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

• Published in: The European journal of neuroscience 2019-08, Vol.50 (3), p.2054-2064
• Main Authors: Minogianis, Ellie‐Anna, Shams, Waqqas M., Mabrouk, Omar S., Wong, Jenny‐Marie T., Brake, Wayne G., Kennedy, Robert T., Souich, Patrick, Samaha, Anne‐Noël
• Format: Article
• Language: English
• Subjects: Animal behavior; Caudate-putamen; Cocaine; cocaine addiction; Dopamine; Dopamine receptors; Drug abuse; Drug delivery; Influence; Intravenous administration; in vivo microdialysis; Liquid chromatography; Locomotion; locomotor activity; male Wistar rats; Mass spectroscopy; Microdialysis; Neostriatum; pharmacokinetics; Rodents
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.13941

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. Varying the rate of i.v. cocaine delivery between 5 and 90 s determines the drug's effects on brain and behaviour. We show that injecting cocaine between 5 and 90 s in rats alters the rates of rise of cocaine and dopamine in the dorsal striatum, without significantly changing peak concentrations. Faster injections also increase locomotor behaviour earlier than slower injections. Thus, beyond achieved dose, differences in the rates of rise of cocaine and dopamine can determine outcome.