Abstract
Repeated, intermittent administration of amphetamine or amphetamine derivatives leads to sensitization to the effects of the drug, expressed as heightened locomotor response or operant responding, but also higher self-administration of the drug and emission of 50-kHz ultrasonic vocalizations (USVs). Sensitization appears after a drug-free period and is persistent. The development of sensitization is associated with increased response of the dopamine neurons of the ventral tegmental area; expression of sensitization depends on enhanced dopamine release in the nucleus accumbens. During sensitization, further alterations occur in extended neural circuits involving medial prefrontal cortex, amygdala, pallidum, and hippocampus and contribute to the expression of enhanced response. Sensitization is context-dependent: Previously neutral stimuli, while associated with the pharmacological drug effect, acquire incentive salience and guide future behavior, including self-administration of the drug. Cross-sensitization occurs between amphetamine and other addictive substances and between amphetamine and stress. Sensitization to amphetamine has direct relevance to understanding of the neurobiology of such psychiatric conditions as schizophrenia and addiction.
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Abbreviations
- AMPA:
-
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- BDNF:
-
Brain-derived neurotrophic factor
- BOLD:
-
Blood oxygen level dependent
- CREB:
-
cAMP response element-binding protein
- DSP-4:
-
N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine
- fMRI:
-
Functional magnetic resonance imaging
- GABA:
-
Gamma-aminobutyric acid
- GAD67:
-
The major isoform of glutamate decarboxylase
- HE:
-
High-exploring rats
- HR:
-
High-responding rats
- LE:
-
Low-exploring rats
- LR:
-
Low-responding rats
- PET:
-
Positron emission tomography
- STAT3:
-
Signal transducer and activator of transcription 3
- trkB:
-
Tropomyosin/tyrosine receptor kinase B
- USV:
-
Ultrasonic vocalization
- VTA:
-
Ventral tegmental area
References
Alttoa A, Harro J (2004) Effect of CCK1 and CCK2 receptor blockade on amphetamine-stimulated exploratory behavior and sensitization to amphetamine. Eur Neuropsychopharmacol 14:324–331
Alttoa A, Kõiv K, Eller M et al (2005) Effects of low dose N-(2-chloroethyl-)-N-ethyl-2-bromobenzylamine administration on exploratory and amphetamine-induced behavior and dopamine D2 receptor function in rats with high or low exploratory activity. Neuroscience 132:979–990
Alttoa A, Eller M, Herm L et al (2007) Amphetamine-induced locomotion, behavioral sensitization to amphetamine, and striatal D2 receptor function in rats with high or low spontaneous exploratory activity: differences in the role of locus coeruleus. Brain Res 1131:138–148
Arvanitogiannis A, Sullivan J, Amir S (2000) Time acts as a conditioned stimulus to control behavioral sensitization to amphetamine in rats. Neuroscience 101:1–3
Azmitia EC, Segal M (1978) An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat. J Comp Neurol 179:641–667
Barr AM, Hofmann CE, Weinberg J, Phillips AG (2002) Exposure to repeated, intermittent d-amphetamine induces sensitization of HPA axis to a subsequent stressor. Neuropsychopharmacology 26:286–294
Bernstein IL (2003) Interaction between natural motivational systems and those which respond to drugs of abuse. Appetite 41:333–334. https://doi.org/10.1016/j.appet.2003.06.001
Boileau J, Payer D, Chugani B et al (2014) In vivo evidence for greater amphetamine-induced dopamine release in pathological gambling: a positron emission tomography study with [11C]-(+)-PHNO. Mol Psychiatry 19:1305–1313
Booij L, Welfeld K, Leyton M et al (2016) Dopamine cross-sensitization between psychostimulant drugs and stress in healthy male volunteers. Transl Psychiatry 6:e740. https://doi.org/10.1038/tp.2016.6
Brake WG, Zhang TY, Diorio J et al (2004) Influence of early postnatal rearing conditions on mesocorticolimbic dopamine and behavioural responses to psychostimulants and stressors in adult rats. Eur J Neurosci 19:1863–1874. https://doi.org/10.1111/j.1460-9568.2004.03286.x
Burke AR, Miczek KA (2014) Stress in adolescence and drugs of abuse in rodent models: role of dopamine, CRF, and HPA axis. Psychopharmacology 231:1557–1580. https://doi.org/10.1007/s00213-013-3369-1
Cador M, Bjijou Y, Cailhol S, Stinus L (1999) D-amphetamine-induced behavioral sensitization: implication of a glutamatergic medial prefrontal cortex-ventral tegmental area innervation. Neuroscience 94:705–721
Carr CC, Ferrario CR, Robinson TE (2020) Intermittent access cocaine self-administration produces psychomotor sensitization: effects of withdrawal, sex and cross-sensitization. Psychopharmacology 237:1795–1812
Castner SA, Goldman-Rakic PS (1999) Long-lasting psychotomimetic consequences of repeated low dose amphetamine exposure in rhesus monkeys. Neuropsychopharmacology 20:10–28
Castner SA, Williams GV (2007) From vice to virtue: insights from sensitization in the nonhuman primate. Prog Neuro-Psychopharmacol Biol Psychiatry 31:1572–1592. https://doi.org/10.1016/j.pnpbp.2007.08.026
Cauli O, Pinna A, Valentini V, Morelli M (2003) Subchronic caffeine exposure induces sensitization to caffeine and cross-sensitization to amphetamine ipsilateral turning behavior independent from dopamine release. Neuropsychopharmacology 28:1752–1759. https://doi.org/10.1038/sj.npp.1300240
Childs E, de Wit H (2013) Contextual conditioning enhances the psychostimulant and incentive properties of D-amphetamine in humans. Addict Biol 18:985–992. https://doi.org/10.1111/j.1369-1600.2011.00416.x
Cleal M, Fontana BD, Parker MO (2021) The cognitive and behavioral effects of D-amphetamine and nicotine sensitization in adult zebrafish. Psychopharmacology 238:2191–2200. https://doi.org/10.1007/s00213-021-05844-5
Engelke DS, Filev R, Mello LE, Santos-Junior JG (2017) Evidence of memory generalization in contextual locomotor sensitization induced by amphetamine. Behav Brain Res 317:522–527. https://doi.org/10.1016/j.bbr.2016.10.018
Featherstone RE, Kapur S, Fletcher PJ (2007) The amphetamine-induced sensitized state as a model of schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 31:1556–1571. https://doi.org/10.1016/j.pnpbp.2007.08.025
Ferguson SM, Eskenazi D, Ishikawa M et al (2011) Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization. Nat Neurosci 14:22–24. https://doi.org/10.1038/nn.2703
Flores C, Stewart J (2000) Basic fibroblast growth factor as a mediator of the effects of glutamate in the development of long-lasting sensitization to stimulant drugs: studies in the rat. Psychopharmacology 151(2–3):152–165. https://doi.org/10.1007/s002130000417
Frohmader KS, Pitchers KK, Balfour ME, Coolen LM (2010) Mixing pleasures: review of the effects of drugs on sex behavior in humans and animal models. Horm Behav 58:149–162. https://doi.org/10.1016/j.yhbeh.2009.11.009
Grace AA (2010) Dopamine system dysregulation by the ventral subiculum as the common pathophysiological basis for schizophrenia psychosis, psychostimulant abuse, and stress. Neurotox Res 18:367–376. https://doi.org/10.1007/s12640-010-9154-6
Grant JE, Chamberlain SR (2020) Gambling and substance use: comorbidity and treatment implications. Prog Neuro-Psychopharm Biol Psychiatry 99:109852
Haleem DJ (2013) Extending therapeutic use of psychostimulants: focus on serotonin-1A receptor. Prog Neuro-Psychopharmacol Biol Psychiatry 46:170–180. https://doi.org/10.1016/j.pnpbp.2013.07.015
Harro J (2010) Inter-individual differences in neurobiology as vulnerability factors for affective disorders: implications for psychopharmacology. Pharmacol Ther 125:402–422
Harro J (2015) Neuropsychiatric adverse effects of amphetamine and methamphetamine. Int Rev Neurobiol 120:179–204. https://doi.org/10.1016/bs.irn.2015.02.004
Hausknecht K, Haj-Dahmane S, Shen RY (2013) Prenatal stress exposure increases the excitation of dopamine neurons in the ventral tegmental area and alters their response to psychostimulants. Neuropsychopharmacology 38:293–301
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
Hökfelt T, Barde S, Xu ZQ et al (2018) Neuropeptide and small transmitter coexistence: fundamental studies and relevance to mental illness. Front Neural Circuit 12:106
Huber R, Imeh-Nathaniel A, Nathaniel TI et al (2018) Drug-sensitive reward in crayfish: exploring the neural basis of addiction with automated learning paradigms. Behav Process 152:47–53. https://doi.org/10.1016/j.beproc.2018.03.015
Kameda SR, Fukushiro DF, Trombin TF et al (2011) Adolescent mice are more vulnerable than adults to single injection-induced behavioral sensitization to amphetamine. Pharmacol Biochem Behav 98:320–324. https://doi.org/10.1016/j.pbb.2011.01.013
Kõiv K, Vares M, Kroon C et al (2019) Effect of chronic variable stress on sensitization to amphetamine in high and low sucrose-consuming rats. J Psychopharmacol 33:1512–1523
Laruelle M (2000) The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res Rev 31:371–384
Le Dorce C, Tassin JP, Chauveau F, Gisquet-Verrier P (2019) Behavioral and noradrenergic sensitizations in vulnerable traumatized rats suggest common bases with substance use disorders. Mol Neurobiol 56:611–620
Lehner M, Gruz M, Wislowska-Stanek A et al (2017) The amphetamine-associated contexts exerts a stronger motivational effect in low-anxiety rats than in high-anxiety rats. Behav Brain Res 330:97–107
Leyton M, Vezina P (2013) Striatal ups and downs: their roles in vulnerability to addictions in humans. Neurosci Biobehav Rev 37:1999–2014
Lieberman JA, Kane JM, Alvir J (1987) Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology 91:415–433
Lodge DJ, Grace AA (2008) Amphetamine activation of hippocampal drive of mesolimbic dopamine neurons: a mechanism of behavioral sensitization. J Neurosci 28:7876–7882
Manev H, Uz T (2009) Dosing time-dependent actions of psychostimulants. Int Rev Neurobiol 88:25–41. https://doi.org/10.1016/S0074-7742(09)88002-1
Mascia P, Wang Q, Brown J et al (2020) Maladaptive consequences of repeated intermittent exposure to uncertainty. Prog Neuro-Psychopharmacol Biol Psychiatry 99:109864. https://doi.org/10.1016/j.pnpbp.2020.109864
Meaney MJ, Brake W, Gratton A (2002) Environmental regulation of the development of mesolimbic dopamine systems: a neurobiological mechanism for vulnerability to drug abuse? Psychoneuroendocrinology 27:127–138. https://doi.org/10.1016/s0306-4530(01)00040-3
Moal ML (2016) Individual vulnerabilities relative for potential pathological conditions. Brain Res 1645:65–67. https://doi.org/10.1016/j.brainres.2015.12.037
Muhammad A, Kolb B (2011) Maternal separation altered behavior and neuronal spine density without influencing amphetamine sensitization. Behav Brain Res 223:7–16. https://doi.org/10.1016/j.bbr.2011.04.015
Nakata KG, Yin E, Sutlief E, Ferguson SM (2021) Chemogenetic modulation reveals distinct roles of the subthalamic nucleus and its afferents in the regulation of locomotor sensitization to amphetamine in rats. Psychopharmacology (Berl). https://doi.org/10.1007/s00213-021-05985-7
Nocjar C, Panksepp J (2002) Chronic intermittent amphetamine pretreatment enhances future appetitive behavior for drug- and natural-reward: interaction with environmental variables. Behav Brain Res 128:189–203
O’Daly OG, Joyce D, Stephan KE et al (2011) Functional magnetic resonance imaging investigation of the amphetamine sensitization model of schizophrenia in healthy male volunteers. Arch Gen Psychiatry 68:545–554. https://doi.org/10.1001/archgenpsychiatry.2011.3
O’Daly OG, Joyce D, Tracy DK et al (2014) Amphetamine sensitization alters reward processing in the human striatum and amygdala. PLoS One 9:e93955. https://doi.org/10.1371/journal.pone.0093955
Piazza PV, Deminiére JM, Le Moal M, Simon H (1989) Factors that predict individual vulnerability to amphetamine self-administration. Science 245:1511–1513
Pitchers KK, Balfour ME, Lehman MN et al (2010) Neuroplasticity in the mesolimbic system induced by natural reward and subsequent reward abstinence. Biol Psychiatry 67:872–879
Rada P, Avena NM, Hoebel BG (2005) Daily bingeing on sugar repeatedly releases dopamine in the accumbens shell. Neuroscience 134:737–744. https://doi.org/10.1016/j.neuroscience.2005.04.043
Reisinger SN, Sideromenos S, Horvath O et al (2021) STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology. Mol Psychiatry 26:2886–2899. https://doi.org/10.1038/s41380-020-00904-2
Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res 396:157–198. https://doi.org/10.1016/s0006-8993(86)80193-7
Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18:247–291
Robinson TE, Becker JB, Presty SK (1982) Long-term facilitation of amphetamine-induced rotational behavior and striatal dopamine release produced by a single exposure to amphetamine: sex differences. Brain Res 253:231–241
Robinson TE, Browman KE, Crombag HS, Badiani A (1998) Modulation of the induction or expression of psychostimulant sensitization by the circumstances surrounding drug administration. Neurosci Biobehav Rev 22:347–354. https://doi.org/10.1016/s0149-7634(97)00020-1
Schmidt WJ, Beninger RJ (2006) Behavioural sensitization in addiction, schizophrenia, Parkinson’s disease and dyskinesia. Neurotox Res 10:161–166. https://doi.org/10.1007/BF03033244
Sequeira-Cordero A, Brenes JC (2021) Time-dependent changes in striatal monoamine levels and gene expression following single and repeated amphetamine administration in rats. Eur J Pharmacol 904:174148. https://doi.org/10.1016/j.ejphar.2021.174148
Singer BF, Scott-Railton J, Vezina P (2012) Unpredictable saccharin reinforcement enhances locomotor responding to amphetamine. Behav Brain Res 226:340–344
Smart K, Nagano-Saito A, Milella MS et al (2021) Metabotropic glutamate type 5 receptor binding ability during dextroamphetamine sensitization in mice and humans. J Psychiatry Neurosci 46:E1–E13. https://doi.org/10.1503/jpn.190162
Sofuoglu M, Sewell RA (2009) Norepinephrine and stimulant addiction. Addict Biol 14(2):119–129. https://doi.org/10.1111/j.1369-1600.2008.00138.x
Steketee JD (2003) Neurotransmitter systems of the medial prefrontal cortex: potential role in sensitization to psychostimulants. Brain Res Rev 41:203–228. https://doi.org/10.1016/s0165-0173(02)00233-3
Strakowski SM, Sax KW, Setters MJ, Keck PE Jr (1996) Enhance response to repeated d-amphetamine challenge: evidence for behavioral sensitization in humans. Biol Psychiatry 40:872–880. https://doi.org/10.1016/0006-3223(95)00497-1
Strakowski SM, Sax KW, Setters MJ et al (1997) Lack of enhanced response to repeated d-amphetamine challenge in first-episode psychosis: implications for a sensitization model of psychosis in humans. Biol Psychiatry 42:749–755
Tassin JP (2008) Uncoupling between noradrenergic and serotonergic neurons as a molecular basis of stable changes in behavior induced by repeated drugs of abuse. Biochem Pharmacol 75:85–97. https://doi.org/10.1016/j.bcp.2007.06.038
Tirelli E, Laviola G, Adriani W (2003) Ontogenesis of behavioral sensitization and conditioned place preference induced by psychostimulants in laboratory rodents. Neurosci Biobehav Rev 27:163–178. https://doi.org/10.1016/s0149-7634(03)00018-6
Tõnissaar M, Herm L, Rinken A, Harro J (2006) Individual differences in sucrose intake and preference in the rat: circadian variation and association with dopamine D2 receptor function in striatum and nucleus accumbens. Neurosci Lett 403:119–124
Valvassori SS, Mariot E, Varela RB et al (2019) The role of neurotrophic factors in manic-, anxious- and depressive-like behaviors induced by amphetamine sensitization: implications to the animal model of bipolar disorder. J Affect Disord 245:1106–1113
Vanderschuren LJ, Kalivas PW (2000) Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology 151:99–120. https://doi.org/10.1007/s002130000493
Vares M, Metelitsa M, Kõiv K et al (2020) Chronic stress sensitizes amphetamine-elicited 50-kHz calls in the rat: dependence on positive affective phenotype and effects of long-term fluoxetine pretreatment. Pharmacol Biochem Behav 171:10–19
Vezina P (2004) Sensitization of midbrain dopamine neuron reactivity and the self-administration of psychomotor stimulant drugs. Neurosci Biobehav Rev 27:827–839. https://doi.org/10.1016/j.neubiorev.2003.11.001
Wearne TA, Cornish JL (2019) Inhibitory regulation of the prefrontal cortex following behavioral sensitization to amphetamine and/or methamphetamine psychostimulants: a review of GABA-ergic mechanisms. Prog Neuro-Psychopharmacol Biol Psychiatry 95:109681. https://doi.org/10.1016/j.pnpbp.2019.109681
Weidenauer A, Bauer M, Sauerzopf U et al (2020) On the relationship of first-episode psychosis to the amphetamine-sensitized state: a dopamine D2/3 receptor agonist radioligand study. Transl Psychiatry 10:2. https://doi.org/10.1038/s41398-019-0681-5
Weiss IC, Domeney AM, Heidbreder CA et al (2001) Early social isolation, but not maternal separation, affects behavioral sensitization to amphetamine in male and female adult rats. Pharmacol Biochem Behav 70:397–409. https://doi.org/10.1016/s0091-3057(01)00626-8
Werner CT, Altshuler RD, Shaham Y, Li X (2021) Epigenetic mechanisms in drug relapse. Biol Psychiatry 89:331–338. https://doi.org/10.1016/j.biopsych.2020.08.005
Wickens JR, Horvitz JC, Costa RM, Killcross S (2007) Dopaminergic mechanisms in actions and habits. J Neurosci 27:8181–8183. https://doi.org/10.1523/JNEUROSCI.1671-07.2007
Wolf ME (1998) The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol 54:679–720. https://doi.org/10.1016/s0301-0082(97)00090-7
Womersley JS, Mpeta B, Dimatelis JJ et al (2016) Developmental stress elicits preference for methamphetamine in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder. Behav Brain Funct 12:18. https://doi.org/10.1186/s12993-016-0102-3
Yau YHC, Potenza MN (2015) Gambling disorder and other behavioral addictions: recognition and treatment. Harv Rev Psychiatry 23:134–146
Zack M, Featherstone RE, Mathewson S, Fletcher PJ (2014) Chronic exposure to a gambling-like schedule of reward predictive stimuli can promote sensitization to amphetamine in rats. Front Behav Neurosci 8:7–21
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Relevant research of the authors was supported by the Estonian Research Council (PRG1213).
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Harro, J., O’Leary, A. (2022). Sensitization to Amphetamine. In: Patel, V.B., Preedy, V.R. (eds) Handbook of Substance Misuse and Addictions. Springer, Cham. https://doi.org/10.1007/978-3-030-92392-1_108
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