Body weight, gender and pregnancy affect enantiomer-specific ketorolac pharmacokinetics.

AIMS: Although ketorolac analgesia is linked only to the S-enantiomer, there is limited information on the stereo-selective pharmacokinetics of this agent. We studied the stereo-selective pharmacokinetics of ketorolac in a pooled dataset of two studies, with women at delivery and 4-5 months postpartum, and males and nonpregnant females. METHODS: Nonlinear mixed-effect modelling was used to evaluate the stereo-selective pharmacokinetics of ketorolac tromethamine after a single intravenous injection immediately after delivery (n = 41), 4-5 months postpartum (n = 8, paired), and in male (n = 12) and nonpregnant female (n = 14) subjects. All of the males and six of the nonpregnant females were recruited from another study, in which they were undergoing blood sampling for 24 h. All remaining cases underwent blood sampling for 8 h. RESULTS: For both the R- and S-enantiomers, body weight affected ketorolac clearance. In addition, clearance for both enantiomers was 36% [95% confidence interval (CI) 15%, 58%] higher in male than in female subjects of the same body weight, and 55% (95% CI 33%, 78%) higher in women at delivery than in nonpregnant women of the same body weight. Women at delivery also had a 27% (95% CI 8%, 46%) higher distribution volume than nonpregnant women. The proportional effects of the covariates were not significantly different for the two ketorolac enantiomers. CONCLUSIONS: Besides the anticipated impact of body weight on clearance, R- and S-ketorolac clearance is increased in male subjects and in women at delivery. To reach an exposure equivalent to that in nonpregnant women, males should receive a 36% increased ketorolac dose and pregnant women a 55% increased dose, in addition to a dose adjustment by body weight.

Enhanced Extracellular Glutamate and Dopamine in the Ventral Pallidum of Alcohol-Preferring AA and Alcohol-Avoiding ANA Rats after Morphine.

The purpose of the present study was to investigate the role of ventral pallidal opioidergic mechanisms in the control of ethanol intake by studying the effects of acute administration of morphine on the levels of GABA, glutamate, and dopamine in the ventral pallidum. The study was conducted using the alcohol-preferring Alko Alcohol (AA) and alcohol-avoiding Alko Non-Alcohol (ANA) rat lines that have well-documented differences in their voluntary ethanol intake and brain opioidergic systems. Therefore, examination of neurobiological differences between the lines is supposed to help to identify the neuronal mechanisms underlying ethanol intake, since selection pressure is assumed gradually to lead to enrichment of alleles promoting high or low ethanol intake, respectively. The effects of an acute dose of morphine (1 or 10 mg/kg s.c.) on the extracellular levels of GABA and glutamate in the ventral pallidum were monitored with in vivo microdialysis. The concentrations of GABA and glutamate in the dialyzates were determined with a high performance liquid chromatography system using fluorescent detection, while electrochemical detection was used for dopamine. The levels of glutamate in the rats injected with morphine 1 mg/kg were significantly above the levels found in the controls and in the rats receiving morphine 10 mg/kg. Morphine 10 mg/kg also increased the levels of dopamine. Morphine could not, however, modify the levels of GABA. The rat lines did not differ in any of the effects of morphine. The data suggest that the glutamatergic and dopaminergic systems in the ventral pallidum may mediate some effects of morphine. Since there were no differences between the AA and ANA lines, the basic hypothesis underlying the use of the genetic animal model suggests that the effects of morphine detected probably do not underlie the different intake of ethanol by the lines and contribute to the control of ethanol intake in these animals.

Role for ventral pallidal GABAergic mechanisms in the regulation of ethanol self-administration.

RATIONALE: The striatopallidal medium spiny neurons have been viewed as a final common path for drug reward, and the ventral pallidum (VP) as a convergent point for hedonic and motivational signaling. The medium spiny neurons are GABAergic, but they colocalize enkephalin. OBJECTIVE: The present study investigated the role of the GABAergic mechanisms of the VP in ethanol consumption. METHODS: The effects of bilateral microinjections of GABA(A) and GABA(B) receptor agonists and antagonists into the VP on voluntary ethanol consumption were monitored in alcohol-preferring Alko alcohol rats given 90 min limited access to ethanol in their home cages every other day. The influences of coadministration of GABA and opioid receptor modulators were also studied. RESULTS: The GABA(A) receptor agonist muscimol (1-10 ng/site) decreased ethanol intake dose-dependently, while administration of the GABA(A) receptor antagonist bicuculline (10-100 ng) had an opposite effect. The GABA(B) receptor agonist baclofen (3-30 ng) also suppressed ethanol intake, but the GABA(B) receptor antagonist saclofen (0.3-3 µg) failed to modify it. Animals coadministered with bicuculline (30 ng) and baclofen (30 ng) consumed ethanol significantly less than those treated with bicuculline alone. Coadministration of the µ-receptor agonist D-Ala2,N-Me-Phe4,Glyol5-enkephalin (DAMGO, 0.1 µg) with bicuculline counteracted, whereas the µ-receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP, 1 µg) enhanced the bicuculline-induced increase of ethanol intake. When given alone, DAMGO decreased while CTOP increased ethanol intake. CONCLUSIONS: The study provides evidence for the ventral pallidal GABAergic mechanisms participating in the regulation of ethanol consumption and supports earlier work suggesting a role for pallidal opioidergic transmission in ethanol reward.

Opioidergic modulation of ethanol self-administration in the ventral pallidum.

BACKGROUND: Striatopallidal medium spiny neurons have been viewed as a final common path for drug reward and the ventral pallidum as an essential convergent point for hedonic and motivational signaling in the brain. The medium spiny neurons are GABAergic, but they colocalize enkephalin. Purpose of this study was to investigate the role of the opioidergic mechanisms of the ventral pallidum in ethanol self-administration behavior. METHODS: Effects of bilateral microinjections of µ-, δ-, and κ-opioid receptor agonists and antagonists into the ventral pallidum on voluntary ethanol consumption were monitored in alcohol-preferring Alko Alcohol (AA) rats using the 90-minute limited access paradigm. RESULTS: Stimulation of µ-opioid receptors with DAMGO (0.01 to 0.1 µg) or morphine (1 to 10 µg) in the ventral pallidum decreased ethanol intake dose-dependently. Conversely, blocking µ-receptors with CTOP (0.3 to 3 µg) increased ethanol intake significantly. Unlike CTOP, DAMGO also increased locomotor activity. Consumption of ethanol was not modified significantly by a broad-spectrum opioid receptor antagonist naltrexone, by δ-opioid receptor agonist DPDPE or antagonist naltrindole, or by a κ-opioid receptor agonist U50,488H or antagonist nor-BNI. CONCLUSIONS: The study provides evidence for µ- but not δ- or κ-opioid receptors in the ventral pallidum playing a role in the regulation of voluntary ethanol consumption. Furthermore, present findings give support to earlier work, suggesting an essential role of pallidal opioidergic transmission in drug reward.

GABA and glutamate overflow in the VTA and ventral pallidum of alcohol-preferring AA and alcohol-avoiding ANA rats after ethanol.

AIMS: Earlier findings suggest that dopaminergic neurons are probably not critically involved in ethanol self-administration behavior and in the differential intake of ethanol by the alcohol-preferring AA (Alko Alcohol) and non-preferring ANA (Alko Non-Alcohol) rat lines selected for differential ethanol intake. The purpose of the present study was, therefore, to clarify the role of GABAergic and glutamatergic afferents and efferents with the mesolimbic dopamine system in the control of ethanol intake as well as in differential intake of ethanol by AA and ANA rats. METHODS: The effects of an acute dose of ethanol (1 or 2 g/kg i.p.) on the levels of GABA and glutamate in the ventral pallidum and the ventral tegmental area of AA and ANA rats were monitored with in vivo microdialysis. The concentrations of GABA and glutamate in the dialysates were determined with a high performance liquid chromatography system using fluorescent detection. RESULTS: Ethanol significantly decreased the extracellular levels of GABA in the ventral pallidum but not in the ventral tegmental area. The ANA rats were more sensitive than the AA rats to the suppressive effect of ethanol on pallidal GABA levels. Ethanol did not have any effect on the concentrations of glutamate in either rat line. CONCLUSIONS: The suppressive effect of ethanol on the extracellular levels of GABA in the ventral pallidum suggests a role for pallidal GABAergic transmission in the control of ethanol consumption.

Behavioral consequences of repeated nicotine during adolescence in alcohol-preferring AA and alcohol-avoiding ANA rats.

BACKGROUND: Epidemiological studies suggest that exposure to nicotine at adolescent age is associated with increased potential to use alcohol and that genetic predisposition may further increase the risk. The present study addressed adolescent vulnerability to repeated nicotine exposure and its influence on subsequent ethanol self-administration by investigating interactions between nicotine-induced behavioral sensitization and voluntary ethanol consumption in alcohol preferring AA (Alko Alcohol) and alcohol nonpreferring ANA (Alko Non-Alcohol) rat lines selected for differential ethanol intake. METHODS: Adolescent and adult rats received 10 injections of nicotine (0.5 mg/kg s.c.), given every second day from postnatal day (Pnd) 27 and 75, respectively. Nicotine-induced (0.5 mg/kg) locomotor activity was measured acutely after the first injection, and after the repeated treatment with nicotine on Pnds 52 and 86 in the adolescent groups and on Pnd 99 in the adult groups. After this, acquisition of voluntary ethanol (10% v/v) consumption as well as nicotine-induced (0.5 mg/kg) ethanol intake was measured in the AA rats. RESULTS: Adolescent AA rats were more sensitive than adolescent ANA rats to the locomotor effects of nicotine. They were also stimulated more than adult AA rats, but such a difference was not found among ANA rats. Adolescent and adult rats did not differ in their susceptibility to nicotine-induced behavioral sensitization. Genetic predisposition to ethanol self-administration did not interact with development of behavioral sensitization in either adolescents or adults. Acquisition of ethanol intake was enhanced in the adolescent groups relative to the adult groups in a manner that was independent of the nicotine treatment. An increase in ethanol intake was found after challenging animals with nicotine, and this effect was enhanced in the nicotine-treated adolescent group. CONCLUSIONS: These findings provide no or little support for the views that adolescent animals are more sensitive to the neurobehavioral effects of repeated exposure to nicotine and that exposure to nicotine in adolescence may contribute to enhanced vulnerability to ethanol abuse. Furthermore, genetic predisposition to high or low ethanol self-administration does not seem to be a factor that influences individual vulnerability to the neurobehavioral effects of repeated administration of nicotine.