Potential regulation of nicotine and ethanol actions by alpha4-containing nicotinic receptors.

A restriction fragment length polymorphism (RFLP) associated with a major nicotinic receptor subunit (i.e., alpha4) has been identified in two mouse lines that were selectively bred for differences in sensitivity to ethanol. These mice, referred to as Long-Sleep (LS) and Short-Sleep (SS) mice, also differ in sensitivity to several effects of nicotine. The potential role of the alpha4 RFLP in regulating several responses to nicotine and ethanol was evaluated by using the LSxSS-derived recombinant inbred (RI) strains. Those RI strains that carried the LS-like alpha4 RFLP were more sensitive to the depressant effects of nicotine on Y-maze crossing and rearing activities and ethanol-induced increases in Y-maze crossing activity than were those RI strains that carry the SS-like alpha4 RFLP. The LS-like RI strains were also more sensitive to nicotine-induced hypothermia. The RFLP was not associated with strain differences in ethanol-induced body temperature or sleep time. The potential role of the RFLP in regulating ethanol and nicotine consumption was evaluated in heterogeneous stock (HS) mice. An association was found between the alpha4 RFLP and variation in ethanol consumption, but not in nicotine consumption, as measured in a four-bottle choice test. Recent studies of ethanol and tobacco abuse by human beings suggest that common genes may influence these two forms of substance abuse. The results of the studies reported here suggest that the alpha4 nicotinic receptor gene should be evaluated for its potential role in regulating ethanol and tobacco abuse in human beings.

Oral creatine supplementation and upper extremity anaerobic response in females.

The purpose of this study was to investigate the influence of creatine monohydrate (CrH2O) on upper extremity anaerobic response in strength-trained females involved in overhand sports. Two movements were utilized in this evaluation: elbow flexion (EF) and shoulder internal rotation (IR). Subjects were pair-matched and assigned to receive placebo (n = 13) or 25 g CrH2O (n = 11) for 7 days. Pre- and post-treatment measurements included peak concentric and eccentric isokinetic torque, isotonic 1RM, and fatigue (FAT) during EF; isotonic 1RM, FAT, and peak velocity during IR; and body weight. MANOVAs revealed significant interaction between treatment and trial for EF (p <.05) but not for IR or weight. Univariate analysis indicated a significantly greater change in EFFAT following CrH2O than following placebo. Thus, CrH2O did not influence peak EF or IR strength, IR work to fatigue, or IR velocity, but was associated with greater work capacity during fatiguing EF. These data suggest that CrH2O may enhance upper extremity work capacity, but this enhancement may not extend to the muscles primarily responsible for overhand sports performance.

Sensitivity to cocaine and amphetamine among mice selectively bred for differential cocaine sensitivity.

Selective breeding of mice for differences in response to a drug offers a powerful means for testing hypotheses regarding underlying mechanisms and relationships between drug-induced behaviors. Starting from a heterogeneous stock of mice, we have selectively bred lines of mice for extreme differences in their locomotor response to 10 mg/kg cocaine HCl. Selection pressure has been maintained for 12 generations and has resulted in two cocaine sensitive (CAHI) and two cocaine insensitive (CALO) lines. Across the generations of selection, the CAHI lines showed progressively greater amounts of cocaine-induced locomotion, with mice from the S12 generation traveling over 21,000 cm/30 min. following 10 mg/kg cocaine. The CALO lines, in contrast, did not substantially diverge from control values until the S8 generation. By generation 12, however, the LO lines traveled no further following 10 mg/kg cocaine (7000 cm/30 min), than they did following an initial saline injection. Cocaine and amphetamine dose-response analyses were conducted on drug-naive mice from the tenth generation. The CAHI lines were extremely sensitive to the locomotor activating effects of all doses of cocaine, displaying from 2- to 6-fold greater amounts of cocaine-induced locomotion than the CALO lines. The CALO lines, in contrast, were completely insensitive to the psychomotor stimulant effects of cocaine. The CAHI lines were also more sensitive to the locomotor activating effects of amphetamine. Both lines showed dose-dependent amphetamine-induced locomotion that peaked at 3 mg/kg. However, at all doses, the CAHI lines showed a 2- to 4-fold greater amount of locomotion than CALO lines. Thus, the sensitivity to cocaine developed through selection using a single dose of cocaine has generalized to a range of doses of cocaine and to at least one other psychostimulant.

Differential cocaine sensitivity between two closely related substrains of C57BL mice.

While there is evidence that individual differences in response to cocaine are mediated, in part, by genetic factors, no single gene has been identified that can account for differential responsivity to cocaine. Recent studies in our laboratory may have moved us closer to identification of the gene(s) underlying cocaine sensitivity. We have identified several cocaine-related phenotypes on which two substrains of C57BL mice (6J and ByJ) differ. The genealogy of these two substrains leads to the expectation that they should be genetically very similar, differing at only a few loci. The large differences between the two substrains in cocaine sensitivity may be influenced by allelic differences at a major gene mediating the actions of cocaine. Naive ByJ mice are more resistant to cocaine-induced seizures than are 6J mice. Furthermore, among 6J mice repeated exposure to cocaine results in a decreased susceptibility to cocaine-induced seizure, while among ByJ mice, the same treatment gives rise to an increased susceptibility to seizures. In contrast to their lower sensitivity to cocaine-induced seizures, ByJ mice show a greater sensitivity to cocaine's locomotor stimulant effects. Furthermore, the repeated pairing of cocaine and the test environment results in the development of conditioned locomotion during subsequent exposure to that environment among 6J, but not ByJ, mice. Similarly, a greater degree of conditioned sensitization to the locomotor stimulant effects of cocaine develops in 6J mice.

One-way cross-sensitization and cross-tolerance to seizure activity from cocaine to lidocaine.

The present study examined the effects of daily treatment with a subconvulsant dose (50 mg/kg) of cocaine or lidocaine on susceptibility to seizures induced by cross-injections of the same dose of the other local anesthetic, and to seizures induced by pentylenetetrazol (PTZ) or N-methyl-DL-aspartate (NMDLA) in ddY mice. Repeated administration of 50 mg/kg cocaine caused the development of sensitization to cocaine-induced seizures during an initial 3 or 4 days, followed by the development of tolerance on days 4-6. The same dose of lidocaine, however, produced little or no seizure activity following repeated administration. In contrast, when injected 24 hr after 2-4 days of cocaine treatment, 50 mg/kg lidocaine produced severe seizures. Interestingly, this cross-sensitization from cocaine to lidocaine diminished upon further cocaine treatment. In contrast, treatment with lidocaine for 2-6 days had no effect on subsequent changes in seizure susceptibility following repeated cocaine injections. Neither treatment with cocaine nor lidocaine for 2 or 5 days influenced susceptibility to seizures induced by a challenge injection of PTZ (50 mg/kg, i.p.) or NMDLA (300 mg/kg, i.p.) 24 hr after treatment. HPLC analyses revealed that the cocaine treatment paradigm used in these studies increased the levels of the polyamines, putrescine and spermidine, in mouse brain, while lidocaine treatment had no effect on cerebral polyamine levels. These results suggest that there are differences in the neural mechanisms underlying the convulsant properties of cocaine and lidocaine in ddY mice.

Chromosomal mapping of the psychomotor stimulant effects of cocaine in BXD recombinant inbred mice.

To elucidate genes associated with cocaine's locomotor stimulant effects, we used recombinant inbred-quantitative trait loci (RI-QTL) analyses to identify chromosomal loci associated with locomotor activity before (baseline) and after cocaine treatment. RI-QTL analyses seek to identify associations between a quantitative measure of a phenotype and one or more previously mapped marker loci across a panel of RI strains. In the present study, 11 BXD RI strains were used to identify several putative QTLs for each phenotype. Both baseline locomotor activity and cocaine's locomotor stimulant effects are polygenic, with both unique and overlapping genetic influences. The largest associations for baseline activity were observed on chromosomes 5 and 9 and the largest associations for cocaine's psychomotor stimulant effects on chromosomes 3 and 17.

Differential effects of NMDA receptor and dopamine receptor antagonists on cocaine toxicities.

Cocaine produces not only euphoric effects but also a wide range of detrimental effects, including seizures and lethality. The present study examined the involvement of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptors and the dopamine D1 and D2 receptors in seizure activity and lethality observed following single and repeated injections of cocaine in ddY mice. Repeated injections of 60 mg/kg cocaine resulted in the development of sensitization to the convulsant effects of cocaine during an initial 3 or 4 days, followed by the development of tolerance at day 5 and day 6. Repeated injections of 90 mg/kg cocaine augmented the lethal effect of cocaine progressively over the course of treatment. Treatment with 0.1-0.4 mg/kg of the noncompetitive NMDA receptor antagonist, MK-801, prevented the development of sensitization to cocaine-induced seizures in a dose-dependent manner, and attenuated partially the cocaine-induced lethality. In contrast, treatment with 10-50 mg/kg of the dopmaine D2 receptor antagonist, sulpiride, had no effects on the development of sensitization and tolerance to cocaine-induced seizures. On the other hand, treatment with 0.1-0.5 mg/kg of the dopamine D1 receptor antagonist, SCH 23390, not only prolonged the latency to 90 mg/kg cocaine-induced seizures but also delayed the development of sensitization to the convulsant effects of cocaine. The increased lethality observed following repeated injection of cocaine was unaffected by treatment with SCH 23390, but was severely aggravated by treatment with sulpiride.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased polyamine levels and changes in the sensitivity to convulsions during chronic treatment with cocaine in mice.

Polyamines have been demonstrated to modulate seizure activity in animals. Repeated administration of a subthreshold dose of cocaine resulted in the development of sensitization to cocaine-induced seizures during an initial 3 or 4 days, followed by the development of tolerance to seizures on days 5 and 6. In the present study, polyamines, such as putrescine, spermidine and spermine, were measured in regions of the brain obtained from mice that showed differential sensitivity in seizure activity during repeated cocaine injections. Animals were sacrificed for polyamine measurements 24 h after the second and the fifth injections of either cocaine or saline (on day 3 and day 6, respectively), and 3 days after the last injection. On day 3, there were significant increases in putrescine in the striatum, hippocampus and cerebellum, and in spermine in the cerebellum of cocaine-treated mice, as compared to saline-treated mice. On day 6, treatment with cocaine significantly increased putrescine in all regions, and spermidine in striatum and hippocampus, as compared to saline treatment. Cocaine treatment had no effect on any polyamine levels measured 3 days after the last injection, except for spermidine in the cortex. Because putrescine has been shown to be an antagonist of the polyamine-binding site on the N-methyl-D-aspartate receptor and to retard the development of amygdala-kindling, the present results suggest that the increases in putrescine content may be associated with the development of tolerance to convulsant effects observed during the later period of repeated administration of cocaine.

Psychophysical frequency and sustained exertion at varying wrist postures for a drilling task.

Two laboratory experiments were conducted; first, to utilize the psychophysical approach (method of adjustment) to establish maximum acceptable frequency (MAF) for a sheet metal drilling task and, second, to examine the effect of sustained, static exertion upon objective and subjective measures under similar task conditions. In both experiments, the wrist posture (flexation, ulnar deviation) required by the task was varied. Twelve healthy females served as subjects. Results show that the psychophysically adjusted task frequency was significantly lower when wrist deviation was required, particularly flexion. MAF for one-third (25 degrees) and two-thirds (50 degrees) flexion were 88% and 73%, respectively, of those selected in the neutral posture. Furthermore, these results were supported by trends in grip strength, heart rate, blood pressure, EMG and perceived exertion. Results from the sustained exertion trials revealed that significant increases in physiological parameters occurred during 3-minute sessions and that this trend was exasperated with deviated wrist posture, particularly flexion. Considering results of both experiments, it was concluded that while the neutral wrist posture may be preferred for a drilling operation, task frequency should be reduced for deviated postures when redesign is not feasible and it is further recommended that deviation be limited to one-third maximum flexion (25 degrees) and two-thirds maximum ulnar deviation (30 degrees). It is also suggested that the psychophysical approach may be utilized to establish 'acceptable' parameters for other industrial tasks involving upper extremity stress, particularly in the current absence of more objective biomechanical and/or physiological criteria for reducing the risk of exposure to cumulative trauma disorders.

Chromosomal mapping of loci influencing sensitivity to cocaine-induced seizures in BXD recombinant inbred strains of mice.

Among inbred mice, genetic factors mediate differences in sensitivity to the convulsant properties of cocaine; however, the gene(s) underlying cocaine's effects have not been identified. To help elucidate the gene(s) responsible for cocaine seizure susceptibility, we used recombinant inbred-quantitative trait loci (RI-QTL) analyses to identify chromosomal loci associated with cocaine-induced seizures. RI-QTL analyses seek to identify associations between a quantitative measure of a particular phenotype and one or more previously mapped marker genes across a panel of RI strains. This report describes an RI-QTL analysis of cocaine seizure susceptibility among 26 BXD RI strains. These strains showed a skewed, bimodal range of seizure susceptibility which could be the result of one or more modifying genes acting in concert with a major gene to influence cocaine sensitivity. Correlating the percent seizures displayed by each strain following 60 mg/kg cocaine with chromosomal marker data for these strains revealed a number of significant correlations clustered in two regions on chromosomes 12 and 6. This is the first identification of putative chromosomal loci associated with a cocaine-related phenotype and should facilitate identification of the gene(s) underlying cocaine toxicity and other cocaine-related phenotypes.

Long-term sensitization to the behavioral effects of naltrexone is associated with regionally specific changes in the number of mu and delta opioid receptors in rat brain.

Enhanced sensitivity to some of the behavioral effects of the opioid antagonist naltrexone (NTX) develops following once-weekly injections of cumulative doses of the drug. Rats treated with this regimen of NTX injections show enhanced sensitivity to the operant response rate decreasing effects of NTX and NTX-induced salivation. The enhanced sensitivity is long-lasting and appears to be produced through conditioning processes. We have conducted saturation binding assays to assess possible changes in the number and affinity of mu and delta opioid receptors in cortical, midbrain and hindbrain membrane preparations from Long-Evans rats treated once weekly for 8 weeks with cumulative doses of the drug (1, 3, 10, 30 and 100 mg/kg). 3H-DAMGO (0.5-21 nM) and 3H-pCl-DPDPE (0.04-4 nM) were used to characterize mu and delta receptors, respectively. NTX treatment had no effect on 3H-DAMGO binding in cortex, but decreased binding in midbrain and increased binding in hindbrain relative to saline-treated controls. Saturation analyses revealed that these differences reflected changes in the number, but not the affinity of mu receptors. NTX treatment also increased the amount of 3H-pCl-DPDPE bound to delta receptors in midbrain and hindbrain, but not in cortex. Again, these changes were due to changes in the number of receptors. Thus, chronic NTX differentially affects the number of mu and delta opioid receptors in various brain regions.

GABA receptor-linked chloride channels and the behavioral effects of naltrexone in rats.

The present study was conducted to determine whether the effects of naltrexone on schedule-controlled behavior in rats were mediated, at least in part, by the GABAergic system. Because the enhanced sensitivity that has been shown to occur following naltrexone treatment might alter the effects of the treatment compounds, a variety of compounds interacting with the GABA system were tested in both sensitized and nonsensitized animals. Of all the compounds tested in this manner, only the dose-effect function for the GABA agonist muscimol was altered by the naltrexone treatment, with the higher doses of muscimol producing response-rate decreasing effects only in naltrexone-sensitized rats. In the naltrexone-treated animals, these same GABA agonists and antagonists were used as pretreatments prior to the determination of the naltrexone dose-effect function. Although shifts in the naltrexone dose-effect function were observed, the effects were not consistent either within or across receptor class. In contrast, the chloride-channel antagonist picrotoxin clearly shifted the naltrexone dose-effect function in sensitized animals to the left, while the chloride-channel facilitator pentobarbital shifted the function to the right. These results indicate that the effects of naltrexone are at least partially mediated by an action at the GABA-linked chloride channel, rather than directly at the GABA receptor.

Genotype-specific blockade of cocaine-induced weight loss by the protein synthesis inhibitor, anisomycin.

Cocaine has been shown to reduce food intake and body weight in rodents and humans. The results of recent research suggest that de novo protein synthesis in the brain is associated with neuroadaptive changes in the central nervous system. The present study reports the effect of anisomycin, a protein synthesis inhibitor with limited toxicity, on the reduction in body weight resulting from repeated daily injections of cocaine (50 mg/kg) to mice from 7 inbred strains (AKR/J, BALB/cByJ, C3H/HeJ, C57BL/6J, CBA/J, DBA/2J and SJL/J). Repeated cocaine administration resulted in substantial weight loss in all but the BALB strain. Anisomycin (5-30 mg/kg), administered 5 min. prior to each daily cocaine injection, significantly attenuated cocaine-induced weight loss in SJL, C3H and CBA mice. The same treatment, however, had no effect on reduction in body weight in C57, AKR and DBA mice. In BALB mice, neither cocaine, anisomycin alone, nor the coadministration of the two drugs, affected weight gain during the experiment. The results suggest that there is a genotype-specific involvement of protein synthesis associated with cocaine-induced weight loss.

Tolerance to the behavioral effects of chlordiazepoxide: pharmacological and biochemical selectivity.

There is a dynamic interaction between a drug's pharmacological effects and the behavioral context in which it is administered. The present study evaluated the influence of behavioral processes on the development of tolerance and cross-tolerance to the rate-decreasing effects of chlordiazepoxide in rats. Sprague-Dawley rats responded under a fixed-ratio 30 schedule of food delivery. Different groups of rats received 18 mg/kg/day of chlordiazepoxide either before (PRE, n = 8) or after (POST, n = 10) daily experimental sessions for 8 weeks. Cumulative dose-response curves for chlordiazepoxide were obtained before and during chronic chlordiazepoxide administration and during chronic saline administration. Cumulative dose-response curves for midazolam, FG 7142 (N-methyl-beta-carboline-3-carboxamide) flumazenil, pentobarbital, caffeine, morphine and d-amphetamine were determined before, during and 4.5 to 5 months after chronic chlordiazepoxide administration. Group PRE developed tolerance to chlordiazepoxide, whereas group POST did not develop tolerance. Although cross-tolerance developed to midazolam in both groups, it was greater in group PRE. Both groups showed comparable sensitization to FG7142 and neither group showed a significant change in sensitivity to any of the other drugs. Biochemical studies of gamma-aminobutyric acid (GABA)-related functioning in groups of rats that received chronic chlordiazepoxide administration either before (BIO-PRE, n = 6) or after (BIO-POST, n = 6) daily sessions found that GABA-stimulated 36Cl-uptake increased in both cortical and cerebellar preparations. However, GABA sensitivity in cerebellar tissue was significantly lower in group BIO-PRE compared with group BIO-POST. Thus, behavioral tolerance to chlordiazepoxide was associated with both pharmacological and biochemical effects, which suggests a relationship between behavioral tolerance to benzodiazepines and changes in the functional state of the GABA-benzodiazepine receptor complex.

A treatment for carpal tunnel syndrome: results of a follow-up study.

OBJECTIVE: This study was a follow-up evaluation of carpal tunnel syndrome (CTS) subjects based on objective and subjective measures utilizing a conservative treatment method. It was hypothesized that the CTS individuals would maintain their improvements over the course of a 6-mo period after treatments. DESIGN: The design used was a case control study in which the improvements of the CTS subjects were compared within themselves and with a matched comparison group. The treatments were performed at a private chiropractic clinic, and the objective and subjective measures were independently taken in an industrial engineering laboratory. All CTS subjects were volunteers from a random sample. Forty-three individuals were evaluated at the pretreatment period and in the 6-mo follow-up. Only 22 subjects returned for reevaluation. The treatment duration was not controlled. RESULTS: The results indicate that CTS subjects had maintained improvements in most of the objective measures and pain and distress ratings over the pretreatment level (p < .05) at 6 mo post-treatment. When compared to a matched comparison group, CTS-treated subjects demonstrated no significant differences (p < .05) in grip strength (for females), pinch strength, forearm pronation and supination forces, assembly task performance and pain and distress scores. CONCLUSION: The results of statistical analyses indicate that CTS subjects can be treated and achieve a significant recovery to within normal comparative levels of non-CTS subjects in most subjective and objective measures.

Pharmacogenetic approaches to drug dependence.

The aim of this volume is to bring together information about both the neurochemical mechanisms associated with the actions of drugs of abuse and the psychopharmacological and behavioural effects of these drugs. One approach that is proving to be quite useful for bringing together these two very diverse fields is the use of classical pharmacogenetic techniques. Pharmacogenetics is defined as the study of genetic and environmental factors underlying individual differences in response to pharmacological or toxicological agents. Much of the early work in this field dealt with genetic differences in drug metabolism and other pharmacokinetic parameters [1]. More recently, however, attention has been directed towards understanding the implications of genetic differences associated with pharmacodynamic parameters mediating the actions of drugs. This paper discusses the use of pharmacogenetic techniques in drug abuse research. It presents an overview of some of the more common genetic techniques available for use in drug research and provides some examples from research projects that have employed these approaches.

Genetic differences in the time course for the development and persistence of the anticonvulsant effects of carbamazepine against cocaine seizures.

Initial studies of the effect of chronic carbamazepine (CBZ) against cocaine-induced seizures indicated that there were genetic differences in both the time course for the development of the anticonvulsant effects of CBZ against cocaine-induced seizures and the persistence of these effects. The present studies were initiated to investigate the time course for the development and persistence of the anticonvulsant effects of chronic CBZ against cocaine seizures in BALB/cByJ, C57Bl/6J and SJL/J mice. The anticonvulsant actions of CBZ were dependent on the duration of CBZ administration, requiring 4-7 days to achieve maximal efficacy. However, once the anticonvulsant effects of CBZ were manifest, the effect persisted for up to 5 days after stopping CBZ treatment depending on the genotype. The levels of CBZ and its active epoxide metabolite were determined in plasma and brain at various time points during and after chronic CBZ treatment. The levels of CBZ and CBZ-10,11-epoxide were substantially reduced over the course of treatment in all three strains, such that the levels of the two compounds in plasma and brain could not account for the decreased susceptibility to cocaine seizures observed following chronic CBZ. These results suggest that the effects of CBZ on cocaine seizures are mediated by relatively long-term changes in one or more biological systems associated with cocaine's convulsant effects.

Aggression modulates genetic influences on morphine analgesia as assessed using a classical mendelian cross analysis.

Pharmacogenetic techniques allow for the examination of genetic and environmental factors underlying phenotypes associated with drug response. Initial studies of mice bred at Jackson Laboratories (JAX) indicated that C57BL/6J mice were more sensitive to morphine-induced analgesia, as measured by latency to paw lick, than SJL/J mice. A classical Mendelian cross breeding program was initiated in which F1, F2 and backcross generations were derived from C57BL/6J and SJL/J breeding pairs purchased from JAX to examine the genetic factors underlying morphine analgesia. Genetic analysis indicated significant dominance or heterosis for a reduced drug response. The F1 generation was less sensitive to morphine-induced analgesia than either parental strain. Mathematical analysis of the generation means revealed that a simple dominance model with no epistatic interaction between genes best described the data. Environmental factors also affected sensitivity to morphine analgesia, in that C57BL and SJL mice raised in our facility did not differ in latency to paw lick. SJL mice from JAX exhibit a high degree of aggression, while SJL mice raised in our facilities show little or no aggression. The levels of aggression among groups of SJL mice were characterized and found to correlate with sensitivity to morphine analgesia. Mice exposed to increasingly greater levels of aggression were the least sensitive to morphine. Thus, the changes observed in sensitivity to morphine-induced analgesia appear to be related to the degree of aggression to which these mice are exposed, possibly resulting from the stress and/or prolonged exposure to painful stimuli associated with aggressive encounters.

Lipid solubility of sedative-hypnotic drugs influences hypothermic and hypnotic responses of long-sleep and short-sleep mice.

The anesthetic potency of many agents, including alcohols, barbiturates and other sedative-hypnotic drugs, is influenced by lipid solubility. Previous studies from our laboratory, however, have demonstrated that genetic factors influence this relationship. We have reported that mouse lines selectively bred for differences in duration of ethanol-induced anesthesia, the long-sleep (LS) and short-sleep (SS) mice, differ in sleep-time response to water-soluble, but not lipid-soluble, sedative-hypnotic drugs. The studies described here sought to determine whether this same relationship exists for the hypothermic response produced by 17 sedative-hypnotic drugs in the LS and SS mice. Dose-response and time course relationships for hypothermic actions were determined and were compared with the dose-related anesthetic effects of the drugs. Hypothermic potencies increased along with lipid solubility for both the LS and SS mouse lines, but the rate of change differed for the two mouse lines. LS mice were more responsive to ethanol and other water-soluble drugs whereas the SS were more responsive to lipid-soluble drugs; significant correlations were obtained between lipid solubility (log P-octanol-water partition coefficient) and relative LS-SS responsiveness to both the hypothermic and hypnotic actions of the 17 test drugs. Thus, both hypnotic and hypothermic actions of sedative-hypnotic drugs are correlated with lipid solubility. Possible explanation for these correlations include greater LS central nervous system sensitivity to water-soluble drugs and LS-SS differences in distribution of lipid-soluble drugs.