Real time computation of in vivo drug levels during drug self-administration experiments

Abstract

A growing body of evidence suggests that the drug concentration in the effect compartment of the body is the major factor regulating self-administration behavior. A novel computer-based protocol was developed to facilitate studies on mechanisms of drug addiction by determining correlations between drug levels and behavior during multiple drug injections and infusions. The core of the system is a user's program written in Medstate Notation language® (Med-Associates, Inc.), which runs the self-administration session (with MED-PC® software and hardware, Med-Associates, Inc.) and calculates the levels of infused and/or injected drugs in real time during the session. From the comparison of classical exponential and simple linear models of first-order kinetics, it is concluded that exponential solutions for the appropriate differential equations may be replaced with linear equations if the cycle of computation is much shorter than the shortest half-life for the drug. The choice between particular computation equations depends on assumptions about the pharmacokinetics of the particular drug: (i) one-, two-or three-compartment model, (ii) zero-, first-or second-order process of elimination, (iii) the constants of distribution and elimination half-lives of the drug are known or can be reasonably assumed, (iv) dependence of the constants on the drug level, and (v) temporal stability of all parameters during the session. This method of drug level computation can be employed not only for self-administration but also for other behavioral paradigms to advance pharmacokinetic/pharmacodynamic modeling.

Rapid EEG desynchronization and EMG activation induced by intravenous cocaine in freely moving rats: a peripheral, nondopamine neural triggering

“…In contrast to pharmacodynamic predictions (55), all of these effects are relatively transient, peaking well within the first postinjection minute, and they are mostly or entirely dose independent. Moreover, COC-induced euphoria, vasoconstriction, and a blood pressure increase remain generally intact during a dopamine (DA) receptor blockade (16,23,41,49), suggesting the importance of non-DA mechanisms.…”

The effects of a repeated dose of a recombinant humanized anti-cocaine monoclonal antibody on cocaine self-administration in rats

“…Buprenorphine (0.03 mg/rat s.c) was administered post-surgery for pain control and gentamycin (25 mg/rat s.c) for three days was used to prevent infection following surgery. Detailed protocols for cocaine self-administration training can be found in (Tsibulsky and Norman, 2005). In brief, beginning at least 5 days after surgery, rats were trained to self-administer cocaine HCl.…”

“…Complete protocols for the calculation of cocaine in the rats’ bodies can be found in Tsibulsky and Norman (2005). Briefly, the drug level in the body was calculated every second using a one-compartment pharmacokinetic model with an assumption of a 500 s elimination half-life of cocaine.…”

Explaining the Escalation of Drug Use in Substance Dependence: Models and Appropriate Animal Laboratory Tests

“…'direct pharmacological') drug effects as opposed to drug 'reinforcement', which per definition requires multiple exposures and associative learning (D.M., however, would argue that FR1 schedules, by requiring the experimental subject to give an all-or-none answer, are very good for determining whether a drug is reinforcing or not). Consequently, FR1 schedules are preferred by those researchers who investigate whether within-session titration of drug levels occurs [9,59,60,175,226,227] but are much less useful -exactly because of confounding acute drug effects on responding -when trying to assess the 'true' reinforcing effects of a drug, i.e. the incentive value of the drug and the incentive salience of drug-associated stimuli ( fig.…”

“…One of the predictions of the reward allostasis model is that, over a large range of unit doses, preresponse brain levels of the self-administered drug should be the same regardless of unit dose, a prediction that is fulfilled for cocaine (see also Andrew Norman's and Vladimir Tsibulsky's experimental work testing their 'satiety threshold' model [226,227] ) but not for the -opioid agonist remifentanil [59] . Preresponse remifentanil levels, obtained 30 min after the start of the self-administration session, were found to be proportional to the remifentanil unit dose over the whole tested 128-fold range [0.00025-0.032 mg/(kg ؒ injection)], the relationship between unit dose and mean levels being saturable ( fig.…”