Varying the rate of intravenous cocaine infusion influences the temporal dynamics of both drug and dopamine concentrations in the striatum

Abstract

The faster drugs of abuse reach the brain, the greater is the risk of addiction. Even small differences in the rate of drug delivery can influence outcome. Infusing cocaine intravenously over 5 vs. 90-100 s promotes sensitization to the psychomotor and incentive motivational effects of the drug and preferentially recruits mesocorticolimbic regions. It remains unclear whether these effects are due to differences in how fast and/or how much drug reaches the brain. Here, we predicted that varying the rate of intravenous cocaine infusion between 5 and 90 s produces different rates of rise of brain drug concentrations, while producing similar peak concentrations. Freely moving male Wistar rats received acute intravenous cocaine infusions (2.0 mg/kg/infusion) over 5, 45 and 90 s. We measured cocaine concentrations in the dorsal striatum using rapid-sampling microdialysis (1 sample/min) and high-performance liquid chromatography-tandem mass spectrometry. We also measured extracellular concentrations of dopamine and other neurochemicals. Regardless of infusion rate, acute cocaine did not change concentrations of non-dopaminergic neurochemicals. Infusion rate did not significantly influence peak concentrations of cocaine or dopamine, but concentrations increased faster following 5-s infusions. We also assessed psychomotor activity as a function of cocaine infusion rate. Infusion rate did not significantly influence total locomotion, but locomotion increased earlier following 5-s infusions. Thus, small differences in the rate of cocaine delivery influence both the rate of rise of drug and dopamine concentrations, and psychomotor activity. A faster rate of rise of drug and dopamine concentrations might be an important issue in making rapidly delivered cocaine more addictive.

Pharmacokinetics trumps pharmacodynamics during cocaine choice: a reconciliation with the dopamine hypothesis of addiction

“…For instance, in a previous study, we reduced the duration of intravenous cocaine infusion from 4 s (which is the duration of infusion used in our drug choice studies, including the present study) to 1 s, but this had no observable impact on drug choice outcomes (unpublished findings). This negative finding was not unexpected, however, since the duration of infusion should have little effect on the time course of drug concentration in the body and the brain, and thus on the delay to cocaine reward, except, of course, when the infusion duration is excessively long [28,64]. Thus, it is not possible to offer rats a drug reward with either a known delay or no delay at all, a limitation that considerably restricts our ability to compare drug rewards with nondrug rewards.…”

Intermittent intake of rapid cocaine injections promotes the risk of relapse and increases mesocorticolimbic BDNF levels during abstinence

“…These effects are likely mediated by differences in the temporal kinetics with which cocaine reaches its sites of action in the brain, rather than by differences in achieved dose. Indeed, varying infusion duration between 5 and 100 s produces differences in the rate of rise of cocaine concentrations in the brain, without producing large effects on peak concentrations [8,9,14].…”

Cocaine-Induced Changes in Tonic Dopamine Concentrations Measured Using Multiple-Cyclic Square Wave Voltammetry in vivo

“…This may again be attributed to the underestimation of baseline in microdialysis, as well as the possibility that cocaine-induced increases in synaptic dopamine may be affected by factors related to the physical presence of the microdialysis probe, such as the formation of a layer of traumatized tissue ( Di Chiara et al, 1993 ; Blaha et al, 1996 ). The rate and dose of drug administration may also have an impact ( Minogianis et al, 2019 ). As mentioned in the Methods section, the rate was controlled at 5-min duration to avoid overdosing.…”