PubMed · 14137170
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J MELON. 1964-02-01. [NOSE DROPS].. https://pubmed.ncbi.nlm.nih.gov/14137170/
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Volatile organic solvents, fuels and anesthetics are subject to abuse. The aim of the present study was to evaluate i.v. self-administration of several of these chemicals in drug- and experiment-naive mice using a commercially available vehicle, intralipid. Two strains of mice (DBA/2 and Swiss) were allowed to self-administer toluene (0.0017-0.17 micromol/infusion), 1,1,1-trichloroethane (0.006-0.19 micromol/infusion), ethanol (0.32-1.6 micromol/infusion), cyclohexane (0.0017-0.052 micromol/infusion), propofol (0.01-0.53 micromol/infusion) and flurothyl (0.00042-0.072 micromol/infusion) or their vehicles during 30-min tests. During the test, each nose-poke of the master mouse resulted in a 1.88-microl i.v. infusion to the master mouse and a yoked control mouse. When the delivery line was loaded with a reinforcing drug solution, the number of nose-pokes of the master mice significantly exceeded that for yoked control mice. In the present experiments, significant differences in rates of nose-poking were observed between mice receiving response-contingent and response-noncontingent deliveries of ethanol and toluene in both strains of mice and of 1,1,1-trichloroethane in Swiss mice. These data suggest that the reinforcing effects of abused inhalants can be studied using i.v. self-administration procedures.
BACKGROUND: Some limitations of traditional ("mamillary") compartmental pharmacokinetic models of anaesthetic related drugs arise from representing the blood as a central compartment. Recirculatory pharmacokinetic models overcome these limitations. It is proposed that the simplest recirculatory model has only two compartments, and that understanding the properties of this model is a useful introduction to recirculatory pharmacokinetic concepts. METHODS: The compartments of the model are the lungs and the remainder of the body. The traditional rate constants (e.g. k12 and k21) are replaced by terms that include cardiac output. Drug infusion is into the lung compartment, and drug clearance is from the "body" compartment. The "total" drug concentrations can be thought of as the sum of the first-pass and recirculated drug concentrations at any time. Equations for both first-pass and total drug concentrations in arterial and mixed venous blood are presented. The effects of cardiac output and injection time on these concentrations were analysed. RESULTS: The first-pass arterial concentrations were shown to make a significant contribution to the total concentrations for high-clearance drugs and/or bolus drug administration. There was an inverse relationship between these first-pass concentrations and cardiac output, and a direct relationship with bolus injection rate. Thus, the total arterial concentrations are affected by these factors in these circumstances. CONCLUSIONS: The two-compartment recirculatory model is the simplest tool available for elaborating recirculatory pharmacokinetic concepts. The recirculatory approach may provide a conceptual framework of drug disposition that better matches the clinical experience of anaesthetists.
RATIONALE: Although positive modulators of gamma-aminobutyric acid(A) (GABA(A)) receptors generally produce similar behavioral effects, regardless of which modulatory site on the GABA(A) receptor complex mediates these effects, some differences have been observed between the effects of neuroactive steroids and those of other positive GABA(A) modulators. OBJECTIVE: The current study was designed to compare the behavioral effects of a neuroactive steroid to those of other positive GABA(A) modulators. METHODS: Rats responded under a multiple schedule of repeated acquisition and performance of response chains, with responding maintained under a second-order fixed-ratio 2 schedule of food presentation. RESULTS: Pregnanolone, flunitrazepam, pentobarbital and ketamine, an antagonist at NMDA receptors, dose-dependently decreased response rates and increased the percentage of errors in both components of the multiple schedule. Although the rate-decreasing and error-increasing effects of pregnanolone, pentobarbital and ketamine were quantitatively similar to each other, flunitrazepam was less effective in decreasing response rates and more effective in increasing errors than the other three drugs. A dose of 3.2 mg/kg pregnanolone potentiated the effects of flunitrazepam and pentobarbital, producing 2- to 3-fold shifts to the left in the dose-effect curves. In contrast, pregnanolone did not alter the ketamine dose-effect curves. CONCLUSIONS: The disruptive effects of the neuroactive steroid pregnanolone are qualitatively similar to those of other positive GABA(A) modulators as well as ketamine; however, the potentiation of the effects of flunitrazepam and pentobarbital, and not ketamine, emphasizes the importance of GABA(A) receptors in the behavioral effects of pregnanolone.