Brain-Cocaine Concentrations Determine the Dose Self-Administered by Rats on a Novel Behaviorally Dependent Dosing Schedule

Abstract

A novel behaviorally dependent dosing (BDD) schedule was used to examine the relationship between doses of cocaine selfadministered by rats and brain drug levels within a session. The BDD schedule used a hold-down response to activate a syringe pump. The length of time the lever was held down determined the duration that the syringe pump was activated. In the first experiment, rats self-administered cocaine for daily 3 h sessions and brain levels of cocaine were modeled using well-established parameters. Although analysis revealed that rats self-administered doses within a predicted range, one extremely large dose was consistently observed at the beginning of each session when brain levels of cocaine were low. In the second experiment, we introduced a range of timeout periods (10-25 min) in order to produce variability in brain-cocaine concentrations. Animals self-administered larger doses immediately following each timeout period and the dose size was inversely correlated with the length of the timeout. These results show that the dose of cocaine that rats self-administer within a session is inversely related to the amount of drug on board.

The Motivation to Self-Administer is Increased After a History of Spiking Brain Levels of Cocaine

“…usually in the beginning of the trial and in a relatively short period of time (B60 s). This pattern is consistent with our previous report (Zimmer et al, 2011) showing that rats rapidly self-administer large doses of drug when blood levels have been forced to low levels. These results suggest that rapid spiking of brain-cocaine levels is sufficient to increase Pmax.…”

“…The pattern of intake was virtually identical between the IntA-HD and the IntA-FR groups. Subjects were observed to selfadminister large doses (43.0 mg/kg) mostly in the first minute of the trial as previously described (Zimmer et al, 2011). It is important to note that the IntA-FR animals had no timeouts within their 5-min access period allowing them to self-administer clusters of injections at the beginning of the access period in a similar manner as the IntA-HD group.…”

“…Rats were given daily 3-h sessions until the response pattern stabilized (which generally took 2-3 days). After they had acquired the HD response, the schedule was switched to an IntA schedule in which subjects were given access to the retractable HD lever for twelve 5-min access periods on the HD schedule as previously described (Zimmer et al, 2011). In between each 5-min trial, a 25-min timeout period was enforced during which the lever was retracted.…”

“…Brain-cocaine concentrations were calculated as previously described (Zimmer et al, 2011) using equations employed by Pan et al (1991). Briefly, the equation c ¼ dk vða À bÞ ðe Àbt À e Àat Þ estimates the amount of cocaine in the brain compartment at time t. This equation accounts for the dose of cocaine (d), the transfer of cocaine between the blood and the brain (k ¼ 0.233 min À1 ), the apparent brain volume (v ¼ 0.15 l kg À1 ), and the removal of cocaine from the blood through redistribution (a ¼ 0.642 min À1 ) and elimination (b ¼ 0.097 min À1 ).…”

“…Rats were given intermittent access (IntA) to cocaine during 5-min trials that alternated with 25-min timeout periods. This IntA procedure, which was developed while investigating the relationship between the preferred dose of cocaine and the amount of drug on board, results in substantial fluctuations in cocaine brain levels (Zimmer et al, 2011). The IntA procedure offers the opportunity to test whether maintained levels are necessary for a change in addiction phenotype and whether rapid spikes in brain levels are sufficient.…”