Abstract
Chronic methamphetamine (METH) abuse has been shown to elicit strong neurotoxic effects. Yet, with an increasing number of children born to METH abusing mothers maturing into adulthood, one important question is how far do the neurotoxic effects of METH alter various neurotransmitter systems in the adult METH-exposed offspring. The purpose of this study was to investigate long-term trans-generational neurochemical changes, following prenatal METH exposure, in the adult Wistar rat brain. METH or saline (SAL—control animals) was administered to pregnant dams throughout the entire gestation period (G0-G22). At postnatal day 90, dopamine, serotonin, glutamate and GABA were measured in the adult brain before (baseline) and after a METH re-administration using in vivo microdialysis and liquid chromatography/mass spectrometry. The results show that METH-exposure increased basal levels of monoamines and glutamate, but decreased GABA levels in all measured brain regions. Acute challenge with METH injection in the METH-exposed group induced a lower increase in the monoamine system relative to the increase in the GABAergic and glutamatergic system. The data show that prenatal METH exposure has strong effects on the monoaminergic, GABAergic and glutamatergic system even when exposure to METH was limited to the prenatal phase. Toxicological effects of METH have therefore longer lasting effects as currently considered and seem to affect the excitatory-inhibitory balance in the brain having strong implications for cognitive and behavioral functioning.
Similar content being viewed by others
References
Abekawa T, Ito K, Nakagawa S, Koyama T (2007) Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats. Psychopharmacology 192:303–316
Acuff-Smith KD, Schilling MA, Fisher JE, Vorhees CV (1996) Stage-specific effects of prenatal d-methamphetamine exposure on behavioral and eye development in rats. Neurotoxicol Teratol 18:199–215
Berridge KC, Robinson TE (2016) Liking, wanting, and the incentive-sensitization theory of addiction. Am Psychol 71(8):670–679
Bubenikova-Valesova V, Kacer P, Syslova K, Rambousek L, Janovsky M, Schutova B, Hruba L, Slamberova R (2009) Prenatal methamphetamine exposure affects the mesolimbic dopaminergic system and behavior in adult offspring. Int J Dev Neurosci 27:525–530
Chang L, Cloak C, Jiang CS, Farnham S, Tokeshi B, Buchthal S, Hedemark B, Smith LM, Ernst T (2009) Altered neurometabolites and motor integration in children exposed to methamphetamine in utero. Neuroimage 48(2):391–397
Crandall JE, McCarthy DM, Araki KY, Sims JR, Ren JQ, Bhide PG (2007) Dopamine receptor activation modulates GABA neuron migration from the basal forebrain to the cerebral cortex. J Neurosci 27:3813–3822
Daubert EA, Condron BG (2010) Serotonin: a regulator of neuronal morphology and circuitry. Trends Neurosci 33(9):424–434
du Bois TM, Huang XF (2007) Early brain development disruption from NMDA receptor hypofunction: relevance to schizophrenia. Brain Res Rev 53(2):260–270
du Bois TM, Deng C, Han M, Newell KA, Huang XF (2009) Excitatory and inhibitory neurotransmission is chronically altered following perinatal NMDA receptor blockade. Eur Neuropsychopharmacol 19(4):256–265
Estelles J, Rodríguez-Arias M, Maldonado C, Manzanedo C, Aguilar MA, Miñarro J (2006) Prenatal cocaine alters later responses to morphine in adult male mice. Prog Neuropsychopharmacol Biol Psychiatry 30(6):1073–1082
Fanselow MS, Dong H-W (2010) Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65:7–19
Fialová M, Šírová J, Bubeníková-Valešová V, Šlamberová R (2015) The effect of prenatal methamphetamine exposure on recognition memory in adult rats. Prague Med Rep 116:31–39
Franke RM, Park M, Belluzzi JD, Leslie FM (2008) Prenatal nicotine exposure changes natural and drug-induced reinforcement in adolescent male rats. Eur J Neurosci 27(11):2952–2961
Galineau L, Belzung C, Kodas E et al (2005) Prenatal 3,4-methylenedioxymethamphetamine (ecstasy) exposure induces long-term alterations in the dopaminergic and serotonergic functions in the rat. Brain Res Dev 154:165–176
Goldstein RZ, Volkow ND (2011) Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci 12(11):652–669
Greenfield SF, Back SE, Lawson K, Brady KT (2010) Substance abuse in women. Psychiatr Clin N Am 33(2):339–355
Halpin LE, Collins SA, Yamamoto BK (2013) Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine. Life Sci 97:37–44
Han DD, Gu HH (2006) Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacol 6:6
Henry DJ, White FJ (1995) The persistence of behavioral sensitization to cocaine parallels enhanced inhibition of nucleus accumbens neurons. J Neurosci 15:6287–6299
Henry C, Guegant G, Cador M et al (1995) Prenatal stress in rats facilitates amphetamine-induced sensitization and induces long-lasting changes in dopamine receptors in the nucleus accumbens. Brain Res 685:179–186
Heyser CJ, Miller JS, Spear NE, Spear LP (1992) Prenatal exposure to cocaine disrupts cocaine-induced conditioned place preference in rats. Neurotoxicol Teratol 14(1):57–64
Hondebrink L, Meulenbelt J, van Kleef RGDM et al (2011) Modulation of human GABAA receptor function: a novel mode of action of drugs of abuse. Neurotoxicology 32:823–827
Hruba L, Schutova B, Slamberova R, Pometlova M, Rokyta R (2009) Effect of methamphetamine exposure and cross-fostering on sensorimotor development of male and female rat pups. Dev Psychobiol 51(1):73–83
Hruba L, Schutova B, Slamberova R (2012) Sex differences in anxiety-like behavior and locomotor activity following prenatal and postnatal methamphetamine exposure in adult rats. Physiol Behav 105(2):364–370
Huang CC, Liang YC, Hsu KS (2011) Prenatal cocaine exposure enhances long-term potentiation induction in rat medial prefrontal cortex. Int J Neuropsychopharmacol 14:431–443
Jablonski SA, Williams MT, Vorhees CV (2016) Neurobehavioral effects from developmental methamphetamine exposure. Curr Top Behav Neurosci 29:183–230
Kalivas PW, Duffy P (1993) Time course of extracellular dopamine and behavioral sensitization to cocaine. I. Dopamine axon terminals. J Neurosci 13(1):266–275
Kalivas PW, LaLumiere RT, Knackstedt L, Shen H (2009) Glutamate transmission in addiction. Neuropharmacology 56(Suppl 1):169–173
Kandel ER, Dudai Y, Mayford MR (2014) The molecular and systems biology of memory. Cell 157:163–186
Keller RW Jr, Maisonneuve IM, Nuccio DM, Carlson JN, Glick SD (1994) Effects of prenatal cocaine exposure on the nigrostriatal dopamine system: an in vivo microdialysis study in the rat. Brain Res 634(2):266–274
Khalaf-Nazzal R, Francis F (2013) Hippocampal development—old and new findings. Neuroscience 248:225–242
Kubrusly RCC, Bhide PG (2010) Cocaine exposure modulates dopamine and adenosine signaling in the fetal brain. Neuropharmacology 58:436–443
Lanciego JL, Luquin N, Obeso JA (2012) Functional neuroanatomy of the basal ganglia. Cold Spring Harb Perspect Med 2(12):a009621
Lepelletier FX, Tauber C, Nicolas C et al (2014) Prenatal exposure to methylphenidate affects the dopamine system and the reactivity to natural reward in adulthood in rats. Int J Neuropsychopharmacol 18(4):1–11
Malanga CJ, Kosofsky BE (2003) Does drug abuse beget drug abuse? Behavioral analysis of addiction liability in animal models of prenatal drug exposure. Brain Res Dev Brain Res 147(1–2):47–57
Malinová-Ševčíková M, Hrebíčková I, Macúchová E, Nová E, Pometlová M, Šlamberová R (2014) Differences in maternal behavior and development of their pups depend on the time of methamphetamine exposure during gestation period. Physiol Res 63(Suppl 4):S559–S572
McCabe RT, Hanson GR, Dawson TM, Wamsley JK, Gibb JW (1987) Methamphetamine-induced reduction in D1 and D2 dopamine receptors as evidenced by autoradiography: comparison with tyrosine hydroxylase activity. Neuroscience 23(1):253–261
McCarthy DM, Bhide PG (2012) Prenatal cocaine exposure decreases parvalbumin-immunoreactive neurons and GABA-to-projection neuron ratio in the medial prefrontal cortex. Dev Neurosci 34(2–3):174–183
McCarthy DM, Kabir ZD, Bhide PG, Kosofsky BE (2014) Effects of prenatal exposure to cocaine on brain structure and function. Prog Brain Res 211:277–289
McFarland K, Lapish CC, Kalivas PW (2003) Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 23(8):3531–3537
Mora F, Segovia G, Del Arco A, de Blas M, Garrido P (2012) Stress, neurotransmitters, corticosterone and body-brain integration. Brain Res 1476:71–85
Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates. 5th edn. Academic Press, New York
Ricaurte GA, Schuster CR, Seiden LS (1980) Long-term effects of repeated methylamphetamine administration on dopamine and serotonin neurons in the rat brain: a regional study. Brain Res 193(1):153–163
Sato M, Fujiwara Y (1986) Behavioral and neurochemical changes in pups prenatally exposed to methamphetamine. Brain Dev 8(4):390–396
Schmidt CJ, Gibb JW (1985) Role of the dopamine uptake carrier in the eurochemical response to methamphetamine: effects of amfonelic acid. Eur J Pharmacol 109(1):73–80
Schutova B, Hruba L, Pometlova M, Slamberova R (2009) Impact of prenatal and acute methamphetamine exposure on behaviour of adult male rats. Prague Med Rep 110(1):67–78
Sirova J, Kristofikova Z, Vrajova M, Fujakova-Lipski M, Ripova D, Klaschka J, Slamberova R (2016) Sex-dependent changes in striatal dopamine transport in preadolescent rats exposed prenatally and/or postnatally to methamphetamine. Neurochem Res 41(8):1911–1923
Slamberova R, Rokyta R (2005) Seizure susceptibility in prenatally methamphetamine-exposed adult female rats. Brain Res 1060(1–2):193–197
Slamberova R, Yamamotova A, Schutova B, Hruba L, Pometlova M (2011) Impact of prenatal methamphetamine exposure on the sensitivity to the same drug in adult male rats. Prague Med Rep 112(2):102–114
Slamberová R, Charousová P, Pometlová M (2005) Methamphetamine administration during gestation impairs maternal behavior. Dev Psychobiol 46(1):57–65
Stephans SE, Yamamoto BK (1994) Methamphetamine-induced neurotoxicity: roles for glutamate and dopamine efflux. Synapse 17(3):203–209
Stephans SE, Yamamoto BY (1995) Effect of repeated methamphetamine administrations on dopamine and glutamate efflux in rat prefrontal cortex. Brain Res 700(1–2):99–106
Sulzer D, Sonders MS, Poulsen NW, Galli A (2005) Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol 75(6):406–433
Syslová K, Rambousek L, Kuzma M, Najmanová V, Bubeníková-Valešová V, Slamberová R, Kačer P (2011) Monitoring of dopamine and its metabolites in brain microdialysates: method combining freeze-drying with liquid chromatography-tandem mass spectrometry. J Chromatogr A 1218:3382–3391
Szczurowska E, Mareš P (2013) NMDA and AMPA receptors: development and status epilepticus. Physiol Res 62(Suppl 1):S21–S38
Tewari A, Jog R, Jog MS (2016) The striatum and subthalamic nucleus as independent and collaborative structures in motor control. Front Syst Neurosci 10:17
Vitalis T, Cases O, Passemard S, Callebert J, Parnavelas JG (2007) Embryonic depletion of serotonin affects cortical development. Eur J Neurosci 26(2):331–344
Volkow ND, Wang GJ, Fowler JS, Tomasi D, Telang F, Baler R (2010) Addiction: decreased reward sensitivity and increased expectation sensitivity conspire to overwhelm the brain’s control circuit. BioEssays 32(9):748–755
Vrajova M, Schutova B, Klaschka J, Stepankova H, Ripova D, Slamberova R (2014) Age-related differences in NMDA receptor subunits of prenatally methamphetamine-exposed male rats. Neurochem Res 39(11):2040–2046
Weissman AD, Caldecott-Hazard S (1993) In utero methamphetamine effects: I. Behavior and monoamine uptake sites in adult offspring. Synapse 13(3):241–250
Wirth A, Holst K, Ponimaskin E (2016) How serotonin receptors regulate morphogenic signalling in neurons. Prog Neurobiol 151:35–56
Wyvell CL, Berridge KC (2000) Intra-accumbens amphetamine increases the conditioned incentive salience of sucrose reward: enhancement of reward “wanting” without enhanced liking” or response reinforcement. J Neurosci 20(21):8122–8130
Acknowledgements
This work was supported from the project “Sustainability for the National Institute of Mental Health”, under Grant Number LO1611, with a financial support from the Ministry of Education, Youth and Sports of the Czech Republic under the NPU I program, Grant GA 14-3708S from Grant Agency of the Czech Republic, Charles University Research Development Schemes—Progres Q35, institutional support RVO:67985807 and Specific Academic Research 260388/SVV/2017 from Charles University in Prague.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Fujáková-Lipski, M., Kaping, D., Šírová, J. et al. Trans-generational neurochemical modulation of methamphetamine in the adult brain of the Wistar rat. Arch Toxicol 91, 3373–3384 (2017). https://doi.org/10.1007/s00204-017-1969-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-017-1969-y