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Biomedical subjects

T J Phillips

Publications and source records attributed to T J Phillips.

At least 19 recordsLinked to original sources
PubMed1992

Genetic determinants of ethanol reinforcement.

In this paper, we present examples of some of the several behaviors which have been taken to indicate the reinforcing efficacy of drugs, including ethanol. Efforts to identify the genetic determinants of these behaviors have employed diverse pharmacogenetic methods. For example, we have used selective breeding to develop mice selected for severe or attenuated ethanol withdrawal and have found that Withdrawal Seizure Prone mice show a greater conditioned preference for ethanol-associated locations than the selected Withdrawal Seizure Resistant line. Similarly, HOT mice, selected for insensitivity to ethanol-induced hypothermia, had greater conditioned place preference after ethanol training than COLD mice, selected for ethanol hypothermic sensitivity. We have also developed selected mouse lines responsive or unresponsive to ethanol-stimulated locomotor activity. These FAST and SLOW lines develop sensitization rather than tolerance to ethanol-induced activity. Using inbred strains of mice, others had shown that strains differed in preference for drinking ethanol solutions. We found that these strains also differed in acceptance of ethanol. Single-gene techniques have been used to show that preference drinking is significantly altered in mutant rodent strains lacking hypothalamic vasopressin, or with nephrogenic diabetes insipidus. In a specific panel of Recombinant Inbred mouse strains, we found that a single gene appeared to control a significant portion of the variance in preference drinking. These examples show that traits putatively related to drug reinforcement show substantial genetic control. Specifically, single-gene methods show promise of identification and mapping of genes related to drug reinforcement.

Animals↗
PubMed1992

Locomotor responses to benzodiazepines, barbiturates and ethanol in diazepam-sensitive (DS) and -resistant (DR) mice.

Diazepam-sensitive (DS) and -resistant (DR) mice were selectively bred for increased and reduced sensitivity to the ataxic effects of diazepam (40 mg/kg). Other response differences between DS and DR mice may reflect pleiotropic effects of the genes fixed during their selection. These mice were tested for their sensitivity to the locomotor stimulant effects of several doses of diazepam, flunitrazepam, pentobarbital, phenobarbital, and ethanol. DR mice were more sensitive than DS mice to the locomotor stimulant effects of all drugs except phenobarbital. These results largely support the hypothesis that a common biological mechanism mediates sensitivity to the stimulant effects of sedative-hypnotic drugs. Receptor mediation of the benzodiazepine effects was examined by administering the benzodiazepine receptor antagonist, RO15-1788. Locomotor depression produced by diazepam and flunitrazepam in DS mice was blocked by RO15-1788. However, while the locomotor stimulation produced by diazepam in DR mice was antagonized, the stimulant effect of flunitrazepam was not. This suggests that binding of flunitrazepam to the GABAA-benzodiazepine receptor is not necessary for production of locomotor stimulation.

Analysis of Variance↗
PubMed1992

Clinical applications of cultured epithelium.

Techniques that allowed the successful serial subcultivation of human keratinocytes into sheets of epithelium suitable for grafting have made possible a variety of clinical applications for cultured epithelium. Following the first description of this technique in 1981 to treat third-degree burns, cultured keratinocytes derived from a small biopsy of the patient's normal skin (autografts) have been used in centres throughout the world to provide permanent wound coverage for extensive burns. Over the years, applications have expanded to include the treatment of leg ulcers and blistering skin disorders. A further development in this field has been the use of cultured epithelium derived not from the patients own skin, but from an allogeneic donor (cultured allograft). Cultured allografts have also been widely used in the treatment of burns, leg ulcers, the donor sites for split-thickness grafts, and other dermatological disorders. These allografts seem to act as a potent stimulus to wound healing, but do not survive permanently on the wound bed. Their postulated mechanism of action is through release of multiple cytokines that stimulate epithelialization from the wound periphery as well as from adnexal elements within the wound bed. Allograft application is a simple outpatient procedure which involves no discomfort for the patient. No skin biopsy is necessary and cryo-preservation of grafts for future use is possible.

Burns↗
PubMed1992

Acute sensitivity of FAST and SLOW mice to the effects of abused drugs on locomotor activity.

The universal nature of the stimulant or euphoric effect of addictive drugs suggests that it may be an important predictor of a drug's addiction potential. Furthermore, assessment of stimulant sensitivity could be useful for predicting the liability of individuals to drug abuse. The stimulant actions of abused drugs from different pharmacological classes may share a common biological mechanism. We investigated this notion by assessing the drug responses relative to base-line locomotor activity of mice selectively bred for increased (FAST) and reduced (SLOW) sensitivity to ethanol-induced stimulation. FAST mice were more sensitive than SLOW mice to the stimulant effects of methanol (1.5-3.0 g/kg), t-butanol (0.2-0.6 g/kg), n-propanol (0.15-1.2 g/kg), pentobarbital (10-40 mg/kg) and phenobarbital (15-120 mg/kg). FAST and SLOW mice were similarly stimulated by d-amphetamine (1.25-10 mg/kg) and caffeine (2.5-20 mg/kg). The activity of FAST and SLOW mice was equally depressed by nicotine (0.5-2.0 mg/kg) and morphine (4-75 mg/kg). Finally, FAST mice were unaffected, whereas SLOW mice were depressed by diazepam (1-8 mg/kg). Selection for relative sensitivity to stimulation by ethanol has generalized to other alcohols and to barbiturates, but not to several other abused drugs, including amphetamine. The data presented here support a hypothesized common mechanism of stimulant action for alcohols and barbiturates, and suggest that differences in sensitivity to drug stimulant effects can be seen in the absence of dopamine system differences.

Alcohols↗
PubMed1991

Response to selection for ethanol-induced locomotor activation: genetic analyses and selection response characterization.

Selectively bred FAST mice are highly susceptible, while SLOW mice are less susceptible, to the locomotor stimulant effects of ethanol. Heritability estimates indicate that approximately 15% of the variance in the FAST lines is of additive genetic origin, while low susceptibility is ostensibly nonheritable. Inbreeding has increased at the rate of 2% per generation, but fertility has been unaffected. Measurement reliability for sensitivity to this ethanol effect was high when measured in both circular (r = 0.6) and square (r = 0.7) open-fields. In addition, our results indicate that we have selected for differences in sensitivity to ethanol rather than for differences in habituation to the test environment. The difference in response to ethanol between FAST and SLOW mice extended to tests varying in duration, and to a range of ethanol doses. We conclude that the divergence between FAST and SLOW mice generalizes to related test parameters, and speculate that the genetic architecture underlying the locomotor stimulant response may be simpler than previously proposed.

Animals↗
PubMed1991

Use of recombinant inbred strains to identify quantitative trait loci in psychopharmacology.

Unlike simple Mendelian characteristics, individual differences in complex quantitative phenotypes studied in psychopharmacology are generally distributed continuously and are likely to be influenced by many genes. Recombinant inbred (RI) strains are valuable not only for their traditional use of detecting major gene segregation and linkage but also for identifying associations between quantitative traits and quantitative trait loci (QTL) that account for relatively small amounts of variation in phenotypes as well as loci that account for greater amounts of variation. When applied to published data on genetic markers and on amphetamine, alcohol, and morphine responses in BXD RI strains (RI strains developed from the cross between C57BL/6J and DBA/2J progenitor inbred strains), the RI QTL approach identified several significant associations beyond known major gene effects. Together, significant associations explain more than half of the genetic variance for these measures. The RI QTL approach is especially valuable for investigating the QTL underpinnings of genetic correlations among measures. It is recommended that psychopharmacogenetic research focus on the BXD RI strains. The cumulative and integrative nature of such a program of research is the major benefit of the RI QTL association approach for molecular genetic analysis of psychopharmacological processes, their physiological infrastructure, and their interface with other behavioral and biological systems.

Animals↗
PubMed1991

Leg ulcers.

The treatment of leg ulcers is a common and sometimes difficult problem. They can be costly to treat and are associated with loss of working capacity and sometimes significant morbidity. In the western world, leg ulcers are most frequently caused by venous insufficiency, arterial insufficiency, neuropathy (usually diabetic), or a combination of these factors. The pathogenesis, clinical features, and management of these types of leg ulcers are emphasized in this review.

Humans↗
PubMed1991

Locomotor activity responses to ethanol in selectively bred long- and short-sleep mice, two inbred mouse strains, and their F1 hybrids.

Locomotor activity responses to sub-hypnotic doses of ethanol (ETOH) were assessed in selected lines of mice (LS and SS), inbred strains, and their F1 hybrids. Data were obtained as photocell beam interruptions in a 15-min test for a dose range of 0 to 2.75 or 3.5 g/kg for LS and SS mice, respectively. Biphasic dose-response curves were obtained for LS and SS mice with the SS mice showing a sedative limb of the dose-response curve shifted to the right. The effects of 2.0 g/kg ETOH were also assessed in a diallel cross of the selected LS/SS lines and C57BL/6Abg and MOLD/RkAbg inbred strains. The 2.0 g/kg dose produced a wide range of responses, from sedation in C57BL/6Abg mice to extreme activation in SS and MOLD/RkAbg mice, and no effect in LS mice. The responses of F1 hybrids reflected a typical pattern of partial dominance, with heterosis in some crosses. When present, dominance was in the direction of greater locomotor activation. These patterns were confirmed by biometrical genetic analysis of the 4 x 4 diallel cross of the two lines and the two inbred strains. The data indicate that loci in addition to those responsible for selection for sedative sensitivity in LS and SS mice can influence locomotor activation produced by sub-hypnotic ETOH doses, and that SS and MOLD mice show locomotor activation for different genetic reasons.

Animals↗
PubMed1991

Genetic analyses of the biphasic nature of the alcohol dose-response curve.

Ethanol (ETOH)-induced locomotor activation and depression were studied in 23 genotypes of mice. This included a diallel cross of four inbred strains tested with a range of ETOH doses from 0 to 2.75 g/kg. The diversity in shapes of the biphasic ETOH dose-response curves was both qualitative and quantitative, and additive gene action characterized the genetic control of the dose-response curve. Small dominance effects were typically directional in the direction of more activation, or resistance to sedation. No evidence was found for maternal effects, sex linkage, or epistasis. Sex differences were seen in the increased susceptibility of male mice to locomotor sedation at higher ETOH doses. In the diallel cross, there was no correlation between the degree of activation produced by low ETOH doses and sedation produced by higher doses. This indicates that while considerable genetic influences exist for both activational and sedative domains of ETOH effects, these genetic influences are relatively independent.

Adult↗
PubMed1991

Use of recombinant inbred strains to assess vulnerability to drug abuse at the genetic level.

The use of Recombinant Inbred mouse Strains (RIS) to derive information about the complexity of the genetic architecture underlying various traits is increasing in popularity. Behaviors measured to index sensitivity to drug effects and vulnerability to drug abuse are considered here. Potential uses of RIS are identification of major gene effects, mapping of traits to particular chromosomal sites, determining genetic correlations between characters, and identifying behaviorally extreme genotypes. This approach has led to identification of a major gene moderating alcohol acceptance in mice and has revealed a more complex polygenic system influencing morphine consumption.

Alcohol Drinking↗
PubMed1991

Locomotor activity response to chronic ethanol treatment in selectively bred FAST and SLOW mice.

FAST and SLOW mice were selectively bred for differential sensitivity to the acute locomotor stimulant effects of alcohol. On average, FAST mice are stimulated by low alcohol doses, while SLOW mice are depressed or unaffected. We report here that, with chronic treatment, SLOW mice develop tolerance to an acute depressant effect, and subsequently exhibit a stimulant response. No evidence was obtained for tolerance to alcohol's stimulant effects during chronic exposure of FAST mice. However, evidence for the development of a sensitized response was found. If locomotor stimulation reflects reinforcement, and models the alcohol-induced euphoria reported by man, perhaps the absence of tolerance development to reinforcing effects provide a strong impetus for the development of alcoholism.

Alcoholism↗
PubMed1991

Cultured epidermal allografts as biological wound dressings.

Recent advances in cell culture technology permit the generation of large stratified epithelial sheets appropriate for wound coverage. Autografts (sheets prepared from the patient's own skin) have proven life-saving in the treatment of large third-degree burns and have been successfully employed in the management of chronic ulcers. Allografts (sheets prepared from the skin of an unrelated donor) have also been used. In our experience, cultured allografts derived from neonatal foreskin provide a potent stimulus to healing in a variety of partial thickness wounds. Their application is a simple outpatient procedure which involves no discomfort for the patient. In contrast to autografting, no biopsy is necessary and use of cultured allogenic cells permits immediate grafts availability and possibility of stockpiling and preserving grafts for future use. Preparation of epithelial sheets suitable for grafting is also faster and easier with newborn than with adult donor cells. Newborn allografts have caused rapid healing of most previously refractory ulcers with long-term results comparable to those obtained with conventional split thickness grafting. We postulate that cultured allografts act by providing a temporary wound covering while releasing multiple cytokines that synergistically promote permanent reepitheliazation by previously quiescent host keratinocytes then stimulated to divide and migrate. Whether allografts are immunologically rejected in a clinically undetectable reaction or simply replaced stochastically by host keratinocytes is presently unknown.

Biological Dressings↗