Abstract
Oral, intraperitoneal, or intravenous have been the common routes of administration used to study the behavioral and neurochemical pharmacology of caffeine, one of the most widely used psychoactive substances worldwide. We have reported that caffeine is an active adulterant frequently found in coca-paste (CP)-seized samples, a highly addictive form of smokable cocaine. The role of caffeine in the psychostimulant and neurochemical effects induced by CP remains under study. No preclinical animal studies have been performed so far to characterize the effects of caffeine when it is administered through the pulmonary inhalation route. Caffeine (10, 25, and 50 mg) was volatilized and rats were exposed to one inhalation session of its vapor. The stimulant effect was automatically recorded and plasmatic levels of caffeine were measured. Caffeine capability (50 mg) to increase extracellular dopamine (DA) levels in nucleus accumbens shell was also studied by in vivo microdialysis in non-anesthetized animals. A dose-dependent stimulant effect induced by volatilized caffeine was observed and this effect was directly related with caffeine plasmatic levels. A significant increase in the extracellular DA was achieved after 50 mg of volatilized caffeine exposure. This is the first report showing pharmacological acute effects of caffeine through the pulmonary inhalation route of administration and suggests that this could be a condition under which caffeine can elevate its weak reinforcing effect and even enhance the psychostimulant effect and abuse liability of smokable adulterated psychostimulant drugs.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Acquas E, Tanda G, Di Chiara G (2002) Differential effects of caffeine on dopamine and acetylcholine transmission in brain areas of drug-naive and caffeine-pretreated rats. Neuropsychopharmacol 27:182–193
Broséus J, Gentile N, Esseiva P (2016) The cutting of cocaine and heroin: a critical review. Forensic Sci Int 262:73–83
Cauli O, Morelli M (2005) Caffeine and the dopaminergic system. Behav Pharmacol 16:63–77
Cole C, Jones L, Mcveigh J, Kicman A, Syed Q, Bellis M (2011) Adulterants in illicit drugs: a review of empirical evidence. Drug Test Anal 3:89–96
De Luca M, Bassareo V, Bauer A, Di Chiara G (2007) Caffeine and accumbens shell dopamine. J Neurochem 103:157–163
Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85:5274–5278
Díaz-Mataix L, Scorza MC, Bortolozzi A, Toth M, Celada P, Artigas F (2005) Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: role in atypical antipsychotic action. J Neurosci 25(47):10831–10843
Evrard I, Legleye S, Cadet-Taïrou A (2010) Composition, purity and perceived quality of street cocaine in France. Int J Drug Policy 1(5):399–406
Ferré S (2008) An update on the mechanisms of the psychostimulant effects of caffeine. J Neurochem 105(4):1067–1079
Ferré S (2016) Mechanisms of the psychostimulant effects of caffeine: implications for substance use disorders. Psychopharmacology. doi:10.1007/S00213-016-4212-2
Fredholm BB, Svenningsson P (2003) Adenosine-dopamine interactions: development of a concept and some comments on therapeutic possibilities. Neurology 61:S5–S9
Fukushima AR, Carvalho VM, Carvalho DG, Diaz E, Bustillos JO, Spinosa HD et al (2014) Purity and adulterant analysis of crack seizures in Brazil. Forensic Sci Int 243C:95–98
Galvalisi G, Prieto JP, Martínez M, Abin-Carriquiry JA, Scorza C (2015) Smoked cocaine: chemical analysis of seized samples and the role of caffeine in its central actions. In: IBRO 9th World Congress, Rio de Janeiro. http://ibro.info/events/meetings/
Garrett B, Griffiths R (1997) The role of dopamine in the behavioral effects of caffeine in animals and humans. Pharmacol Biochem Behav 57:533–541
González CR, González B, Matzkin ME, Muñiz JA, Cadet JL, Garcia-Rill E, Urbano FJ, Vitullo AD, Bisagno V (2015) Psychostimulant-induced testicular toxicity in mice: evidence of cocaine and caffeine effects on the local dopaminergic system. Plos One 10(11):e0142713
Gossop M, Griffiths P, Powis B, Strang J (1992) Severity of dependence and route of administration of heroin, cocaine and amphetamines. Br J Addict 87:1527–1536
Gostic T, Klemenc S, Stefane B (2009) A study of the thermal decomposition of adulterated cocaine samples under optimized aerobic pyrolytic conditions. Forensic Sci Int 187:19–28
Griffiths RR, Woodson PP (1988) Reinforcing properties of caffeine: studies in humans and laboratory animals. Pharmacol Biochem Behav 29(2):419–427
Harris JL, Munsell CR (2015) Energy drinks and adolescents: what’s the harm? Nutr Rev 73(4):247–257
Herculiani PP, Pires-Neto RC, Bueno HM, Zorzetto JC, Silva LC, Santos AB, Garcia RC, Yonamine M, Detregiachi CR, Saldiva PH, Mauad T (2009) Effects of chronic exposure to crack cocaine on the respiratory tract of mice. Toxicol Pathol 37(3):324–332
Hoffman RS, Kirrane BM, Marcus SM (2008) A descriptive study of an outbreak of clenbuterol-containing heroin. Ann Emerg Med 52(5):548–553
Kalivas P, Volkow N (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162:1403–1413
Khairnar A, Plumitallo A, Frau L, Schintu N, Morelli M (2010) Caffeine enhances astroglia and microglia reactivity induced by 3,4-methylenedioxymethamphetamine (‘ecstasy’) in mouse brain. Neurotox Res 17(4):435–439
Koob G, Bloom F (1988) Cellular and molecular mechanisms of drug dependence. Science 242:715–723
López-Hill X, Prieto J, Meikle M, Urbanavicius J, Abín-Carriquiry A, Prunell G, Umpiérrez E, Scorza C (2011) Coca-paste seized samples characterization: chemical analysis, stimulating effect in rats and relevance of caffeine as a major adulterant. Behav Brain Res 221:134–141
Malave LB, Broderick PA (2014) Caffeine’s attenuation of cocaine-induced dopamine release by inhibition of adenosine. J Caffeine Res 4(2):35–40
Mcnamara R, Kerans A, O’neill B, Harkin A (2006) Caffeine promotes hyperthermia and serotonergic loss following co-administration of the substituted amphetamines, MDMA (“Ecstasy”) and MDA (“Love”). Neuropharmacology 50(1):69–80
Morelli M, Simola N (2011) Methylxanthines and drug dependence: a focus on interactions with substances of abuse. Handb Exp Pharmacol 200:483–507
Muñiz JA, Gomez G, González B, Rivero-Echeto MC, Cadet JL, García-Rill E, Urbano FJ, Bisagno V (2016) Combined effects of simultaneous exposure to caffeine and cocaine in the mouse striatum. Neurotox Res 29(4):525–538
Nehlig A (1999) Are we dependent upon coffee and caffeine? A review on human and animal data. Neurosci Biobehav Rev 23:563–576
Parrott AC (2004) Is ecstasy MDMA? A review of the proportion of ecstasy tablets containing MDMA, their dosage levels, and the changing perceptions of purity. Psychopharmacology 173(3–4):234–241
Pawlik E, Mahler H (2001) Smoke analysis of adulterated illicit drug preparations. Toxichem Krimtech 78:200–210
Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 5th edn. Academic press, Sydney
Petzer A, Pienaar A, Petzer JP (2013) The interactions of caffeine with monoamine oxidase. Life Sci 93:283–287
Prieto JP, Galvalisi M, López-Hill X, Meikle MN, Abin-Carriquiry JA, Scorza C (2015) Caffeine enhances and accelerates the expression of sensitization induced by coca paste indicating its relevance as a main adulterant. Am J Addict 24(5):475–481
Prieto JP, Scorza C, Serra GP, Perra V, Piras G, Galvalisi M, Abin-Carriquiry JA, Valentini V (2016) Cocaine motivational value is enhanced when co-administered with caffeine: relevance of adulterants in reinforcement. Psychopharmacology 233(15–16):2879–2889
Samaha AN, Robinson TE (2005) Why does the rapid delivery of drugs to the brain promote addiction? Trends Pharmacol Sci 26(2):82–87
Solinas M, Ferré S, You Z, Karcz-Kubicha M, Popoli P, Goldberg S (2002) Caffeine induces dopamine and glutamate release in the shell of the nucleus accumbens. J Neurosci 22:6321–6324
Strain E, Griffiths R (1995) Caffeine dependence: fact of fiction? J R Soc Med 88:437–440
Verster JC (2014) Caffeine consumption in children, adolescents and adults. Curr Drug Abuse Rev 7(3):133–134
Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J, Gatley JS, Dewey S, Ashby C, Liebermann J, Hitzemann R et al (1995) Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. Arch Gen Psychiatry 52:456–463
Volkow ND, Fowler JS, Wang GJ, Baler R, Telang F (2009) Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology 56:3–8
Volkow ND, Wang GJ, Logan J, Alexoff D, Fowler JS, Thanos PK, Wong C, Casado V, Ferre S, Tomasi D (2015) Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain. Transl Psychiatry 5:e549
Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94:469–492
Acknowledgments
This study was partially supported by Smoked Cocaine in South Cone Countries Grant CICAD-OEA/USINL, Premio Concursable Junta Nacional de Drogas (Uruguay), and PEDECIBA (Uruguay). Martín Galvalisi and José Pedro Prieto had postgraduate fellowships from ANII (Uruguay). We are grateful to Manuel Minteguiaga (GC–MS Platform) for his technical support.
Author information
Authors and Affiliations
Corresponding author
Additional information
Martín Galvalisi and José Pedro Prieto have contributed equally to this work.
Rights and permissions
About this article
Cite this article
Galvalisi, M., Prieto, J.P., Martínez, M. et al. Caffeine Induces a Stimulant Effect and Increases Dopamine Release in the Nucleus Accumbens Shell Through the Pulmonary Inhalation Route of Administration in Rats. Neurotox Res 31, 90–98 (2017). https://doi.org/10.1007/s12640-016-9667-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-016-9667-8