested by the finding that the (+)-isomer of the 3-methyl piperidine derivative of PCP was significantly more potent than the (-)-isomer for inhibition of spontaneous activity. Mg++, which blocks presynaptic release of neurotransmitter, significantly antagonized inhibitory effects of PCP on spontaneous activity, which suggests a presynaptic effect of PCP. DA, which acts postsynaptically, was much less affected by Mg++. The potency of PCP was significantly less in rats treated with reserpine or 6-hydroxydopamine than in control rats, suggesting the endogenous DA is required for the action of PCP. Fluphenazine and (+)-butaclamol, potent DA-receptor antagonists, blocked the effect of PCP, but (-)-butaclamol did not. These results support the hypothesis that PCP facilitates release and/or inhibits reuptake of DA in nerve terminals and thereby acts as an indirect DA agonist in the caudate. However, there may be a subpopulation of caudate neurons in which PCP acts by a nondopaminergic mechanism.     

A quantitative assessment of phencyclidine dependence produced by oral self-administration in rhesus monkeys

Three rhesus monkeys were trained to self-administer orally delivered phencyclidine (PCP) and water under concurrent fixed-ratio schedules. Liquid deliveries were contingent upon lip-contact responses on solenoid-operated drinking spouts. PCP deliveries exceeded water deliveries throughout the experiment, indicating that the drug was functioning as a positive reinforcer. The monkeys were also trained to lever press under a fixed-ratio 64 or fixed-ratio 80 schedule of food delivery. Food was available during three 1 hr periods each day, with 6.5 hr of liquid availability between each food component. After behavior stabilized for at least 10 days under these conditions, water was substituted for PCP for 2, 4, 8 or 24 days. Food-maintained responding was severely disrupted for the first 2 days of water substitution, with a steady recovery over the following 6 days. The monkeys were noticeably irritable during water substitution, but there were no other physical signs of PCP withdrawal. Disruptions in food-maintained responding were immediately reversed when PCP was reinstated. Subsequently, the PCP concentration was varied (0.062, 0.125, 0.25, 0.5 and 1 mg/ml), and PCP intake (milligrams per kilogram), as well as the magnitude of disruptions in pellet deliveries (upon termination of PCP access), also varied directly with PCP intake. The amount of PCP intake was also altered by limiting PCP (0.25 mg/ml) access to every 2nd or 4th day, with water available on intervening days. Pellet deliveries were substantially disrupted during water substitution, and food-maintained responding immediately returned to control levels when PCP became available.(ABSTRACT TRUNCATED AT 250 WORDS)     

Continuous intravenous infusion of phencyclidine in unrestrained rats results in the rapid induction of tolerance and physical dependence

The continuous infusion of 45 mg/kg/24 hr of phencyclidine (PCP) into the jugular vein of unrestrained rats induced tolerance to PCP-induced impairment of forced motor activity and physical dependence in 3.5 and 7 days, respectively. In drug-naive rats, an i.v. 2-mg/kg PCP test dose abolished rotarod performance for more than 20 min which returned to pretreatment values at 40 min. Eight hours after the termination of 3.5 days of infusion, rotarod performance of PCP-infused rats was significantly less impaired by the PCP test dose at 20 min than that of saline-infused controls. After infusion of PCP for 7 days, the duration of performance abolition produced by the PCP test dose (given 8 hr after the termination of infusion) was shortened further with performance significantly better than that of saline-infused controls at both 10 and 20 min. The results showed a greater than 2-fold tolerance development to this PCP effect and suggest the observed tolerance to be mainly functional in nature. Abrupt withdrawal of PCP after infusion for 7 days resulted in an abstinence syndrome with the following signs: piloerection, increased susceptibility to audiogenic seizures, transient weight loss and reductions in exploratory activity and rotarod performance. The first withdrawal signs were noted 4 hr after the termination of infusion. At 24 hr of abstinence, most of the withdrawal signs had subsided. The reduced rotarod performance, associated with withdrawal, could be reversed by a single i.v. dose of 2 mg/kg of PCP. The reversibility of this sign supports the interpretation of impaired rotarod performance after withdrawal as being an abstinence sign and adds to the experimental evidence that physical dependence on PCP is inducible within 7 days in rats.     

Presynaptic activation of the spinal serotonergic system in the rat by phencyclidine in vitro

Electrophysiological studies were carried out to investigate the mechanism of action of phencyclidine [PCP; 1-(phenylcyclohexyl)piperidine] on a segmental monosynaptic reflex using isolated spinal cord preparations from neonatal rats. PCP and its related compounds produced a concentration-dependent depression of the monosynaptic reflex with a relative potency as follows: PCP = 1-[1-(2-thienyl)cyclohexyl]piperidine greater than 1-(1-m-aminophenylcyclohexyl)piperidine much greater than 1-(1-m-nitrophenylcyclo-hexyl)piperidine approximately MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] much greater than (+)-N-allylnormetazocine. The N-methyl-D-aspartate receptor antagonists 2-amino-5-phosphonovalerate and 2-amino-7-phosphonoheptanoate had no effect on the monosynaptic reflex. The depression of the monosynaptic reflex by PCP was antagonized by serotonin (5-HT) receptor antagonists (methiothepin, spiperone and ketanserin) but unaffected by noradrenergic (phentolamine and timolol), dopaminergic (chlorpromazine and pimozide) and cholinergic antagonists (atropine and mecamylamine). Whereas 5-HT and a putative 5-HT releaser, p-chloroamphetamine, also depressed the monosynaptic reflex, the blockade of monoamine uptake by imipramine did not. Furthermore, pretreatment of rats with desipramine and 5,7-dihydroxytryptamine largely diminished the depression of the monosynaptic reflex by PCP and p-chloroamphetamine while enhancing the depressant action of 5-HT. These results suggest that PCP acts at sites located on presynaptic terminals of spinal serotonergic neurons, enhancing 5-HT release and thereby depressing the monosynaptic reflex.     

Biodisposition of ketamine in the rat: self-induction of metabolism.

Four pharmacologic actions of intravenous ketamine (30mg/kg) were studied in the rat. To elucidate the mechanism(s) terminating the pharmacologic effects, animals were pretreated with ketamine and agents anticipated to modify hepatic microsomal metabolism, including phenobarbital and SKF 525A. SKF 525A pretreatment markedly prolonged ataxia, analgesia and agitation, in addition to significantly elevating brain and plasms ketamine levels subsequent to the initial 10 minutes following injection; thus hepatic metabolism appeared to play a prominent role in the termination of the posthypnotic effects of the drug. While significantly shortening the durations of the three posthypnotic events, phenobarbital and ketamine pretreatments also lowered the brain and plasma levels of ketamine. With all pretreatments, brain ketamine levels were almost identical at the cessation of hypnosis (25 mug/g of tissue) and ataxia (8-10mug/g of tissue). No pretreatment altered either the duration of loss of righting reflex (hypnosis) or brain and plasma ketamine levels during the initial 10 minutes after injection. Approximately 70% of the injected drug was recovered from four tissues, skeletal muscle, gut, skin and liver, at 10 minutes after injection; thus redistribution from brain to other tissues appeared to play a major role in the cessation of hypnosis. Ketamine pretreatment caused a 2-fold increase in the rate of its in vitro hepatic microsomal metabolism. Brain and plasma ketamine levels 30 minutes after injection were nearly identical in rats pretreated with ketamine and phenobarbital, although phenobarbital pretreatment resulted in a 4-fold increase in in vitro ketamine hepatic metabolism.     

In vivo electrochemical demonstration of the presynaptic actions of phencyclidine in rat caudate nucleus

In vivo electrochemical recordings, coupled with local application of drugs from micropipettes, were used to determine the presynaptic effects of phencyclidine (PCP) on dopamine-containing nerve terminals in the intact rat striatum. Local application of PCP did not elicit an observable increase in extracellular levels of the monoamine neurotransmitters. However, pretreatment with PCP significantly potentiated the potassium-evoked release of monoamines. Nomifensine, a potent catecholamine reuptake blocker, produced effects that were analogous with PCP. Local pretreatment with PCP was also found to potentiate the electrochemical signal detected after pressure ejection of dopamine directly into the caudate nucleus. Finally, electrophysiological studies showed that locally applied PCP and nomifensine solutions had similar potencies in depressing the spontaneous firing of striatal neurons. Taken together, these data suggest that the major presynaptic action of PCP in the rat caudate nucleus is inhibition of the reuptake, and not alteration of release, of the monoamine neurotransmitters.     

Interactions of sigma and phencyclidine receptor ligands with the norepinephrine uptake carrier in both rat brain and rat tail artery.

The interaction of several sigma and PCP receptor ligands with the norepinephrine uptake carrier was investigated in the rat tail artery and brain. These ligands include haloperidol; (+)- and (-) 3-(3-hydroxy- phenyl)-N-(1-propyl)piperidine (3-PPP), (+/-)-BMY 14802, [(+/-) alpha-(4-fluoro- phenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol]; (+)-SKF 10047, [(+/-)-N-allyl-N-normetazocine]; 1,3-di-ortho-tolyl-guanidine; rimcazole (BW 234U), [cis-9-[3-(3,5-dimethyl-1-piperazinyl)propyl] carbazole dihydrochloride]; and MK 801, [(+)-5-methyl-10,1 1-dihydro-5H-dibenzo[a, d]cyclohepten-5, 10-imine maleate]. Our results show that all ligands used, except 1,3-di-ortho-tolyl-guanidine, inhibit both neuronal [3H]norepinephrine accumulation in the rat tail artery and specific [3H] desmethylimipramine binding in the rat brain. Except for (+)-SKF 10047, the order of potency of the ligands used for inhibiting neuronal [3H]norepinephrine accumulation in the rat tail artery was similar to that measured for inhibition of specific [3H]desmethylimipramine binding in the rat brain. Despite these similarities, our results also suggest that haloperidol, (+)- and (-)3-PPP, MK 801, rimcazole and cocaine interact with the [3H]norepinephrine site in the rat tail artery and with the [3H]desmethylimipramine binding site in the rat brain in a complex fashion. These studies demonstrate an important action on the norepinephrine carrier by these sigma and PCP ligands in the rat tail artery and brain.     

Using the BOLD MR signal to differentiate the stereoisomers of ketamine in the rat

RATIONALE: Ketamine is a chiral molecule that is reported to model aspects of schizophrenia. OBJECTIVES: To investigate the stereospecificity of the isomers of ketamine using pharmacological magnetic resonance imaging (phMRI) in order to further understand ketamine's pharmacodynamic actions. METHOD: Responses to 25 mg kg-1S(+) isomer, R(-) isomer and racemic ketamine in independent groups of Sprague-Dawley rats were investigated using a prepulse inhibition paradigm, locomotor observations, MRI and 2-deoxyglucose techniques. RESULTS: Racemic ketamine and the S(+) isomer were both capable of disrupting sensorimotor gating as measured using prepulse inhibition and produced a longer period of hyperlocomotion comparative to the R(-) isomer. In contrast, large alterations in the BOLD MR signal were observed with R(-) isomer, whereas S(+) isomer and racemate precipitated more localized BOLD signal changes predominantly in cortical, hippocampal and hindbrain regions. Glucose utilization rates in conscious animals are in agreement with previously published data and verify the BOLD responses in the racemic group. However, no significant changes in glucose utilization were observed in the anesthetized cohort. CONCLUSIONS: Ketamine and its isomers have stereospecific effects on sensorimotor gating and locomotion that correlate with the enantiomer's affinity for the NMDA receptor. It would appear that anesthesia, as required for preclinical MRI procedures, may interact with and potentially attenuate the drug's response. Although analysis of the main effect of isomers in comparison to each other or the racemate offers an alternative analysis method that should be less susceptible to anesthetic interactions, only the R(-) isomer comparative to the racemate offers significant differences of interest.     

Electrophysiological evidence for presynaptic actions of phencyclidine on noradrenergic transmission in rat cerebellum

The actions of the psychotomimetic drug phencyclidine (PCP) were studied using Purkinje neurons in the cerebellum of urethane-anesthetized rats. PCP, applied by micropressure ejection through multibarreled micropipettes, depressed the spontaneous activity of these neurons as recorded by extracellular electrophysiological techniques. This depressant effect was blocked by neuroleptic drugs and lithium, both of which also block the depressant effects of norepinephrine, but not those of gamma-aminobutyric acid. PCP-elicited depressions could not be obtained in rats in which the cerebellar noradrenergic terminals had been lesioned selectively by pretreatment with the neurotoxin 6-hydroxydopamine. However, PCP was still an effective depressant in animals after destruction of non-noradrenergic intrinsic excitatory and inhibitory interneurons which synapse on the Purkinje cell by neonatal X-irradiation. Further treatment of the X-irradiated animal with 6-hydroxy-dopamine resulted in Purkinje neurons which were not responsive to PCP. Administration of magnesium ions, which reduces the release of neurotransmitters from afferent terminals, also blocked the depressant effects of PCP. The results of this study suggest that PCP acts in the cerebellum by a presynaptic mechanism involving the release of norepinephrine from intact, functioning noradrenergic terminals.     

Pharmacologic characterization of acute chlordiazepoxide dependence in the rat

A single intoxicating dose of chlordiazepoxide HCl (p.o.) in the rat can induce quantifiable manifestations of physical dependence. Dependence was revealed by antagonist precipitation (Ro 15-1788, CGS-8216) as well as spontaneous emergence of neurobehavioral signs of withdrawal observed by multiple raters blind to treatments. Ro 15-1788 was 45% more effective than CGS-8216 in both reversing chlordiazepoxide intoxication and expressing withdrawal signs. The severity of Ro 15-1788-precipitated withdrawal varied with chlordiazepoxide dose, Ro 15-1788 dose and the agonist-antagonist dose interval. Maximal precipitated dependence was evoked 3 days after chlordiazepoxide HCl (450 mg/kg) by Ro 15-1788 (25 mg/kg i.p.). The precipitated syndrome consisted of tail erection, reduced motor activity, high step, curled claw, arched back, muscle hypertonus and piloerection. Ro 15-1788-precipitated dependence emerged between 28 and 52 hr, peaked at 76 hr and disappeared by 124 hr. Spontaneous withdrawal had emerged from 100 to 124 hr and then faded gradually. The neurobehavioral expression of central nervous system depression and its reversal were necessary but not sufficient conditions for the induction and expression of acute chlordiazepoxide dependence. These results suggest caution in reviving acute benzodiazepine-overdosed patients to avoid iatrogenic withdrawal analogous to naloxone for opiates.     

Behavioral and pharmacological description of oxaliplatin-induced painful neuropathy in rat

Using a gene expression analysis approach we found that the mRNA encoding the lysosomal cysteine protease cathepsin S (CatS) was up-regulated in rat dorsal root ganglia (DRG) following peripheral nerve injury. CatS protein was expressed in infiltrating macrophages in DRG and near the site of injury. At both sites CatS expression progressively increased from day 3 to day 14 after injury. In naïve rats, intraplantar injection of activated rat recombinant (rr) CatS (0.3, 1 μg/rat) induced a mechanical hyperalgesia that developed within half-an-hour, diminished by 3 h and was absent after 24 h. Activated rrCathepsin B (CatB) and non-activated rrCatS injected intraplantarly at the same or higher doses than activated rrCatS had no effect on rat nociceptive thresholds. In nerve-injured rats, mechanical hyperalgesia, but not allodynia, was significantly reversed for up to 3 h by systemic administration of a non-brain penetrant, irreversible CatS inhibitor (LHVS, 3–30 mg/kg s.c.). Depletion of peripheral macrophages by intravenous injection of liposome encapsulate clodronate (1 ml, 5 mg/ml) partially reduced established mechanical hyperalgesia but not allodynia, and abolished the anti-hyperalgesic effect of LHVS. Our results demonstrate a pro-nociceptive effect of CatS and indicate that endogenous CatS released by peripheral macrophages contributes to the maintenance of neuropathic hyperalgesia following nerve injury.     

Behavioral and pharmacological description of oxaliplatin-induced painful neuropathy in rat

We describe an animal model of nociceptive sensory neuropathy induced by repeat intravenous administration of oxaliplatin in which treated animals partly reproduce the characteristic pain symptoms in oxaliplatin-treated patients. We tested the ability of 1, 2 and 4 mg/kg oxaliplatin doses injected twice-weekly for four-and-a-half consecutive weeks to induce a nociceptive peripheral neuropathy in male Sprague–Dawley rats. The behavioral assessment revealed cold allodynia (10 °C) and hyperalgesia (4 °C) symptoms associated with a mechanical allodynia. The rats maintained a good general clinical status without motor dysfunction. The 2 mg/kg oxaliplatin dose and the tail-immersion test in cold water (10 °C) were selected to compare pharmacological sensitivity between single administered drugs as morphine, lidocaine, carbamazepine, gabapentin and repeated administration of drugs as clomipramine, venlafaxine, calcium and magnesium solutions. Magnesium solution (90 mg/kg) and venlafaxine (7.5 mg/kg) administration induced an antinociceptive effect whereas gabapentin (300 mg/kg), clomipramine (2.5 mg/kg) and lidocaine (3 and 6 mg/kg) only induced an antiallodynic effect.     

Metaphit, an acylating ligand for phencyclidine receptors: characterization of in vivo actions in the rat

Metaphit, which acylates phencyclidine (PCP) receptors in vitro, was shown to acylate PCP receptors and antagonize the behavioral and electrophysiological effects of PCP in vivo. Metaphit (2 mumol/rat) administered i.c.v. produced PCP-like stereotyped behavior and ataxia in 10 to 20% of rats. At a lower dose, Metaphit (1 mumol/rat) antagonized the ability of PCP to induce stereotyped behavior and ataxia for 3 and 4 days, respectively. The Metaphit-induced antagonism of PCP induction of stereotyped behavior and ataxia was dose-dependent and specific as Metaphit did not antagonize induction of stereotyped behavior by amphetamine. Further evidence for a specific PCP receptor mechanism was the finding that PCP pretreatment blocked the effects of subsequent Metaphit administration. Metaphit also antagonized PCP-induction of stereotyped behavior, but not ataxia, after i.v. administration. Doses of Metaphit that produced long-term antagonism of the behavioral effects of PCP also produced a significant decrease in the maximum binding, but not Kd, of the binding of the PCP analog, [3H]-1-(2-thienyl)cyclohexyl]piperidine, in Metaphit-pretreated rats. The binding of [3H]etorphine and [3H]spiroperidol was not altered significantly by pretreating rats with Metaphit. (-)-Cyclazocine and (+)-SKF 10,047 induced stereotyped behavior and ataxia that was not antagonized by Metaphit-pretreatment. In electrophysiological experiments, Metaphit, like PCP, initially depressed the firing of caudate neurons as does PCP, but then irreversibly inhibited PCP-induced depression of caudate neurons. These results suggest that metaphit antagonized the effects of PCP by selectively acylating PCP receptors and that (-)-cyclazocine- and (+)-SKF 10,047-induced behavioral effects are not mediated primarily by PCP receptors.     

The dependence of finger tip touch-pressure upon the condition of Braille reading

The finger motions and quickness of braille reading were investigated by way of recording the finger tip pressure on the braille and its time process. Subjects were separated into two groups. One group consisted of 5 experienced blinds and the other group consisted of 5 blinds who were beginners in braille reading. The comparison of obtained results from two groups gave some evidence for the following conclusion. The finger tip pressure was considerably increased for careful or difficult reading.     

氯胺酮诱导不同年龄大鼠脑海马区热休克蛋白70表达的量效依赖性

背景：研究证实，热休克蛋白70家族的蛋白质对细胞有保护作用。氯胺酮可导致患者出现幻觉、谵妄等精神症状，可对大鼠边缘系统神经元产生损害，在这些受损的神经元内用免疫组化染色方法可检测到热休克蛋白70的表达：目的：观察不同剂量的氯胺酮在不同年龄大鼠海马中诱导热休克蛋白70的表达，探讨氯胺酮对神经损害的作用．设计：随机对照实验。单位：四川大学华西医院麻醉学与危重医学教研室。材料：实验于2000—01／05在四川大学华西陕院麻醉学与危重医学教研室实验室完成。选择SD大鼠70只，雌雄不限，清洁级。方法：35只成年SD大鼠随机分为对照组和氯胺酮20．0，40．0，60．0，80．0，100．0，120．0mg／kg6个实验组，每组5只，分别给予生理盐水和氯胺酮20．0，40．0，60．0，80．0，100．0，120．0mg/kg腹腔内注射。另取0～10，11～20，21～30，31～45，46～60，61-90，91～120d年龄阶段大鼠35只，每个年龄段5只，分别腹腔内注射氯胺酮80．0mg/kg。给药后正常喂养24h后，在麻醉状态下快速断头取脑，于海马取5μm冠状切面切片，应用免疫组化染色检测大鼠海马中热休克蛋白70的表达。主要观察指标：大鼠海马热休克蛋白70阳性细胞百分率，密度和灰度值。结果：70只大鼠均进入结果分析。①不同剂量氯胺酮对大鼠脑海马区热休克蛋白70表达：对照组，20．0，40．0，60．0，80．0，100．0，120．0mg／kg剂量氯胺酮组诱导热休克蛋白70表达的阳性细胞密度分别为0，8．12&;#177;1．82，27．07&;#177;5．98，45．35&;#177;5．84，78．51&;#177;7．34，74．16&;#177;8．17，60．84&;#177;6．27。可见氯胺酮剂量在80．0mg／kg以内，随剂量的增加，热休克蛋白70阳性细胞密度显著增加（P〈0.01）；氯胺酮剂量在80．0mg／kg以上，随剂量的增加，热休克蛋白70阳性细胞密度显著降低（P〈0．01）。②氯胺酮对不同年龄段大鼠脑海马区热休克蛋白70表达：20d以下的幼鼠神经细胞热休克蛋白70阳性细胞密度为0；在21-30d，31-45d，46～60d，61～90d大鼠海马中热休克蛋白70阳性细胞密度分别为34．17&;#177;6．18，55.42&;#177;4．80，78．51&;#177;7．34，83．16&;#177;11．10，与前一年龄组相比，随着年龄的增加，热休克蛋白70阳性细胞密度显著增加（P〈0．01）；61～90d和91～120d大鼠海马中热休克蛋白70阳性细胞密度分别为83．16&;#177;11．10和85．83&;#177;9．33（P〉0．05）。结论：氯胺酮可诱导热休克蛋白70在大鼠脑海马区表达，提示海马区的神经元可能受到损害；随剂量的增加，其损害作用加强；氯胺酮对成年大鼠的脑损害作用大于幼鼠。     

氯胺酮诱导不同年龄大鼠脑海马区热休克蛋白70表达的量效依赖性

背景研究证实,热休克蛋白70家族的蛋白质对细胞有保护作用.氯胺酮可导致患者出现幻觉、谵妄等精神症状,可对大鼠边缘系统神经元产生损害,在这些受损的神经元内用免疫组化染色方法可检测到热休克蛋白70的表达.目的观察不同剂量的氯胺酮在不同年龄大鼠海马中诱导热休克蛋白70的表达,探讨氯胺酮对神经损害的作用.设计随机对照实验.单位四川大学华西医院麻醉学与危重医学教研室.材料实验于2000-01/05在四川大学华西医院麻醉学与危重医学教研室实验室完成.选择SD大鼠70只,雌雄不限,清洁级.方法35只成年SD大鼠随机分为对照组和氯胺酮20.0,40.0,60.0,80.0,100.0,120.0 mg/kg 6个实验组,每组5只,分别给予生理盐水和氯胺酮20.0,40.0,60.0,80.0,100.0,120.0 mg/kg腹腔内注射.另取0～10,11～20,21～30,31～45,46～60,61～90,91～120 d年龄阶段大鼠35只,每个年龄段5只,分别腹腔内注射氯胺酮80.0 mg/kg.给药后正常喂养24 h后,在麻醉状态下快速断头取脑,于海马取5 μm冠状切面切片,应用免疫组化染色检测大鼠海马中热休克蛋白70的表达.主要观察指标大鼠海马热休克蛋白70阳性细胞百分率、密度和灰度值.结果70只大鼠均进入结果分析.①不同剂量氯胺酮对大鼠脑海马区热休克蛋白70表达对照组,20.0,40.0,60.0,80.0,100.0,120.0mg/kg剂量氯胺酮组诱导热休克蛋白70表达的阳性细胞密度分别为0,8.12±1.82,27.07±5.98,45.35±5.84,78.51±7.34,74.16±8.17,60.84±6.27.可见氯胺酮剂量在80.0 mg/kg以内,随剂量的增加,热休克蛋白70阳性细胞密度显著增加(P＜0.01);氯胺酮剂量在80.0mg/kg以上,随剂量的增加,热休克蛋白70阳性细胞密度显著降低(P＜0.01).②氯胺酮对不同年龄段大鼠脑海马区热休克蛋白70表达20 d以下的幼鼠神经细胞热休克蛋白70阳性细胞密度为0;在21～30 d,31～45 d,46～60 d,61～90 d大鼠海马中热休克蛋白70阳性细胞密度分别为34.17±6.18,55.42±4.80,78.51±7.34,83.16±11.10,与前一年龄组相比,随着年龄的增加,热休克蛋白70阳性细胞密度显著增加(P＜0.01);61～90 d和91～120 d大鼠海马中热休克蛋白70阳性细胞密度分别为83.16±11.10和85.83±9.33(P＞0.05).结论氯胺酮可诱导热休克蛋白70在大鼠脑海马区表达,提示海马区的神经元可能受到损害;随剂量的增加,其损害作用加强;氯胺酮对成年大鼠的脑损害作用大于幼鼠.