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  • 1
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Cocaethylene is a pharmacologically active metabolite resulting from concurrent cocaine and ethanol consumption. The effects of cocaine and cocaethylene on extracellular levels of dopamine in the nucleus accumbens, and serotonin in the striatum were characterized in vivo in the anesthetized rat. Both intravenous (3 μmol/kg) and intraperitoneal (44 μmol/kg) routes of administration were used. In addition to monitoring neurotransmitter levels, microdialysate levels of cocaine and cocaethylene were determined at 4-min intervals after intravenous administration, and at 20-min intervals after intraperitoneal administration. Extracellular levels of dopamine in the nucleus accumbens were increased to ∼400% of preinjection value by both cocaine and cocaethylene when administered intravenously. Cocaine caused a significant increase of striatal serotonin to 200% preinjection value, whereas cocaethylene had no effect. Brain levels of cocaine and cocaethylene after intravenous administration did not differ. After intraperitoneal administration, extracellular levels of dopamine in the nucleus accumbens were increased to 400% of preinjection levels by cocaine, but were only increased to 200% of preinjection levels by cocaethylene, the difference being statistically significant. Serotonin levels were increased to 360% of preinjection levels by cocaine, but only to 175% of preinjection value by cocaethylene. Levels of cocaine attained in brain were significantly higher than those for cocaethylene, suggesting pharmacokinetic differences with the intraperitoneal route. These results confirm in vivo that cocaethylene is more selective in its actions than cocaine with respect to dopamine and serotonin uptake. In addition, route-dependent differences in attainment of brain drug levels have been observed that may impact on interpretations of the relative potency of the reinforcement value of these compounds.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-1106
    Keywords: MPTP ; Graft ; Behavior ; Parkinson's disease ; Monkey
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Fetal substantia nigra (SN) cells were transplanted into the caudate nucleus (CN) of four vervet monkeys (Cercopithecus aethiops sabaeus) that had been treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP treatment appears to produce a syndrome similar to that observed in patients with idiopathic Parkinson's disease. Normal and parkinsonian behaviors were quantitated by trained observers 5 days/week. Twenty-eight behaviors based on previous factor analyses were individually scored and rated. Parkinsonian signs included freezing, head and limb tremor, difficulty in eating, delayed initiation of movement, poverty of movement, tremor that stopped with intention, decreased response to threats, and lying immobile in the cage. These signs were combined to give an overall rating of parkinsonism. A summary measure of ‘normal’ healthy behavior was also examined, including such behaviors as yawning, scratching, self-grooming, shifting, and eating. Overall ratings of parkinsonism increased and those of healthy behavior decreased after MPTP. In the 4 monkeys grafted with fetal SN cells into the CN, behavior returned to pre-treatment levels by the time of sacrifice (2, 5, or 7.5 months after grafting). Three control subjects were transplanted with either SN cells into an inappropriate brain site (cortex) or inappropriate, non-dopaminergic, cells (cerebellar) into the CN. Subjects were also compared with three control animals that did not receive MPTP but received cryopreserved or fresh SN and other cells into the CN. Only MPTP-treated subjects that received SN cells into the CN showed evidence of a reversal of the MPTP syndrome after transplantation. In addition, grafting in animals that were not MPTP-treated did not appear to affect behavior. This paper reports the specific behavioral effects of severe MPTP toxicity that were or were not reversed after transplantation and suggests that only fetal SN cells grafted into the CN may be able to reverse behavioral deficits in MPTP-treated monkeys.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-2072
    Keywords: Yohimbine ; Morphine ; Naloxone ; Withdrawal ; Tail flick latency ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Noradrenergic neuronal hyperactivity following chronic morphine administration has been postulated to cause withdrawal signs and symptoms. Suppression of this hyperactivity, for example, by clonidine attenuates withdrawal. It might follow, therefore, that the prevention of suppression of noradrenergic systems during chronic morphine administration might diminish hyperactivity and prevent withdrawal. If the normalization of noradrenergic activity during opioid administration did not also suppress analgesia, it might be of medical and theoretical interest. To test this hypothesis, we gave the alpha-2-antagonist yohimbine to rats in order to increase noradrenergic activity during morphine treatment and then subsequently precipitated morphine withdrawal with naloxone. Six groups were examined: saline controls (N=11), morphine (N=11), morphine + 2.0 mg/kg/day yohimbine (N=15), morphine + 3.0 mg/kg/day yohimbine (N=5), 2.0 mg/kg/day yohimbine (N=11) and 3.0 mg/kg/day yohimbine (N=5). Subjects received 75 mg morphine pellets implanted on day 1,4 and 6 of the treatment or sham implantation. Yohimbine was delivered throughout the morphine treatment by subcutaneously implanted osmotic pumps. On day 7, all subjects were given 1.0 mg/kg naloxone and rated for behavioral signs of withdrawal. Analgesia was measured by observing tail flick latencies (TFL) before and after chronic drug treatments. Naloxone-precipitated withdrawal was characterized by irritability, ptosis, penile erection, diarrhea, rhinorrhea, abnormal posture, wetdog shakes, jumping, and teeth chattering, none of which were observed in groups receiving only saline or yohimbine. Withdrawal behavior was attenuated in a dose-dependent manner when yohimbine was administered during morphine treatment but analgesia was not attenuated. It appears that yohimbine-induced antagonism of alpha-2-adrenergic receptors diminishes the development of the potential for adrenergic hyperactivity and morphine withdrawal without reducing opioid analgesia.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1435-1463
    Keywords: Firing rate ; mesocortical dopamine neurons ; tyrosine ; precursor availability ; catecholamine synthesis ; Β-carboline
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Mesocortical dopamine (DA) neurons projecting to the prefrontal and cingulate cortices possess a faster basal firing rate and exhibit more bursting than other midbrain DA neurons. Thus, we examined whether tyrosine administration could preferentially affect DA synthesis in these DA neurons. Tyrosine administered at doses as low as 25 mg/kg significantly increased in vivo tyrosine hydroxylation in the prefrontal and cingulate cortices without affecting it in other mesocortical, mesolimbic, and nigrostriatal DA terminal fields examined. Further studies in the mesoprefrontal DA neurons showed that tyrosine administered at higher doses of 50 mg/kg initially enhanced tyrosine hydroxylation and elevated endogenous DA levels within 60 min. The resultant increases in DA levels appeared to feedback and normalize prefrontal tyrosine hydroxylase activity. The levels of DA metabolites in the prefrontal cortex were unaltered by doses of tyrosine from 25–200 mg/kg, suggesting that the functional transmitter outflow from these DA neurons is not normally affected by precursor administration under resting conditions. However, when these mesocortical DA neurons were pharmacologically activated following administration of the anxiogenic Β-carboline, FG 7142, tyrosine administration (25 mg/kg) was effective in increasing DA metabolite levels in the prefrontal cortex. These results thus suggest that enhanced activity of the mesoprefrontal DA neurons renders these DA neurons much more dependent up on tyrosine availability for maintenance of transmitter output.
    Type of Medium: Electronic Resource
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