This study utilised the two injection protocol of sensitisation (TIPS) and the conditioned place preference test to validate and extend previous findings on the effects of amphetamine on positive reinforcement-related 50 kHz ultrasonic vocalisation (USV) in rats. We also examined changes in the expression of c-Fos and the NMDA receptor 2B (GluN2B) subunit, markers of neuronal activity and plasticity, in brain regions of rats in response to TIPS. We used low anxiety-responsive (LR) and high anxiety-responsive (HR) rats, which are known to exhibit different fear-conditioned response strengths, different susceptibilities to amphetamine in the TIPS procedure and different amphetamine-dependent 50 kHz USV responses. The LR rats, compared to the HR rats, not only vocalised much more intensely but also spent significantly more time in the amphetamine-paired compartment. After the second dose of amphetamine, the LR rats exhibited more c-Fos and GluN2B activation in layers II and III of the M1/M2 motor cortex area and prefrontal cortex (PRE, PRL, IL) and also presented with more GluN2B activation in the basal amygdala. These data reveal that HR and LR rats exhibit different levels of reactivity in the cortical-limbic pathway, which controls reward-related motivational processes. These findings contribute to the general hypothesis that heterogeneity in emotional processes is one of the causes of sensitisation to amphetamine and drug addiction.

References

Ahrens, AM, Nobile, CW, Page, LE. ( 2013 ) Individual differences in the conditioned and unconditioned rat 50-kHz ultrasonic vocalizations elicited by repeated amphetamine exposure . Psychopharmacology (Berlin) 229: 687 – 700 .

Google Scholar Crossref | Medline | ISI

Bolla, KI, Cadet, JL, London, ED ( 1998 ) The neuropsychiatry of chronic cocaine abuse . J Neuropsychiatry Clin Neurosci 10: 280 – 289 .

Google Scholar Crossref | Medline | ISI

Brudzynski, SM ( 2013 ) Ethotransmission: communication of emotional states through ultrasonic vocalization in rats . Curr Opin Neurobiol 23: 310 – 317 .

Google Scholar Crossref | Medline | ISI

Brudzynski, SM, Komadoski, M, St Pierre, J ( 2012 ) Quinpirole-induced 50 kHz ultrasonic vocalization in the rat: role of D2 and D3 dopamine receptors . Behav Brain Res 226: 511 – 518 .

Google Scholar Crossref | Medline | ISI

Cain, ME, Saucier, DA, Bardo, MT ( 2005 ) Novelty seeking and drug use: contribution of an animal model . Exp Clin Psychopharmacol 13: 367 – 375 .

Google Scholar Crossref | Medline | ISI

Calu, DJ, Stalnaker, TA, Franz, TM. ( 2007 ) Withdrawal from cocaine self-administration produces long-lasting deficits in orbitofrontal-dependent reversal learning in rats . Learn Mem 14: 325 – 328 .

Google Scholar Crossref | Medline | ISI

Costa, G, Morelli, M, Simola, N ( 2015 ) Involvement of Glutamate NMDA Receptors in the Acute, Long-Term, and Conditioned Effects of Amphetamine on Rat 50kHz Ultrasonic Vocalizations . Int J Neuropsychopharmacol 18: pyv057 . DOI: 10.1093/ijnp/pyv057.

Google Scholar Crossref | Medline | ISI

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 85: 5274 – 5278 .

Google Scholar Crossref | Medline | ISI

Di Miceli, M, Gronier, B ( 2015 ) Psychostimulants and atomoxetine alter the electrophysiological activity of prefrontal cortex neurons, interaction with catecholamine and glutamate NMDA receptors . Psychopharmacology (Berlin) 232: 2191 – 2205 .

Google Scholar Crossref | Medline | ISI

Drevets, WC ( 2003 ). Neuroimaging abnormalities in the amygdala in mood disorders . Ann N Y Acad Sci 985: 420 – 444 .

Google Scholar Crossref | Medline | ISI

Ersche, KD, Jones, PS, Williams, GB. ( 2013 ) Distinctive personality traits and neural correlates associated with stimulant drug use versus familial risk of stimulant dependence . Biol Psychiatry 74: 137 – 144 .

Google Scholar Crossref | Medline | ISI

Everitt, BJ ( 2014 ) Neural and psychological mechanisms underlying compulsive drug seeking habits and drug memories – indications for novel treatments of addiction . Eur J Neurosci 40: 2163 – 2182 .

Google Scholar Crossref | Medline | ISI

Fu, XW, Brudzynski, SM ( 1994 ) High-frequency ultrasonic vocalization induced by intracerebral glutamate in rats . Pharmacol, Biochem Behav 49: 835 – 841 .

Google Scholar Crossref | Medline | ISI

Fuchs, RA, Evans, KA, Ledford, CC. ( 2005 ) The role of the dorsomedial prefrontal cortex, basolateral amygdala, and dorsal hippocampus in contextual reinstatement of cocaine seeking in rats . Neuropsychopharmacology 30: 296 – 309 .

Google Scholar Crossref | Medline | ISI

Ghasemzadeh, MB, Vasudevan, P, Mueller, C ( 2009 ) Locomotor sensitization to cocaine is associated with distinct pattern of glutamate receptor trafficking to the postsynaptic density in prefrontal cortex: early versus late withdrawal effects . Pharmacol, Biochem Behav 92: 383 – 392 .

Google Scholar Crossref | Medline | ISI

Giorgi, O, Piras, G, Corda, MG ( 2007 ) The psychogenetically selected Roman high- and low-avoidance rat lines: a model to study the individual vulnerability to drug addiction . Neurosci Biobehav Rev 31: 148 – 163 .

Google Scholar Crossref | Medline | ISI

Hédou, G, Jongen-Rêlo, AL, Murphy, CA. ( 2002 ) Sensitized Fos expression in subterritories of the rat medial prefrontal cortex and nucleus accumbens following amphetamine sensitization as revealed by stereology . Brain Res 950: 165 – 179 .

Google Scholar Crossref | Medline | ISI

Helmstetter, FJ, Bellgowan, PS ( 1994 ) Effects of muscimol applied to the basolateral amygdala on acquisition and expression of contextual fear conditioning in rats . Behav Neurosci 108: 1005 – 1109 .

Google Scholar Crossref | Medline | ISI

Jackson, ME, Frost, AS, Moghaddam, B ( 2001 ) Stimulation of prefrontal cortex at physiologically relevant frequencies inhibits dopamine release in the nucleus accumbens . J Neurochem 78: 920 – 923 .

Google Scholar Crossref | Medline | ISI

Jia, Z, Worhunsky, PD, Carrol, KM. ( 2011 ). An initial study of neural responses to monetary incentives as related to treatment outcome in cocaine dependence . Biol Psychiatry 70: 553 – 560 .

Google Scholar Crossref | Medline | ISI

Kalivas, PW ( 2007 ) Cocaine and amphetamine-like psychostimulants: neurocircuitry and glutamate neuroplasticity . Dialogues Clin Neurosci 9: 389 – 397 .

Google Scholar Medline

Klebaur, JE, Ostrander, MM, Norton, CS. ( 2002 ) The ability of amphetamine to evoke arc (Arg 3.1) mRNA expression in the caudate, nucleus accumbens and neocortex is modulated by environmental context . Brain Res 930: 30 – 36 .

Google Scholar Crossref | Medline | ISI

Kolb, B ( 1984 ) Functions of the frontal cortex of the rat: a comparative review . Brain Res 320: 65 – 98 .

Google Scholar Crossref | Medline | ISI

Krimer, LS, Jakab, RL, Goldman-Rakic, PS ( 1997 ). Quantitative three-dimensional analysis of the catecholaminergic innervation of identified neurons in the macaque prefrontal cortex . J Neurosci 17: 7450 – 7461 .

Google Scholar Medline | ISI

Laakso, A, Mohn, AR, Gainetdinov, RR. ( 2002 ) Experimental genetic approaches to addiction . Neuron 36: 213 – 228 .

Google Scholar Crossref | Medline | ISI

LeDoux, JE ( 1993 ) Emotional memory systems in the brain . Behav Brain Res 58: 69 – 79 .

Google Scholar Crossref | Medline | ISI

Lee, KW, Kim, HC, Lee, SY. ( 2011 ) Methamphetamine-sensitized mice are accompanied by memory impairment and reduction of N-methyl-d-aspartate receptor ligand binding in the prefrontal cortex and hippocampus . Neuroscience 178: 101 – 107 .

Google Scholar Crossref | Medline | ISI

Lehner, M, Taracha, E, Skórzewska, A. ( 2008 ) Expression of c-Fos and CRF in the brains of rats differing in the strength of a fear response . Behav Brain Res 188: 154 – 167 .

Google Scholar Crossref | Medline | ISI

Lehner, MH, Taracha, E, Kaniuga, E. ( 2014 ) High-anxiety rats are less sensitive to the rewarding affects of amphetamine on 50kHz USV . Behav Brain Res 275: 234 – 242 .

Google Scholar Crossref | Medline | ISI

Lehner, M, Wisłowska-Stanek, A, Skórzewska, A. ( 2010 ) Differences in the density of GABA-A receptor alpha-2 subunits and gephyrin in brain structures of rats selected for low and high anxiety in basal and fear-stimulated conditions, in a model of contextual fear conditioning . Neurobiol Learn Mem 94: 499 – 508 .

Google Scholar Crossref | Medline | ISI

Lehner, M, Wislowska-Stanek, A, Skorzewska, A. ( 2011 ) Expression of N-methyl- d -aspartate (R)(GluN2B) - subunits in the brain structures of rats selected for low and high anxiety . J Physiol Pharmacol 62: 473 – 582 .

Google Scholar Medline | ISI

Mao, LM, Reusch, JM, Fibuch, EE. ( 2013 ) Amphetamine increases phosphorylation of MAPK/ERK at synaptic sites in the rat striatum and medial prefrontal cortex . Brain Res 1494: 101 – 108 .

Google Scholar Crossref | Medline | ISI

Mao, LM, Wang, W, Chu, XP. ( 2009 ) Stability of surface NMDA receptors controls synaptic and behavioral adaptations to amphetamine . Nat Neurosci 12: 602 – 610 .

Google Scholar Crossref | Medline | ISI

Maren, S, Quirk, GJ ( 2004 ). Neuronal signaling of fear memory . Nat Rev Neurosci 5: 844 – 852 .

Google Scholar Crossref | Medline | ISI

Morshedi, MM, Meredith, GE ( 2008 ) Repeated amphetamine administration induces Fos in prefrontal cortical neurons that project to the lateral hypothalamus but not the nucleus accumbens or basolateral amygdala . Psychopharmacology (Berlin) 197: 179 – 189 .

Google Scholar Crossref | Medline | ISI

Naranjo, CA, Tremblay, LK, Busto, UE ( 2001 ) The role of the brain reward system in depression . Prog Neuro-Psychopharmacol Biol Psychiatry 25: 781 – 823 .

Google Scholar Crossref | Medline | ISI

O’Brien, CP, Childress, AR, Ehrman, R. ( 1998 ) Conditioning factors in drug abuse: can they explain compulsion? J Psychopharmacol 12: 15 – 22 .

Google Scholar SAGE Journals | ISI

O’Daly, OG, Joyce, D, Tracy, DK. ( 2014 ). Amphetamine sensitization and memory in healthy human volunteers a functional magnetic resonance study . J Psychopharmacol, 28: 857 – 865 .

Google Scholar SAGE Journals | ISI

Paxinos, G, Watson, CH ( 1998 ). The rat brain in stereotaxic coordinates. San Diego, CA : Academic Press Inc .

Google Scholar

Petrides, M, Pandya, DN ( 1999 ) Dorsolateral prefrontal cortex: comparative cytoarchitectonic analysis in the human and the macaque brain and corticocortical connection patterns . Eur J Neurosci 11: 1011 – 1036 .

Google Scholar Crossref | Medline | ISI

Phillips, AG, Ahn, S, Howland, JG ( 2003 ) Amygdalar control of the mesocorticolimbic dopamine system: parallel pathways to motivated behavior . Neurosci Biobehav Rev 27: 543 – 554 .

Google Scholar Crossref | Medline | ISI

Rademacher, DJ, Rosenkranz, JA, Morshedi, MM. ( 2010 ) Amphetamine-associated contextual learning is accompanied by structural and functional plasticity in the basolateral amygdala . J Neurosci 30: 4676 – 4686 .

Google Scholar Crossref | Medline | ISI

Rosenkranz, JA, Grace, AA ( 2001 ) Dopamine attenuates prefrontal cortical suppression of sensory inputs to the basolateral amygdala of rats . J Neurosci 21: 4090 – 4103 .

Google Scholar Crossref | Medline | ISI

Samaha, AN, Mallet, N, Ferguson, SM. ( 2004 ) The rate of cocaine administration alters gene regulation and behavioral plasticity: implications for addiction . J Neurosci 24: 6362 – 6370 .

Google Scholar Crossref | Medline | ISI

Schulz, KP, Himelstein, J, Halperin, JM. ( 2000 ) Neurobiological models of attention-deficit/hyperactivity disorder: a brief review of the empirical evidence . CNS Spectrum 5: 34 – 44 .

Google Scholar Crossref | Medline

Shenton, ME, Dickey, CC, Frumin, M. ( 2001 ). A review of MRI findings . Schizophr Res 49: 1 – 52 .

Google Scholar Crossref | Medline | ISI

Shoblock, JR, Maisonneuve, IM, Glick, SD ( 2003 ) Differences between d-methamphetamine and d-amphetamine in rats: working memory, tolerance, and extinction . Psychopharmacology (Berlin) 170: 150 – 156 .

Google Scholar Crossref | Medline | ISI

Shoblock, JR, Maisonneuve, IM, Glick, SD ( 2004 ) Differential interactions of desipramine with amphetamine and methamphetamine: evidence that amphetamine releases dopamine from noradrenergic neurons in the medial prefrontal cortex . Neurochem Res 29: 1437 – 1442 .

Google Scholar Crossref | Medline | ISI

Simola, N, Morelli, M ( 2015 ) Repeated amphetamine administration and long-term effects on 50-kHz ultrasonic vocalizations: possible relevance to the motivational and dopamine-stimulating properties of the drug . Eur Neuropsychopharmacol 25: 343 – 355 .

Google Scholar Crossref | Medline | ISI

Simola, N, Frau, L, Plumitallo, A. ( 2014 ) Direct and long-lasting effects elicited by repeated drug administration on 50-kHz ultrasonic vocalizations are regulated differently: implications for the study of the affective properties of drugs of abuse . Int J Neuropsychopharmacol 17: 429 – 441 .

Google Scholar Crossref | Medline | ISI

Stedenfeld, KA, Clinton, SM, Kerman, IA. ( 2011 ) Novelty-seeking behavior predicts vulnerability in a rodent model of depression . Physiol Behav 103: 210 – 216 .

Google Scholar Crossref | Medline | ISI

Stone, EA, Yan, L, Ahsan, MR. ( 2006 ) Role of CNS alpha1-adrenoceptor activity in central fos responses to novelty . Synapse 59: 299 – 307 .

Google Scholar Crossref | Medline | ISI

Taracha, E, Hamed, A, Krząścik, P. ( 2012 ) Inter-individual diversity and intra-individual stability of amphetamine-induced sensitization of frequency-modulated 50-kHz vocalization in Sprague-Dawley rats . Psychopharmacology (Berlin) 222: 619 – 632 .

Google Scholar Crossref | Medline | ISI

Taracha, E, Kaniuga, E, Chrapusta, SJ. ( 2014 ) Diverging frequency-modulated 50-kHz vocalization, locomotor activity and conditioned place preference effects in rats given repeated amphetamine treatment . Neuropharmacology 83: 128 – 36 .

Google Scholar Crossref | Medline | ISI

Topic, B, Oitzl, MS, Meijer, OC. ( 2008 ) Differential susceptibility to extinction-induced despair and age-dependent alterations in the hypothalamic-pituitary-adrenal axis and neurochemical parameters . Neuropsychobiology 58: 138 – 153 .

Google Scholar Crossref | Medline | ISI

Tseng, KY, O’Donnell, P ( 2004 ) Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms . J Neurosci 24: 5131 – 5139 .

Google Scholar Crossref | Medline | ISI

Tzschentke, TM, Schmidt, WJ ( 1998 ) Blockade of morphine- and amphetamine-induced conditioned place preference in the rat by riluzole . Neurosci Lett 242: 114 – 116 .

Google Scholar Crossref | Medline | ISI

Urban, KR, Li, YC, Gao, WJ ( 2013 ) Treatment with a clinically-relevant dose of ethylphenidate alters NMDA receptor composition and synaptic plasticity in the juvenile rat prefrontal cortex . Neurobiol Learn Mem 101: 65 – 67 .

Google Scholar Crossref | Medline | ISI

Valjent, E, Bertran-Gonzalez, J, Aubier, B. ( 2010 ) Mechanisms of locomotor sensitization to drugs of abuse in a two-injection protocol . Neuropsychopharmacology 35: 401 – 415 .

Google Scholar Crossref | Medline | ISI

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 (Berlin) 151: 99 – 120 .

Google Scholar Crossref | Medline | ISI

Williams, SN, Undieh, AS ( 2010 ) Brain-derived neurotrophic factor signaling modulates cocaine induction of reward-associated ultrasonic vocalization in rats . J Pharmacol Exp Ther 332: 463 – 468 .

Google Scholar Crossref | Medline | ISI