Biomedical subjects

Pawel Mierzejewski

Publications and source records attributed to Pawel Mierzejewski.

7 recordsLinked to original sources

PubMed2006

Rapid and robust protection against cocaine-induced lethality in rats by the bacterial cocaine esterase.

There is no approved means to prevent the toxic actions of cocaine. Cocaine esterase (CocE) is found in a rhodococcal strain of bacteria that grows in the rhizosphere soil around the coca plant and has been found to hydrolyze cocaine in vitro. The esteratic activity of CocE (0.1-1.0 mg, i.v.) was characterized and confirmed in vivo by assessing its ability to prevent cocaine-induced convulsions and lethality in the rat. The therapeutic efficiency of the enzyme was demonstrated by the increasing dose of cocaine (100-1000 mg/kg, i.p.) required to produce toxic effects after a single intravenous injection of CocE. The enzyme demonstrated rapid kinetics for cocaine degradation in rat and human serum. Two catalytically inactive mutants of CocE (S117A or Y44F) failed to protect rats from the toxic effects of cocaine, confirming the protective effects are due to hydrolytic activity. However, butyrylcholinesterase, an endogenous cocaine-hydrolyzing enzyme, was inactive (1.3-13 mg, i.v.) in this rat toxicity procedure. Furthermore, CocE did not block the lethality of WIN-35065-2 (560 mg/kg, i.p.), a cocaine analog that lacks the benzoyl ester moiety targeted by CocE. This characterization of CocE provides preliminary evidence that the enzyme could serve as a suitable antidote to cocaine toxicity in humans.

Animals↗

PubMed2006

Cycloheximide impairs acquisition but not extinction of cocaine self-administration.

The aim of the present study was to assess the role of de novo protein synthesis in the acquisition and extinction of cocaine self-administration. In a first experiment, rats were trained to respond for intravenous cocaine infusions (0.3 mg/kg) and a protein synthesis inhibitor, cycloheximide (CHX; 3 mg/kg, s.c.) was injected immediately after each self-administration session. In a second experiment, rats were allowed to acquire cocaine self-administration and CHX was injected immediately after subsequent extinction sessions. CHX impaired the acquisition, but not extinction, of cocaine self-administration. In control experiments, CHX (3 mg/kg) blocked c-Fos protein expression after foot-shock stress and impaired the acquisition of conditioned freezing but did not inhibit spontaneous locomotor activity and sucrose drinking. Our results suggest that: i) the acquisition and extinction of cocaine-reinforced behaviour have a different molecular basis; and ii) only the former process requires de novo protein synthesis.

Animals↗

PubMed2004

Dissociation of ethanol and saccharin preference in fosB knockout mice.

The Fos family of transcription factors may play a key role in various forms of brain plasticity. Among different genes coding Fos proteins is the fosB gene. Protein products of the fosB gene are thought to be critically involved in neural adaptations produced by chronic treatment with drugs of abuse. fosB gene transcription leads to accumulation of full-length FosB as well as its truncated form, deltafosB. Stable isoforms of deltafosB called chronic FRAs accumulate in the brain after chronic administration of various drugs of abuse. The purpose of the present study was to evaluate the role of the fosB gene in two-bottle choice ethanol self-administration. For this aim, ethanol (2-8% v/v) intake and preference was assessed in fosB mutant (n=17) and wild-type (WT) mice (n=16). For comparison, consumption of saccharin (0.05-0.8% w/v) and quinine (15-960 microM) solutions was assessed in the same animals. Ethanol preference in both groups varied from around 50% for the lowest to 20% for the highest ethanol concentration. Neither ethanol intake (g/kg) nor preference differed between the two genotypes. In contrast, saccharin preference, but not intake, was higher in the fosB mutants. Only slight and inconsistent between-group differences were observed in terms of quinine preference. The present results suggest that permanent elimination of fosB gene products does not alter ethanol intake but may enhance preference for sweet solutions in mice.

Alcohol Drinking↗

PubMed2004

Time-dependent changes in alcohol-seeking behaviour during abstinence.

Exposure of alcohol addicts to alcohol-related environmental cues may elicit alcohol-seeking behaviour even after protracted abstinence. The purpose of the present study was to assess time-dependent changes in alcohol-seeking behaviour in rats trained to respond for alcohol. The rats were re-exposed to alcohol-associated stimuli after 1, 28 or 56 days of withdrawal. During the re-exposure session, the rats were first allowed to respond in extinction. Then, reinstatement of alcohol-seeking behaviour was evoked by a complex of discrete alcohol-associated cues (auditory and light cues combined with taste and smell of alcohol). Extinction behaviour depended on abstinence duration with maximal responding after 28-day abstinence. Reinstatement of alcohol-seeking behaviour evoked by the discrete cues was highest after 56-day abstinence. No correlations were found between individual alcohol intakes, extinction behaviour and cue-induced reinstatement. These results suggest that: (i) alcohol-seeking behaviour may become more intense after long-term imposed abstinence; (ii) alcohol self-administration, extinction behaviour, and reinstatement of alcohol-seeking behaviour may be regulated by separate neural mechanisms.

Alcoholism↗

PubMed2003

Chorda tympani nerve transection does not alter operant oral self-administration of ethanol in the rat.

In experimental conditions, it has been suggested that taste factors may contribute to ethanol preference in rodents. The aim of the current study was to assess the effects of transection of a gustatory branch of the seventh cranial nerve, the chorda tympani (CT), on operant self-administration of ethanol in rats. Male Wistar rats were trained to lever press for 8% [volume/volume (vol./vol.)] ethanol solution. When 8% ethanol intake stabilized, the CT nerve was transected bilaterally in six subjects. Another group received sham operations. There were no between-group differences in terms of self-administration of 8% ethanol, either before or after surgery. In addition, self-administration of 2% and 4% ethanol, measured after surgery, did not differ between the groups. In a control experiment, two-bottle consumption of as well as preference for 0.625% [weight/volume (wt./vol.)] sucrose were significantly decreased in the lesioned subjects. The results may indicate that gustatory input of the CT nerve is not necessary for maintenance of operant oral self-administration of ethanol.

Animals↗

PubMedDate not supplied

Ethanol-reinforced behaviour predicts acquisition but not extinction of cocaine self-administration in the rat.

AIMS: The aim of the present study was to evaluate the relationship between operant oral ethanol self-administration and intravenous (i.v.) cocaine self-administration in male Wistar rats. METHODS: Twenty-four rats were trained to lever press for 8% v/v ethanol in the sucrose-fading procedure. The subjects with the highest (high ethanol responders [HER], n = 7) and lowest (low ethanol responders [LER], n = 7) ethanol intakes were selected for further experiments. After a wash-out period, during which i.v. catheters were implanted, the HER and LER were trained to nose-poke for cocaine infusions (0.33 mg/kg/infusion, a FR1 schedule) for nine daily sessions. RESULTS: The HER emitted more 'active' nose-pokes and obtained more cocaine infusions during sessions 2-4. Drug-seeking behaviour in the absence of cocaine reinforcement was then assessed for three consecutive extinction sessions. No between-group differences were found in terms of extinction of cocaine seeking. Locomotor responses to a novel environment were also similar in both groups. CONCLUSIONS: The present results suggest that a propensity to self-administer ethanol predicts more rapid acquisition of cocaine self-administration behaviour but does not influence subsequent behaviour during extinction.

Animals↗

PubMedDate not supplied

Intravenous self-administration of morphine and cocaine: a comparative study.

The aim of the present study was to estimate differences between patterns of morphine and cocaine use in Sprague-Dawley rats. This was done by first developing a set of conditions under which both drugs would be consistently self-administered over time. Subsequently rats were studied in groups of three, with only one rat actively self-administering morphine or cocaine while others two receiving yoked injections of either the drug or saline. With the exception of the 0.056, 0.1, 0.3 and 1.0 mg/kg/inj. training-dose regimens, intravenous (i..v.)self-administration of morphine was acquired at the dose of 0.56 mg/kg/inj. and subsequently maintained by rats. In contrast to morphine self-administration, rats rapidly acquired cocaine self-administration behavior at either the 0.3 or 0.56 injection dose and showed typical inverted U-shaped dose-response curves with maximal responding occurring at the injection dose of 0.3 mg/kg. With the "yoked" pairs of subjects, the rate of responding of the animal actually self-administering the drug was significantly higher than that of a paired animal which passively received injection whenever the first animal self-administered the drug. Thus, both morphine and cocaine served as a positive reinforcer of self-administration behavior under the fixed ratio 5 schedule of reinforcement. However, the 0.56 mg/kg injection dose of morphine resulted in an acquisition curve that was markedly, temporally delayed relative to the injection dose of cocaine. Finally, cocaine maintained higher rates of responding for its delivery than morphine. These differences between self-administration patterns of morphine and cocaine may provide significant information about the nature of drug reinforcement and dependence.

Animals↗