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.

Keywords: cocaine addiction; in vivo microdialysis; locomotor activity; male Wistar rats; pharmacokinetics.

Figure 1.. The sequence of experimental events.

Panel a illustrates the timeline of experimental events for the in vivo microdialysis study. Rats were implanted with a unilateral cannula into the dorsal striatum and a catheter into the jugular vein. Following recovery, the rats were habituated to the in vivo microdialysis apparatus and to the i.v. infusion procedure on 2 daily sessions. On the following test day, microdialysis probes were inserted into the dorsal striatum and i.v. catheters were tethered to the cocaine infusion set up. Each rat received an i.v. infusion of 2 mg/kg cocaine, delivered over 5, 45 or 90 s, in counterbalanced order, with infusions administered 90 minutes apart. Dialysate samples were collected every minute for 5–10 minutes before each infusion and for 15 minutes thereafter. Panel b shows the sequence of experimental events for the psychomotor activity study. Rats were implanted with an intrajugular catheter and allowed to recover for 7 days. Rats were then habituated to the psychomotor activity cages and i.v. infusion lines on 2 daily sessions. On the following test day, rats were tethered to the cocaine infusion lines and locomotor activity was measured. Each rat received i.v. cocaine (2.0 mg/kg/infusion) delivered over 5, 45 and 90 s, in counterbalanced order, with infusions administered 90 minutes apart.

Figure 2.. Cocaine concentrations detected when microdialysis probes were placed into a solution containing 1 μM cocaine.

Two probes were each transferred from a solution containing aCSF/ascorbic acid to a solution containing aCSF/ascorbic acid/cocaine (1 μM), and back again. All solutions were stirred and tested at room temperature. The data shown are averages (± SEM) from two independent tests carried out with two different probes. Samples were collected at 1-minute intervals, at a flow rate of 2 μL/minute, and analyzed by HPLC-MS/MS. n = 2. μM, micromoles/liter. nM, nanomoles/liter.

Figure 3.. Varying the rate of i.v. infusion between 5–90 s influences the temporal kinetics of extracellular cocaine and dopamine concentrations in the dorsal striatum.

The location of microdialysis probes in the striatum is shown in panel (a). The distance in millimeters (mm) from Bregma is given for each coronal rat brain section. The white boxes at the tips of each probe indicate the segment where glue was applied, and where no exchange is possible. Panels (b) and (c) show striatal cocaine and dopamine concentrations over time, respectively, as a function of i.v. drug infusion rate. All values are mean ± SEM. n = 7 rats/infusion rate. DS, Dorsal Striatum, NacC, Nucleus Accumbens Core, NAcSh, Nucleus Accumbens Shell, nM, nanomoles/liter. s, seconds.

Figure 4.. Varying the rate of i.v. infusion between 5–90 s influences the rate of rise of cocaine and dopamine concentrations (Tmax) in the dorsal striatum without producing large effects on maximum concentrations (Cmax).

Panels (a) and (b) show average Cmax values for cocaine and dopamine, respectively, as a function of the rate of i.v. cocaine infusion. The time to reach peak concentrations (Tmax) of cocaine (c) and dopamine (d) in the dorsal striatum is shown as a function of the rate of i.v. cocaine delivery. Panels (e) and (f) show the time interval before cocaine and dopamine concentrations were significantly greater than baseline levels (> 2 standard deviations above baseline), as a function of the rate of i.v. cocaine delivery. All values are mean ± SEM. n = 7 rats/infusion rate. *P < 0.05 compared to 90 s. nM, nanomoles/liter. s, seconds.

Figure 5.. Extracellular dopamine and cocaine concentrations in the dorsal striatum are linearly correlated.

Panels (a-c) show extracellular concentrations of dopamine and cocaine over time from representative rats, for each i.v. infusion rate. Panel (d) shows a significant positive correlation between dopamine and cocaine concentrations in the dorsal striatum, at each sampling time, across all rats and infusion rates. For this analysis, we used linear regression to model the relationship between dopamine concentrations and cocaine concentrations at each of the 15 post-cocaine samples. n = 7 rats/infusion rate. nM, nanomoles/liter. s, seconds.

Figure 6.. The influence of the rate of i.v. cocaine infusion on locomotor activity.

Locomotor activity (beam breaks per minute) as a function of i.v. drug infusion rate. Saline-induced locomotor activity is also shown for comparison. The shading highlights the first minute after cocaine, where locomotor activity was greater after a 5-s injection than after a 90-s injection. All values are mean ± SEM. n = 12 rats/infusion rate. s, seconds.