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PubMed2004

Voluntary alcohol intake in two rat lines selectively bred for learned helpless and non-helpless behavior.

RATIONALE: A high comorbidity between depression and alcoholism has been reported in several studies, but the mechanisms underlying this relationship remain unknown. OBJECTIVES: We tested whether learned helplessness in rats as a model for depression is associated with enhanced alcohol intake and relapse behavior. METHODS: Congenital learned helplessness (cLH) and congenital non-learned helplessness (cNLH) rats were selectively bred for differences in an escape paradigm. Sucrose preference was tested at the first hour of the dark phase. In order to study an association with alcohol drinking behavior, rats underwent a free-choice procedure with access to water, and 5% and 20% alcohol solutions for 6 weeks. After acquisition of alcohol drinking behavior, the alcohol deprivation effect (ADE) was assessed. Sensitivity to the sedative-hypnotic effect of alcohol was measured by loss of the righting reflex. RESULTS: cLH rats showed significantly lower preference for sucrose solutions during the second half hour of the dark phase than cNLH rats. Alcohol intake of male cLH rats was not significantly different from that of male cNLH rats. In contrast, cLH female rats consumed higher amounts of alcohol than female cNLH rats. The ADE was more pronounced in female animals, although the magnitude of the ADE was similar in both cNLH and cLH female rats. The time to regain the righting reflex was significantly higher in both male and female cLH rats than in cNLH rats. CONCLUSIONS: In summary, these data suggest that an inborn depressive-like behavior in female rats is associated with enhanced alcohol intake.

Alcohol Drinking↗

PubMedDate not supplied

Effect of allopurinol on ischemia and reperfusion-induced cerebral injury in spontaneously hypertensive rats.

In spontaneously hypertensive rats, we studied the participation of xanthine oxidase-linked free radical in ischemia and reperfusion-induced cerebral injury, using allopurinol, a xanthine oxidase inhibitor. The loss of righting reflex was noted in some animals after a 4 hour occlusion of bilateral common carotid arteries and 19 of 25 animals died within 72 hours after reperfusion. One hour after reperfusion, the cerebral water content increased significantly, with an increase in sodium content and a decrease in potassium content. In 7 animals treated with oral administrations of allopurinol (200 mg/kg) 24 hours and 1 hour before occlusion, no death was found either during occlusion or after reperfusion, and the loss of righting reflex was noted in only one animal 24-72 hours following reperfusion. The increase in cerebral water content and accompanied changes in electrolyte contents were clearly prevented by allopurinol. These results suggest the possibility that the production of xanthine oxidase-linked free radical participates in cerebral injury due to ischemia and reperfusion in spontaneously hypertensive rats.

Allopurinol↗

PubMed2005

Lead-induced catalase activity differentially modulates behaviors induced by short-chain alcohols.

Acute lead administration produces a transient increase in brain catalase activity. This effect of lead has been used to assess the involvement of brain ethanol metabolism, and therefore centrally formed acetaldehyde, in the behavioral actions of ethanol. In mice, catalase is involved in ethanol and methanol metabolism, but not in the metabolism of other alcohols such as 1-propanol or tert-butanol. In the present study, we assessed the specificity of the effects of lead acetate on catalase-mediated metabolism of alcohols, and the ability of lead to modulate the locomotion and loss of the righting reflex (LRR) induced by 4 different short-chain alcohols. Animals were pretreated i.p. with lead acetate (100 mg/kg) or saline, and 7 days later were injected i.p. with ethanol (2.5 or 4.5 g/kg), methanol (2.5 or 6.0 g/kg), 1-propanol (0.5 or 2.5 g/kg) or tert-butanol (0.5 or 2.0 g/kg) for locomotion and LRR, respectively. Locomotion induced by ethanol was significantly potentiated in lead-treated mice, while methanol-induced locomotion was reduced by lead treatment. The loss of righting reflex induced by ethanol was shorter in lead-treated mice, and lead produced the opposite effect in methanol-treated mice. There was no effect of lead on 1-propanol or tert-butanol-induced behaviors. Lead treatment was effective in inducing catalase activity and protein both in liver and brain. These results support the hypothesis that the effects of lead treatment on ethanol-induced behaviors are related to changes in catalase activity, rather than some nonspecific effect that generalizes to all alcohols.

Alcohols↗

PubMed2005

Differences in ethanol ingestion between cholecystokinin-A receptor deficient and -B receptor deficient mice.

AIMS: Cholecystokinin (CCK) modulates dopamine release in the nucleus accumbens through the CCK-A receptor (CCK-AR). The dopaminergic neurotransmission between the ventral tegmental area and the limbic forebrain is a critical neurobiological component of alcohol and drug self-administration. Based on the evidence of interaction between CCK and dopamine, we had found previously that the CCK-AR gene -81A/G polymorphism was associated with alcohol dependence. Since the precise mechanism underlying this association has not been elucidated, the role of CCK-AR in ethanol ingestion was examined using CCK-AR gene deficient (-/-) mice and compared with those of CCK-BR(-/-) and wild-type mice. METHODS: The two-bottle choice protocol was conducted and the righting reflex was examined in these three genotypes. Furthermore, the protein level of dopamine 2 receptor (D2R) in the nucleus accumbens was determined by western blotting. RESULTS: CCK-AR(-/-) mice consumed more ethanol than CCK-BR(-/-) and wild-type mice, and showed no aversion to high concentrations of ethanol solution. However, the difference was actually in the total fluid consumption and alcohol preference remained unchanged, indicating that the differences were not specific to alcohol. Behavioral sensitivity to ethanol, examined using the righting reflex, did not differ significantly between the groups. D2R expression in the nucleus accumbens was significantly lower in the CCK-BR(-/-) mice and was significantly higher in CCK-AR(-/-) mice than in wild-type mice. CONCLUSIONS: Voluntary ingestion of ethanol differed between CCK-AR(-/-) and CCK-BR(-/-) mice. The difference might be attributable in part to the different levels of D2R expression in the nucleus accumbens.

Alcohol Drinking↗

PubMed1995

Glycine receptor antagonism. Effects of ACEA-1021 on the minimum alveolar concentration for halothane in the rat.

BACKGROUND: Glycine and glutamate binding sites are allosterically coupled at the N-methyl-D-aspartate (NMDA) receptor complex. Previous studies have shown that antagonism of glutamate at the NMDA receptor reduces the minimum alveolar concentration (MAC) for volatile anesthetics. 5-Nitro-6,7-dichloro-2,3-quinoxalinedione (ACEA-1021) is a competitive antagonist at the glycine recognition site of the NMDA receptor. The purpose of this study was to determine whether glycine receptor antagonism also reduces volatile anesthetic requirements in the rat. METHODS: In experiment 1, Sprague-Dawley rats were anesthetized with halothane in 50% O2-balance N2 and their lungs mechanically ventilated. They were randomly assigned to one of three groups according to the dose of ACEA-1021 administered (0, 20, or 40 mg/kg intravenously; n = 6). The bolus dose of ACEA-1021 was followed by a continuous intravenous infusion of vehicle or ACEA-1021 at 14 mg.kg-1.h-1. Halothane MAC was then determined by the tail-clamp method. In experiment 2, awake rats were randomly assigned to groups according to the same dosages of ACEA-1021 as in experiment 1. Arterial CO2 tension and mean arterial pressure were recorded before and 5 and 30 min after the start of the infusion. The infusion was then stopped, and the time to recovery of the righting reflex was recorded. RESULTS: In experiment 1, ACEA-1021 decreased halothane MAC (mean +/- SD) in a dose-dependent manner (control, 0.95 +/- 0.15 vol%; ACEA-1021 20 mg/kg, 0.50 +/- 0.14 vol%; ACEA-1021 40 mg/kg, 0.14 +/- 0.16 vol%; P < 0.01). In experiment 2, arterial CO2 tension was increased by ACEA-1021 (control, 38 +/- 3 mmHg; ACEA-1021 20 mg/kg, 43 +/- 3 mmHg; ACEA-1021 40 mg/kg, 48 +/- 2 mmHg; P < 0.01). Mean arterial pressure was not affected by any dose of ACEA-1021. The righting reflex was abolished in rats receiving ACEA-1021 40 mg/kg only and recovered 30 +/- 7 min after discontinuation of the infusion. CONCLUSIONS: Halothane MAC reduction by glycine receptor antagonism was greater than that previously observed for antagonism of glutamate at the NMDA or AMPA receptor. In rats receiving ACEA-1021 only, minimal hemodynamic depression and moderate hypoventilation were observed. Antagonism of glycine at the NMDA receptor recognition site offers a potential mechanism of action of anesthesia.

Animals↗

PubMed1986

Neonatal monosodium glutamate lesions alter neurosensitivity to ethanol in adult mice.

A number of studies have indicated a relationship between brain peptide activity and sensitivity to the behavioral effects of ethanol. Specifically, it has been suggested that ethanol effects are mediated by changes in the endogenous opioid peptides derived from the proopiomelanocortin (POMC) precursor. Most cell bodies containing brain POMC-derived peptides are found in the arcuate nucleus of the hypothalamus. Neonatal administration of monosodium glutamate (MSG) has been reported to destroy cell bodies of the arcuate nucleus. We treated WSC strain mice on postnatal Day 4 with a single SC injection of 4 mg/g MSG or saline. When adult, MSG and control mice were challenged with an IP injection of ethanol and its effect on body temperature, open field activity, or duration of loss of righting reflex was assessed. Blood ethanol concentration (BEC) was measured and the hypothalamic content of beta-endorphin like immunoreactivity (beta-EP) was determined by radioimmunoassay. beta-EP was markedly reduced in both females and males by MSG treatment. MSG-treated animals of both sexes showed significantly less ethanol-induced hypothermia than controls. BEC was higher in MSG-treated animals of both sexes than in controls, so the differences were not due to ethanol pharmacokinetics. beta-EP was generally lower in males. Duration of righting reflex was prolonged in MSG treated animals, and the reduction in open field activity was potentiated. These latter effects may be in part attributable to the higher BECs achieved in lesioned animals. These data suggest that beta-EP cell bodies in the arcuate nucleus of the hypothalamus mediate neurosensitivity to some effects of ethanol in mice, but further experiments will be necessary to implicate beta-EP specifically.

Aging↗

PubMed1988

The pharmacodynamic and pharmacokinetic interaction of pentobarbital and chlorpromazine in rats.

The effect of chlorpromazine on the duration of loss of righting reflex (LRR, sleeping time) of pentobarbital and vice versa in a various dosage ranges were studied in rats. The logarithm of the dose versus sleeping time profile of pentobarbital was shifted to the left and the slope of the profile was decreased as the dose of chlorpromazine was increased. The logarithm of chlorpromazine dose versus duration of LRR during pentobarbital coadministration also showed a distinct dose-dependent profile. However, chlorpromazine itself showed ambiguous duration of LRR because the terminal point of the pharmacologic effect, i.e., the recovery of the righting reflex (RRR, the awakening time), was often difficult to determine clearly. The isobolographic method was introduced to describe the drug interaction of pentobarbital and chlorpromazine quantitatively. Assuming that the sites of action of chlorpromazine and pentobarbital were in the brain, the brain concentrations of pentobarbital at RRR were plotted against the brain concentration of chlorpromazine at RRR. The plots showed a hyperbola-like curve, indicating that there was a supra-additive interaction. In order to clarify the relationship between brain concentrations of the two drugs at RRR, a theoretical consideration was made under the following assumptions: (1) chlorpromazine and pentobarbital have a common central depressant effect, (2) the concentration-effect relationship is described by Hill's equation and (3) the mode of interaction of these drugs is simple additive. The results indicated that the isobolographic plot of pentobarbital and chlorpromazine was reasonably described by the theory and that chlorpromazine enhanced the effect of pentobarbital at least in an additive manner.

Animals↗

PubMed1984

Effects of acute low-level microwaves on pentobarbital-induced hypothermia depend on exposure orientation.

Two series of experiments were performed to study the effects of acute exposure (45 min) to 2,450-MHz circularly polarized, pulsed microwaves [1 mW/cm2, 2-mus pulses, 500 pps, specific absorption rate (SAR) 0.6 W/kg] on the actions of pentobarbital in the rat. In the first experiment, rats were irradiated with microwaves and then immediately injected with pentobarbital. Microwave exposure did not significantly affect the extent of the pentobarbital-induced fall in colonic temperature. However, the rate of recovery from the hypothermia was significantly slower in the microwave-irradiated rats and they also took a significantly longer time to regain their righting reflex. In a second experiment, rats were first anesthetized with pentobarbital and then exposed to microwaves with their heads either pointing toward the source of microwaves (anterior exposure) or pointing away (posterior exposure). Microwave radiation significantly retarded the pentobarbital-induced fall in colonic temperature regardless of the orientation of exposure. However, the recovery from hypothermia was significantly faster in posterior-exposed animals compared to those of the anterior-exposed and sham-irradiated animals. Furthermore, the posterior-exposed rats took a significantly shorter time to regain their righting reflex than both the anterior-exposed and sham-irradiated animals.

Animals↗

PubMed2000

Different sensitivity to ethanol in alcohol-preferring sP and -nonpreferring sNP rats.

BACKGROUND AND OBJECTIVES: Clinical research has proposed that initial sensitivity to ethanol may be negatively correlated with levels of subsequent ethanol intake; consistently, alcohol-preferring P rats were found to be less sensitive to the ataxic and sedative/hypnotic effects of ethanol than -nonpreferring NP rats. The present study investigated the initial sensitivity to the ataxic and sedative/hypnotic effects of ethanol and to the sedative/hypnotic effects of pentobarbital and diazepam in selectively bred Sardinian alcohol-preferring sP and -nonpreferring sNP rats. METHODS: In experiment 1, time to lose (onset) and regain (sleep time) the righting reflex after the acute intraperitoneal (ip) administration of 3.0 and 3.5 g/kg ethanol were measured in sP and sNP rats. In experiment 2, sP and sNP rats were required to perform a motor coordination task on a Rota-Rod after the acute intragastric administration of 2.0, 2.5, and 3.0 g/kg ethanol. Experiment 3 assessed onset and sleep time in sP and sNP rats after the acute injection of pentobarbital (40 mg/kg; ip) and diazepam (15 and 20 mg/kg; ip). RESULTS: In experiment 1, sP rats took shorter times to lose the righting reflex and regained this reflex over longer periods of time and at lower blood ethanol levels than sNP rats. In experiment 2, ethanol affected motor coordination to a greater extent in sP than sNP rats. In contrast, results from experiment 3 showed that sP and sNP rats were not differentially sensitive to the sedative/hypnotic effects of pentobarbital and diazepam. CONCLUSIONS: The results of experiments 1 and 2 suggest that sP rats possess a genetically determined, greater sensitivity to the motor impairing and sedative/hypnotic effects of ethanol than sNP rats. Although caution should be adopted before hypothesizing any comparison to humans, these results may feature sP rats as an experimental model of those subsets of human alcoholics with initial high sensitivity to ethanol challenges. Finally, the results of experiment 3 suggest a minimal involvement of the benzodiazepine and barbiturate recognition sites in the differential sensitivity to ethanol of sP and sNP rats.

Alcohol Drinking↗

PubMed1996

Developmental consequences of intermittent and continuous prenatal exposure to 1,1,1-trichloroethane in mice.

The effects of 1,1,1-trichloroethane (TCE) on physical and behavioral development were examined in CD-1 mice prenatally exposed under two regimens. In the first study, pregnant mice were exposed to either 2,000 ppm TCE or filtered air for 17 hrs. during gestational days (GD) 12-17. A third group remained untreated. The results revealed no differences on pregnancy outcome. TCE-exposed pups gained less weight, exhibited delays in developmental landmarks and acquisition of the righting reflex, had poorer performance on tests of motor coordination and exhibited delays in negative geotaxis relative to sham or untreated pups. A second experiment was designed to more closely parallel the intermittent, acute, high-concentration pattern of solvent abuse. Pregnant mice were exposed for 60 min. to 8,000 ppm TCE or sham placement in exposure chambers three times/day during GD's 12-17. The results were very similar to what were obtained in the more continuous exposure study. TCE-exposed pups gained less weight, had delays in developmental landmarks and acquisition of the righting reflex and exhibited weaker grip strength, poorer negative geotaxis and less rooting intensity in comparison to sham pups. These data provide evidence for the behavioral and developmental teratogenicity of prenatal TCE exposure late in gestation.

Animals↗

PubMed1986

Xylazine-ketamine-induced anesthesia in rats and its antagonism by yohimbine.

A combination of xylazine and ketamine was used to anesthetize 60 male rats, and then yohimbine was given to evaluate its reversing effect on xylazine-ketamine-induced anesthesia. In experiment A, xylazine (21 mg/kg of body weight) and ketamine (45 mg/kg) were admixed and administered IM to 12 Sprague-Dawley rats. Anesthesia lasted approximately 70 minutes. The xylazine-ketamine combination also induced polyuria, bradycardia, and bradypnea. When yohimbine (2.1 mg/kg) was given intraperitoneally 20 minutes after the xylazine-ketamine injection, the rats regained consciousness and righting reflexes within approximately 10 minutes. Yohimbine also reversed the bradycardia and bradypnea and appeared to reduce the polyuria induced by the xylazine-ketamine combination. In experiment B, xylazine (15.4 mg/kg) and ketamine (33 mg/kg) were admixed and given IM to 48 Holtzman rats. The combination induced surgical anesthesia for at least 30 minutes, during which a surgical procedure involving grafting a section of the sciatic nerve into the hypothalamus was performed. In rats in which yohimbine (1 mg/kg) was given intraperitoneally 45 to 60 minutes after xylazine-ketamine administration (before natural recovery from the anesthesia), the righting reflex was apparent in less than 10 minutes.

Anesthesia, General↗

PubMed2003

The influence of endotoxemia on the pharmacokinetics and the electroencephalographic effect of propofol in the rat.

Endotoxemia decreases the dose requirement for anesthetics but no data are available for propofol. A rat model was used in which the influence of endotoxin administration on the pharmacokinetics and pharmacodynamics of propofol was investigated. Chronically instrumented rats were randomly allocated to either a control (n = 9) or an endotoxin (n = 9) group. Six hours after pretreatment with either endotoxin or its solvent, propofol was infused (150 mg x kg(-1) x h(-1)) until isoelectric periods of 5 s or longer were observed in the electroencephalogram. The changes observed in the electroencephalogram were quantified using aperiodic analysis and used as a surrogate measure of hypnosis. The righting reflex served as a clinical measure of hypnosis. The propofol dose needed to reach the electroencephalographic end point in the endotoxin-treated rats was reduced by almost 50% (p < 0.01). This could be attributed to a decrease in propofol clearance and in distribution volume related to the degree of physiologic and metabolic disturbances induced by endotoxin. To investigate changes in end organ sensitivity, the biphasic electroencephalographic effect versus effect-site concentration relationship was studied. This relationship was characterized by descriptors that showed an increased intrinsic efficacy of propofol in the endotoxin group. The effect-site concentration at the return of righting reflex was lower in the endotoxin group. Our study demonstrates that endotoxin-treated animals need a lower dose of propofol to reach the same degree of anesthetic effect which can mainly be attributed to changes in pharmacokinetics.

Animals↗

PubMed1987

Kinetics of drug action in disease states. XX. Effects of acute starvation on the pharmacodynamics of phenobarbital, ethanol and pentylenetetrazol in rats and effects of refeeding and diet composition.

Severely ill patients often do not eat or cannot retain ingested food. Malnutrition occurs frequently in hospitalized individuals and is known to be associated with substantial changes in the pharmacokinetics of certain drugs. On the other hand, little is known about the effect of acute starvation or malnutrition on the pharmacodynamics (concentration-effect relationship) of drugs. To explore the effects of acute starvation on the pharmacodynamics of drugs that depress or stimulate the central nervous system, adult male Sprague-Dawley rats were deprived of food (but not water) for 3 days, whereas control animals had free access to food and water. Slow i.v. infusion of phenobarbital to onset of loss of righting reflex showed that the starved animals required a larger body weight normalized dose and that they had higher phenobarbital concentrations in serum, serum water, brain and cerebrospinal fluid at the pharmacologic endpoint. Refeeding of the rats for 2 or 7 days did not normalize the decreased body weight and serum total protein concentration. The starvation-associated decrease in the sensitivity of the central nervous system to the hypnotic effect of phenobarbital was only reversed slightly by refeeding for 2 days and persisted even after 7 days of refeeding. Acute starvation had no apparent effect on the dose of i.v. infused ethanol required to cause loss of righting reflex and on ethanol concentrations in serum, brain and cerebrospinal fluid at that time. The infused dose and the concentrations of pentylenetetrazol in serum, brain and cerebrospinal fluid at onset of maximal seizures did not differ significantly between starved and control (fed) rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Rapid tolerance to the depressive effects of diazepam on guinea pig motor control using divided doses.

The effects of acute and chronic IP injections of diazepam on the guinea pig righting reflex latency (RRL) were measured using an automated measurement system known as a "tolerometer." Single IP injections of 2.0, 6.0, 18.0, and 20.0 mg/kg diazepam significantly increased the RRL compared to no injection (naive animals), diazepam vehicle injections, or 1.0 mg/kg diazepam injections. The effects of chronic IP injection schedules on the RRL were compared: 18 or 20 mg/kg in a single, once daily injection for 5 days; 6 mg/kg in a single, once daily injection for 5 days; and 6 mg/kg, three times a day, for 5 days. Neither 20, 18, nor 6 mg/kg/day for 5 days resulted in significant tolerance to the depressive effects of diazepam on the righting reflex. By contrast, when 6 mg/kg was administered three times a day for 5 days, tolerance developed by the third day of treatment. There were no differences between the three groups in the amount of exposure to the measurement apparatus or the testing situation. These results support the view that species like guinea pig and rat that metabolise diazepam rapidly, develop tolerance more quickly if diazepam is administered in divided doses or by continuous release; this may be because the duration of the occupation of CNS benzodiazepine recognition sites is a critical factor in the development of tolerance.

Animals↗

PubMed1989

Effect of ethanol on the social behavior of group-housed and isolated mice.

The interaction between isolation and the response to ethanol was investigated with a social behavior test and a loss of righting reflex paradigm. The time a pair of mice spent in active social interaction, aggressive behavior, and avoidance-irritability showed an isolation-related increase, while locomotor activity was not affected by 0-10 days of isolation. Ethanol (0.8 g/kg) reduced the social interaction time in mice isolated for 10 days and 2.0 g/kg ethanol reduced it in all groups. Ethanol induced a locomotor stimulatory effect both in group-housed and isolated animals. An aggression-inducing effect of 0.8 g/kg ethanol was observed only in mice isolated for 5 days, while mice isolated for 10 days reduced their aggressive behavior after this dose of ethanol. The loss of righting reflex after 3.5 g/kg ethanol did not appear to vary with isolation. The results suggest that isolation alters some effects of ethanol qualitatively (e.g., its effects on aggressive behavior) but leaves other effects (e.g., its locomotor stimulant and hypnotic effects) unchanged.

Aggression↗

PubMed1985

Kinetics of drug action in disease states XII: Effect of experimental liver diseases on the pharmacodynamics of phenobarbital and ethanol in rats.

This investigation was designed to determine if liver diseases can modify the pharmacodynamics of the central nervous system depressants phenobarbital and ethanol. Two experimental models of liver diseases in rats were used: extrahepatic cholestasis produced by bile duct ligation and hepatic necrosis induced by carbon tetrachloride administration. Phenobarbital (both models) or ethanol (cholestasis model only) was infused slowly intravenously until the rats lost their righting reflex. Drug concentrations in serum, brain, and cerebrospinal fluid at that time were determined in the diseased animals as well as in sham-operated or solvent-treated controls. Phenobarbital concentrations at the onset of action were not significantly different between controls and either 5-d or 12-d cholestatic rats, except for total serum concentrations which were lower in the cholestatic groups due to reduced protein binding. Ethanol concentrations were slightly but statistically significantly lower in 12-d cholestatic rats as compared with controls. Neither 5-d nor 12-d carbon tetrachloride-induced hepatic dysfunction had any significant effect on phenobarbital concentrations at the onset of loss of righting reflex, except for a marginal decrease in the cerebrospinal fluid concentration of rats that had been treated for 5 d with the hepatotoxin. It was concluded that, under the experimental conditions, the hepatic diseases investigated did not have appreciable effects on the central nervous system response to the hypnotic action of phenobarbital and ethanol.

Animals↗

PubMed2004

Halothane augments event-related gamma oscillations in rat visual cortex.

Cortical gamma oscillations have been associated with neural processes supporting cognition and the state of consciousness but the effect of general anesthesia on gamma oscillations is controversial. Here we studied the concentration-dependent effect of halothane on gamma (20-60 Hz) power of event-related potentials (ERP) in rat primary visual cortex. ERP to light flashes repeated at 5-s intervals was recorded with chronically implanted, bipolar, intracortical electrodes at selected steady-state halothane concentrations between 0 and 2%. gamma-Band power was calculated for 0-1000, 0-300 and 300-1000 ms poststimulus periods and corresponding prestimulus (PS) periods. Multitaper power spectral analysis was used to estimate gamma power from both single-trial and average ERP in order to differentiate between phase-locked (evoked) and non-phase-locked (induced) gamma activities. Significant PS gamma power was present at all halothane concentrations. Flash elicited an increase in gamma power that lasted up to 1 s poststimulus at all halothane concentrations. Halothane at intermediate concentrations (0.5-1.2%) augmented both PS and ERP gamma power two to four times relative to the waking baseline. gamma Power was not different between waking and deeply anesthetized (2%) levels. gamma Power reached maximum, as predicted by a Gaussian fit of power-concentration data, at halothane concentration (0.86%) similar to the concentration (0.73%) that abolished the righting reflex, a behavioral index of loss of consciousness. Evoked, i.e. stimulus-locked, gamma power was present during the first 300 ms poststimulus but not later, and was approximately 50% of single-trial ERP gamma power. Single-trial gamma power was present also at 300-1000 ms poststimulus, reflecting ERP not phase-locked to the stimulus. In summary, these observations suggest that (1) gamma activity is present in states ranging from waking to deep halothane anesthesia, (2) halothane does not prevent the transfer of visual input to striate cortex even at surgical plane of anesthesia, and (3) anesthetic-induced loss of consciousness, as reflected by the loss of righting reflex, is not correlated with a reduction in gamma power. Variance with other studies may be due to an underestimation of gamma power by ERP signal averaging as compared with single-trial analysis.

Animals↗

PubMed1987

Effect of age on the pharmacodynamics of phenobarbital and ethanol in rats.

The purpose of this investigation was to determine the effect of age on the sensitivity of the central nervous system (CNS) to the depressant action of phenobarbital and ethanol. For this purpose, one or the other of these drugs was administered by slow iv infusion to male rats of various ages until the animals lost their righting reflex. The drug concentrations at that time in serum, brain, and cerebrospinal fluid were determined. The results obtained in studies on 1, 9, and 18-month-old Sprague-Dawley rats and on 7, 16, and 24-month-old Fischer-344 rats showed that phenobarbital concentrations at the pharmacologic end-point decreased with increasing age, indicative of an increased sensitivity of older animals to the CNS depressant effect of the barbiturate. Similar studies with ethanol on Sprague-Dawley rats (only) showed substantially higher drug concentrations at all sampling sites in 5-week-old animals than in 9- and 12-month-old animals at the onset of loss of righting reflex, but no significant differences between the 9- and 12-month-old groups. This investigation, which was designed to exclude or account for pharmacokinetic variables and to avoid confounding secondary effects, such as hypothermia and development of acute functional tolerance, showed a substantial increase in CNS sensitivity to phenobarbital and ethanol with increasing age in rats between the age of 1 and 9 months, and a less pronounced increase (phenobarbital) or no significant change (ethanol) in rats between 9 and 18 months of age.

Age Factors↗