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Prenatal nicotine is associated with reduced AMPA and NMDA receptor-mediated rises in calcium within the laterodorsal tegmentum: a pontine nucleus involved in addiction processes

Published online by Cambridge University Press:  03 November 2014

L. F. McNair
Affiliation:
Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
K. A. Kohlmeier*
Affiliation:
Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
*
*Address for correspondence: K. A. Kohlmeier, Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitsparken 2, Copenhagen 2100, Denmark. (Email [email protected])

Abstract

Despite huge efforts from public sectors to educate society as to the deleterious physiological consequences of smoking while pregnant, 12–25% of all babies worldwide are born to mothers who smoked during their pregnancies. Chief among the negative legacies bestowed to the exposed individual is an enhanced proclivity postnatally to addict to drugs of abuse, which suggests that the drug exposure during gestation changed the developing brain in such a way that biased it towards addiction. Glutamate signalling has been shown to be altered by prenatal nicotine exposure (PNE) and glutamate is the major excitatory neurotransmitter within the laterodorsal tegmental nucleus (LDT), which is a brainstem region importantly involved in responding to motivational stimuli and critical in development of drug addiction-associated behaviours, however, it is unknown whether PNE alters glutamate signalling within this nucleus. Accordingly, we used calcium imaging, to evaluate AMPA and NMDA receptor-mediated calcium responses in LDT brain slices from control and PNE mice. We also investigated whether the positive AMPA receptor modulator cyclothiazide (CYZ) had differential actions on calcium in the LDT following PNE. Our data indicated that PNE significantly decreased AMPA receptor-mediated calcium responses, and altered the neuronal calcium response to consecutive NMDA applications within the LDT. Furthermore, CYZ strongly potentiated AMPA-induced responses, however, this action was significantly reduced in the LDT of PNE mice when compared with enhancements in responses in control LDT cells. Immunohistochemical processing confirmed that calcium imaging recordings were obtained from the LDT nucleus as determined by presence of cholinergic neurons. Our results contribute to the body of evidence suggesting that neurobiological changes are induced if gestation is accompanied by nicotine exposure. We conclude that in light of the role played by the LDT in motivated behaviour, the cellular changes in the LDT induced by exposures to nicotine prenatally, when combined with alterations in other reward-related regions, could contribute to the increased susceptibility to smoking observed in the offspring.

Type
Original Article
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2014 

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References

1. Slotkin, T. Consensus on postnatal deficits: comparability of human and animal findings. Ann N Y Acad Sci. 1998; 846, 153157.Google Scholar
2. Slotkin, TA. Nicotine and the adolescent brain: insights from an animal model. Neurotoxicol Teratol. 2002; 24, 369384.CrossRefGoogle ScholarPubMed
3. Slotkin, TA. Cholinergic systems in brain development and disruption by neurotoxicants: nicotine, environmental tobacco smoke, organophosphates. Toxicol Appl Pharmacol. 2004; 198, 132151.CrossRefGoogle ScholarPubMed
4. Arria, AM, Derauf, C, Lagasse, LL, et al. Methamphetamine and other substance use during pregnancy: preliminary estimates from the infant development, environment, and lifestyle (ideal) study. Matern Child Health J. 2006; 10, 293302.CrossRefGoogle ScholarPubMed
5. Martin, JA, Hamilton, BE, Ventura, SJ, Menacker, F, Park, MM. Births: final data for 2000. Natl Vital Stat Rep. 2002; 50, 1101.Google ScholarPubMed
6. Martin, JA, Hamilton, BE, Ventura, SJ, Menacker, F, Park, MM. Births: final data for 2001. Natl Vital Stat Rep. 2002; 51, 1102.Google ScholarPubMed
7. Nelson, DE, Giovino, GA, Shopland, DR, et al. Trends in cigarette smoking among US adolescents, 1974 through 1991. Am J Public Health. 1995; 85, 3440.Google Scholar
8. Blood-Siegfried, J, Rende, EK. The long-term effects of prenatal nicotine exposure on neurologic development. J Midwifery Womens Health. 2010; 55, 143152.CrossRefGoogle ScholarPubMed
9. Slotkin, TA, Orband-Miller, L, Queen, KL, Whitmore, WL, Seidler, FJ. Effects of prenatal nicotine exposure on biochemical development of rat brain regions: maternal drug infusions via osmotic minipumps. J Pharmacol Exp Ther. 1987; 240, 602611.Google Scholar
10. Navarro, HA, Seidler, FJ, Eylers, JP, et al. Effects of prenatal nicotine exposure on development of central and peripheral cholinergic neurotransmitter systems. evidence for cholinergic trophic influences in developing brain. J Pharmacol Exp Ther. 1989; 251, 894900.Google Scholar
11. Navarro, HA, Seidler, FJ, Schwartz, RD, et al. Prenatal exposure to nicotine impairs nervous system development at a dose which does not affect viability or growth. Brain Res Bull. 1989; 23, 187192.CrossRefGoogle ScholarPubMed
12. Kandel, DB, Wu, P, Davies, M. Maternal smoking during pregnancy and smoking by adolescent daughters. Am J Public Health. 1994; 84, 14071413.CrossRefGoogle ScholarPubMed
13. Cornelius, MD, Leech, SL, Goldschmidt, L, Day, NL. Prenatal tobacco exposure: is it a risk factor for early tobacco experimentation? Nicotine Tob Res. 2000; 2, 4552.Google Scholar
14. Cornelius, MD, Goldschmidt, L, Day, NL. Prenatal cigarette smoking: long-term effects on young adult behavior problems and smoking behavior. Neurotoxicol Teratol. 2012; 34, 554559.Google Scholar
15. Goldschmidt, L, Cornelius, MD, Day, NL. Prenatal cigarette smoke exposure and early initiation of multiple substance use. Nicotine Tob Res. 2012; 14, 694702.Google Scholar
16. Al Mamun, A, O’Callaghan, FV, Alati, R, et al. Does maternal smoking during pregnancy predict the smoking patterns of young adult offspring? A birth cohort study. Tob Control. 2006; 15, 452457.CrossRefGoogle ScholarPubMed
17. Buka, SL, Shenassa, ED, Niaura, R. Elevated risk of tobacco dependence among offspring of mothers who smoked during pregnancy: a 30-year prospective study. Am J Psychiatry. 2003; 160, 19781984.Google Scholar
18. Shenassa, ED, McCaffery, JM, Swan, GE, et al. Intergenerational transmission of tobacco use and dependence: a transdisciplinary perspective. Nicotine Tob Res. 2003; 5(Suppl. 1), S55S69.CrossRefGoogle ScholarPubMed
19. Oncken, C, McKee, S, Krishnan-Sarin, S, O’Malley, S, Mazure, C. Gender effects of reported in utero tobacco exposure on smoking initiation, progression and nicotine dependence in adult offspring. Nicotine Tob Res. 2004; 6, 829833.CrossRefGoogle ScholarPubMed
20. Lammel, S, Lim, BK, Ran, C, et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature. 2012; 491, 212217.Google Scholar
21. Lodge, DJ, Grace, AA. The laterodorsal tegmentum is essential for burst firing of ventral tegmental area dopamine neurons. Proc Natl Acad Sci U S A. 2006; 103, 51675172.Google Scholar
22. Forster, GL, Blaha, CD. Laterodorsal tegmental stimulation elicits dopamine efflux in the rat nucleus accumbens by activation of acetylcholine and glutamate receptors in the ventral tegmental area. Eur J Neurosci. 2000; 12, 35963604.Google Scholar
23. Forster, GL, Falcon, AJ, Miller, AD, Heruc, GA, Blaha, CD. Effects of laterodorsal tegmentum excitotoxic lesions on behavioral and dopamine responses evoked by morphine and d-amphetamine. Neuroscience. 2002; 114, 817823.Google Scholar
24. Kohlmeier, KA. Off the beaten path: drug addiction and the pontine laterodorsal tegmentum. ISRN Neurosci. 2013; 2013, 24pp.CrossRefGoogle ScholarPubMed
25. Omelchenko, N, Sesack, SR. Laterodorsal tegmental projections to identified cell populations in the rat ventral tegmental area. J Comp Neurol. 2005; 483, 217235.Google Scholar
26. Omelchenko, N, Sesack, SR. Cholinergic axons in the rat ventral tegmental area synapse preferentially onto mesoaccumbens dopamine neurons. J Comp Neurol. 2006; 494, 863875.Google Scholar
27. Dautan, D, Huerta-Ocampo, I, Witten, IB, et al. A major external source of cholinergic innervation of the striatum and nucleus accumbens originates in the brainstem. J Neurosci. 2014; 34, 45094518.CrossRefGoogle Scholar
28. Drevets, WC, Gautier, C, Price, JC, et al. Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria. Biol Psychiatry. 2001; 49, 8196.Google Scholar
29. Pontieri, FE, Tanda, G, Di Chiara, G. Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the ‘shell’ as compared with the ‘core’ of the rat nucleus accumbens. Proc Natl Acad Sci U S A. 1995; 92, 1230412308.Google Scholar
30. Pontieri, FE, Tanda, G, Orzi, F, Di Chiara, G. Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature. 1996; 382, 255257.Google Scholar
31. Grace, AA, Floresco, SB, Goto, Y, Lodge, DJ. Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci. 2007; 30, 220227.Google Scholar
32. Maskos, U. The cholinergic mesopontine tegmentum is a relatively neglected nicotinic master modulator of the dopaminergic system: relevance to drugs of abuse and pathology. Br J Pharmacol. 2008; 153(Suppl. 1), S438S445.CrossRefGoogle ScholarPubMed
33. Mameli-Engvall, M, Evrard, A, Pons, S, et al. Hierarchical control of dopamine neuron-firing patterns by nicotinic receptors. Neuron. 2006; 50, 911921.CrossRefGoogle ScholarPubMed
34. Atluri, P, Fleck, MW, Shen, Q, et al. Functional nicotinic acetylcholine receptor expression in stem and progenitor cells of the early embryonic mouse cerebral cortex. Dev Biol. 2001; 240, 143156.CrossRefGoogle ScholarPubMed
35. Schneider, AS, Atluri, P, Shen, Q, et al. Functional nicotinic acetylcholine receptor expression on stem and progenitor cells of the early embryonic nervous system. Ann N Y Acad Sci. 2002; 971, 135138.Google Scholar
36. Kohlmeier, KA. Nicotine during pregnancy-changes induced in neurotransmission which could heighten proclivity to addict and induce maladaptive control of attention. J Devel Orig Health Dis. 2014; in press, doi:10.1017/S2040174414000531.Google Scholar
37. Christensen, MH, Nielsen, ML, Kohlmeier, KA. Electrophysiological changes in laterodorsal tegmental neurons associated with prenatal nicotine exposure: implications for heightened susceptibility to addict to drugs of abuse. J Devel Orig Health Dis. 2014; E-pub 23 October 2014; doi:10.1017/S204017441400049X.Google Scholar
38. Inglis, WL, Semba, K. Discriminable excitotoxic effects of ibotenic acid, AMPA, NMDA and quinolinic acid in the rat laterodorsal tegmental nucleus. Brain Res. 1997; 755, 1727.Google Scholar
39. Inglis, WL, Semba, K. Colocalization of ionotropic glutamate receptor subunits with NADPH-diaphorase-containing neurons in the rat mesopontine tegmentum. J Comp Neurol. 1996; 368, 1732.Google Scholar
40. Sanchez, RM, Surkis, A, Leonard, CS. Voltage-clamp analysis and computer simulation of a novel cesium-resistant A-current in guinea pig laterodorsal tegmental neurons. J Neurophysiol. 1998; 79, 31113126.Google Scholar
41. Sesack, SR, Deutch, AY, Roth, RH, Bunney, BS. Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin. J Comp Neurol. 1989; 290, 213242.Google Scholar
42. Kohlmeier, KA, Ishibashi, M, Wess, J, Bickford, ME, Leonard, CS. Knockouts reveal overlapping functions of M(2) and M(4) muscarinic receptors and evidence for a local glutamatergic circuit within the laterodorsal tegmental nucleus. J Neurophysiol. 2012; 108, 27512766.CrossRefGoogle Scholar
43. Wang, H, Davila-Garcia, MI, Yarl, W, Gondre-Lewis, MC. Gestational nicotine exposure regulates expression of AMPA and NMDA receptors and their signaling apparatus in developing and adult rat hippocampus. Neuroscience. 2011; 188, 168181.Google Scholar
44. Parameshwaran, K, Buabeid, MA, Karuppagounder, SS, et al. Developmental nicotine exposure induced alterations in behavior and glutamate receptor function in hippocampus. Cell Mol Life Sci. 2012; 69, 829841.Google Scholar
45. Parameshwaran, K, Buabeid, MA, Bhattacharya, S, et al. Long term alterations in synaptic physiology, expression of beta2 nicotinic receptors and ERK1/2 signaling in the hippocampus of rats with prenatal nicotine exposure. Neurobiol Learn Mem. 2013; 106, 102111.Google Scholar
46. Jaiswal, SJ, Pilarski, JQ, Harrison, CM, Fregosi, RF. Developmental nicotine exposure alters AMPA neurotransmission in the hypoglossal motor nucleus and pre-Botzinger complex of neonatal rats. J Neurosci. 2013; 33, 26162625.Google Scholar
47. Pauly, JR, Sparks, JA, Hauser, KF, Pauly, TH. In utero nicotine exposure causes persistent, gender-dependant changes in locomotor activity and sensitivity to nicotine in C57Bl/6 mice. Int J Dev Neurosci. 2004; 22, 329337.CrossRefGoogle ScholarPubMed
48. Matta, SG, et al. Guidelines on nicotine dose selection for in vivo research. Psychopharmacology (Berl). 2007; 190, 269319.Google Scholar
49. Bachmanov, AA, Reed, DR, Beauchamp, GK, Tordoff, MG. Food intake, water intake, and drinking spout side preference of 28 mouse strains. Behav Genet. 2002; 32, 435443.Google Scholar
50. Schneider, T, Bizarro, L, Asherson, PJ, Stolerman, IP. Gestational exposure to nicotine in drinking water: teratogenic effects and methodological issues. Behav Pharmacol. 2010; 21, 206216.CrossRefGoogle ScholarPubMed
51. Leichter, J, Lee, M. Does dehydration contribute to retarded fetal growth in rats exposed to alcohol during gestation? Life Sci. 1984; 35, 21052111.Google Scholar
52. Yuste, RF, Lanni, F, Konnerth, A. Imaging Neurons: A Laboratory Manual. 2000. ColSpring Harbor Laboratory Press: Cold Spring Harbor, New York.Google Scholar
53. Kohlmeier, KA, Inoue, T, Leonard, CS. Hypocretin/orexin peptide signaling in the ascending arousal system: elevation of intracellular calcium in the mouse dorsal raphe and laterodorsal tegmentum. J Neurophysiol. 2004; 92, 221235.Google Scholar
54. Connor, JA, Cormier, RJ. Cumulative effects of glutamate microstimulation on Ca(2+) responses of CA1 hippocampal pyramidal neurons in slice. J Neurophysiol. 2000; 83, 9098.Google Scholar
55. Kohlmeier, KA, Vardar, B, Christensen, MH. Gamma-hydroxybutyric acid induces actions via the GABA receptor in arousal and motor control-related nuclei: implications for therapeutic actions in behavioral state disorders. Neuroscience. 2013; 248C, 261277.Google Scholar
56. Kohlmeier, KA, Leonard, CS. Transmitter modulation of spike-evoked calcium transients in arousal related neurons: muscarinic inhibition of SNX-482-sensitive calcium influx. Eur J Neurosci. 2006; 23, 11511162.Google Scholar
57. Kohlmeier, KA, Watanabe, S, Tyler, CJ, Burlet, S, Leonard, CS. Dual orexin actions on dorsal raphe and laterodorsal tegmentum neurons: noisy cation current activation and selective enhancement of Ca2+ transients mediated by L-type calcium channels. J Neurophysiol. 2008; 100, 22652281.CrossRefGoogle ScholarPubMed
58. Vincent, SR, Kimura, H. Histochemical mapping of nitric oxide synthase in the rat brain. Neuroscience. 1992; 46, 755784.Google Scholar
59. Mychasiuk, R, Muhammad, A, Carroll, C, Kolb, B. Does prenatal nicotine exposure alter the brain’s response to nicotine in adolescence? A neuroanatomical analysis. Eur J Neurosci. 2013; 38, 24912503.CrossRefGoogle ScholarPubMed
60. Mychasiuk, R, Muhammad, A, Gibb, R, Kolb, B. Long-term alterations to dendritic morphology and spine density associated with prenatal exposure to nicotine. Brain Res. 2013; 1499, 5360.CrossRefGoogle ScholarPubMed
61. Berridge, MJ. Neuronal calcium signaling. Neuron. 1998; 21, 1326.Google Scholar
62. Wang, HL, Morales, M. Pedunculopontine and laterodorsal tegmental nuclei contain distinct populations of cholinergic, glutamatergic and GABAergic neurons in the rat. Eur J Neurosci. 2009; 29, 340358.Google Scholar
63. Jia, HG, Yamuy, J, Sampogna, S, Morales, FR, Chase, MH. Colocalization of gamma-aminobutyric acid and acetylcholine in neurons in the laterodorsal and pedunculopontine tegmental nuclei in the cat: a light and electron microscopic study. Brain Res. 2003; 992, 205219.Google Scholar
64. Mieda, M, Hasegawa, E, Kisanuki, YY, et al. Differential roles of orexin receptor-1 and -2 in the regulation of non-REM and REM sleep. J Neurosci. 2011; 31, 65186526.Google Scholar
65. Wang, H, Gondre-Lewis, MC. Prenatal nicotine and maternal deprivation stress de-regulate the development of CA1, CA3, and dentate gyrus neurons in hippocampus of infant rats. PLoS One. 2013; 8, e65517.Google Scholar
66. Berlin, I, Heilbronner, C, Georgieu, S, Meier, C, Spreux-Varoquaux, O. Newborns’ cord blood plasma cotinine concentrations are similar to that of their delivering smoking mothers. Drug Alcohol Depend. 2010; 107, 250252.Google Scholar
67. Rang, HP. Rang and Dale’s Pharmacology. 2007. Elsevier: Edinburgh, Philadelphia.Google Scholar
68. Kauer, JA, Malenka, RC. Synaptic plasticity and addiction. Nat Rev Neurosci. 2007; 8, 844858.Google Scholar
69. Lambers, DS, Clark, KE. The maternal and fetal physiologic effects of nicotine. Semin Perinatol. 1996; 20, 115126.Google Scholar
70. Jauniaux, E, Gulbis, B, Acharya, G, Thiry, P, Rodeck, C. Maternal tobacco exposure and cotinine levels in fetal fluids in the first half of pregnancy. Obstet Gynecol. 1999; 93, 2529.Google Scholar
71. Marin, SJ, Christensen, RD, Baer, VL, Clark, CJ, McMillin, GA. Nicotine and metabolites in paired umbilical cord tissue and meconium specimens. Ther Drug Monit. 2011; 33, 8085.Google Scholar
72. Moretti, M, Mugnaini, M, Tessari, M, et al. A comparative study of the effects of the intravenous self-administration or subcutaneous minipump infusion of nicotine on the expression of brain neuronal nicotinic receptor subtypes. Mol Pharmacol. 2010; 78, 287296.Google Scholar
73. Vaglenova, J, Parameshwaran, K, Suppiramaniam, V, et al. Long-lasting teratogenic effects of nicotine on cognition: gender specificity and role of AMPA receptor function. Neurobiol Learn Mem. 2008; 90, 527536.Google Scholar
74. Traynelis, SF, Wollmuth, LP, McBain, CJ, et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev. 2010; 62, 405496.Google Scholar
75. Liu, SJ, Savtchouk, I. Ca(2+) permeable AMPA receptors switch allegiances: mechanisms and consequences. J Physiol. 2012; 590, 1320.CrossRefGoogle ScholarPubMed
76. Bellone, C, Mameli, M, Luscher, C. In utero exposure to cocaine delays postnatal synaptic maturation of glutamatergic transmission in the VTA. Nat Neurosci. 2011; 14, 14391446.Google Scholar
77. Mameli, M, Bellone, C, Brown, MT, Luscher, C. Cocaine inverts rules for synaptic plasticity of glutamate transmission in the ventral tegmental area. Nat Neurosci. 2011; 14, 414416.Google Scholar
78. Clancy, B, Darlington, RB, Finlay, BL. Translating developmental time across mammalian species. Neuroscience. 2001; 105, 717.Google Scholar
79. Legendre, P, Rosenmund, C, Westbrook, GL. Inactivation of NMDA channels in cultured hippocampal neurons by intracellular calcium. J Neurosci. 1993; 13, 674684.Google Scholar
80. Lieberman, DN, Mody, I. Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature. 1994; 369, 235239.Google Scholar
81. Rosenmund, C, Feltz, A, Westbrook, GL. Calcium-dependent inactivation of synaptic NMDA receptors in hippocampal neurons. J Neurophysiol. 1995; 73, 427430.Google Scholar
82. Benquet, P, Gee, CE, Gerber, U. Two distinct signaling pathways upregulate NMDA receptor responses via two distinct metabotropic glutamate receptor subtypes. J Neurosci. 2002; 22, 96799686.Google Scholar
83. Salter, MW. Src, N-methyl-D-aspartate (NMDA) receptors, and synaptic plasticity. Biochem Pharmacol. 1998; 56, 789798.Google Scholar
84. Lu, WY, Xiong, ZG, Lei, S, et al. G-protein-coupled receptors act via protein kinase C and Src to regulate NMDA receptors. Nat Neurosci. 1999; 2, 331338.Google Scholar
85. Huang, Y, Lu, W, Ali, DW, et al. CAKbeta/Pyk2 kinase is a signaling link for induction of long-term potentiation in CA1 hippocampus. Neuron. 2001; 29, 485496.Google Scholar
86. Skeberdis, VA, Chevaleyre, V, Lau, CG, et al. Protein kinase A regulates calcium permeability of NMDA receptors. Nat Neurosci. 2006; 9, 501510.Google Scholar
87. Desai, MA, Burnett, JP, Ornstein, PL, Schoepp, DD. Cyclothiazide acts at a site on the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor complex that does not recognize competitive or noncompetitive AMPA receptor antagonists. J Pharmacol Exp Ther. 1995; 272, 3843.Google Scholar
88. Yamada, KA, Tang, CM. Benzothiadiazides inhibit rapid glutamate receptor desensitization and enhance glutamatergic synaptic currents. J Neurosci. 1993; 13, 39043915.Google Scholar
89. Donevan, SD, Rogawski, MA. Allosteric regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors by thiocyanate and cyclothiazide at a common modulatory site distinct from that of 2,3-benzodiazepines. Neuroscience. 1998; 87, 615629.Google Scholar
90. Grilli, M, Summa, M, Salamone, A, et al. In vitro exposure to nicotine induces endocytosis of presynaptic AMPA receptors modulating dopamine release in rat nucleus accumbens nerve terminals. Neuropharmacology. 2012; 63, 916926.Google Scholar
91. Orlandi, C, La Via, L, Bonini, D, et al. AMPA receptor regulation at the mRNA and protein level in rat primary cortical cultures. PLoS One 2011; 6, e25350.Google Scholar
92. Volkow, ND, Fowler, JS, Wang, GJ, Swanson, JM. Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol Psychiatry. 2004; 9, 557569.Google Scholar
93. Volkow, ND, Li, TK. Drug addiction: the neurobiology of behaviour gone awry. Nat Rev Neurosci. 2004; 5, 963970.Google Scholar
94. Melis, M, Spiga, S, Diana, M. The dopamine hypothesis of drug addiction: hypodopaminergic state. Int Rev Neurobiol. 2005; 63, 101154.Google Scholar
95. Ishibashi, M, Leonard, CS, Kohlmeier, KA. Nicotinic activation of laterodorsal tegmental neurons: implications for addiction to nicotine. Neuropsychopharmacology. 2009; 34, 25292547.CrossRefGoogle ScholarPubMed
96. Christensen, MH, Ishibashi, M, Nielsen, ML, Leonard, CS, Kohlmeier, KA. Age-related changes in nicotine response of cholinergic and non-cholinergic laterodorsal tegmental neurons: implications for the heightened adolescent susceptibility to nicotine addiction. Neuropharmacology. 2014; 85, 263283.Google Scholar
97. de Leon, J, Dadvand, M, Canuso, C, et al. Schizophrenia and smoking: an epidemiological survey in a state hospital. Am J Psychiatry. 1995; 152, 453455.Google ScholarPubMed
98. Vassoler, FM, Byrnes, EM, Pierce, RC. The impact of exposure to addictive drugs on future generations: physiological and behavioral effects. Neuropharmacology. 2014; 76, 269275.Google Scholar