The atypical dopamine transport inhibitor, JHW 007, prevents amphetamine-induced sensitization and synaptic reorganization within the nucleus accumbens Clara Velázquez-Sánchez a , José M. García-Verdugo b , Juan Murga c , Juan J. Canales a, ⁎ a Behavioural Neuroscience, Department of Psychology, University of Canterbury, Christchurch, New Zealand b Laboratory of Comparative Neurobiology, Cavanilles Institute (ICBiBE), University of Valencia, Valencia, Spain c Department of Inorganic and Organic Chemistry, University Jaime I, Castellón, Spain abstract article info Article history: Received 18 December 2012 Received in revised form 25 January 2013 Accepted 25 January 2013 Available online 4 February 2013 Keywords: Amphetamine Asymmetric synapses Benztropine analog Dendritic spines Nucleus accumbens Sensitization Benztropine (BZT) analogs, a family of agents with high affinity for the dopamine transporter have been pos- tulated as potential treatments in stimulant abuse due to their ability to attenuate a wide range of effects evoked by psychomotor stimulants such as cocaine and amphetamine (AMPH). Repeating administration of drugs, including stimulants, can result in behavioral sensitization, a progressive increase in their psycho- motor activating effects. We examined in mice the sensitizing effects and the neuroplasticity changes elicited by chronic AMPH exposure, and the modulation of these effects by the BZT derivative and atypical dopamine uptake inhibitor, JHW007, a candidate medication for stimulant abuse. The results indicated that JHW007 did not produce sensitized locomotor activity when given alone but prevented the sensitized motor behavior in- duced by chronic AMPH administration. Morphological analysis of medium spiny neurons of the nucleus accumbens revealed that JHW 007 prevented the neuroadaptations induced by chronic AMPH exposure, in- cluding increments in dendritic arborization, lengthening of dendritic processes and increases in spine den- sity. Furthermore, data revealed that AMPH produced an increase in the density of asymmetric, possibly glutamatergic synapses in the nucleus accumbens, an effect that was also blocked by JHW007 pretreatment. The present observations demonstrate that JHW007 is able to prevent not only AMPH-induced behavioral sensitization but also the long-term structural changes induced by chronic AMPH in the nucleus accumbens. Such findings support the development and evaluation of BZT derivatives as possible leads for treatment in stimulant addiction. © 2013 Elsevier Inc. All rights reserved. 1. Introduction Behavioral sensitization refers to the progressive increase in the psychomotor effects that many drugs of abuse produce after repeated and intermittent administration (Robinson and Becker, 1986; Robinson and Berridge, 1993). Drugs such as cocaine, amphetamine (AMPH), meth- amphetamine, ethanol, nicotine, morphine and Δ 9 -tetrahydrocannabinol are all able to induce behavioral sensitization that results in an augmented locomotor response to subsequent challenge with the drug (Pierce and Kalivas, 1997; Vanderschuren and Kalivas, 2000). The mesocorticolimbic dopamine system plays an important role in the development of behavioral sensitization (Koob and Bloom, 1988; Wise and Bozarth, 1987). Research in the last 20 years has identified a range of plasticity changes in the ventral tegmental area (VTA), the nucleus accumbens (NAc) and medial prefrontal cortex (PFC) in the form of both functional and structural adaptations (Kalivas and Stewart, 1991; Pierce and Kalivas, 1997; Robinson and Becker, 1986; Stewart and Badiani, 1993; Wolf, 1998), which may last for prolonged periods of time after drug withdrawal (Kalivas and Stewart, 1991; Paulson et al., 1991; Stewart and Badiani, 1993). Such structural modifications could be responsible for persistent changes in behavior, including stimulant-induced psychosis and addiction (Robinson and Becker, 1986; Segal et al., 1981). Converging evidence has revealed that the administration of cocaine and AMPH, either by the experimenter or self-administered, increases the spine density of medium spiny neurons (MSNs) in both the shell and core regions of NAc (Li et al., 2003; Robinson and Kolb, 1999; Robinson et al., 2001) and also in pyramidal cells of the medial PFC (Robinson and Kolb, 1999). The increase in spine density in the NAc cor- relates with increases in dendritic branching (Kolb et al., 2003; Robinson and Kolb, 1997) and at least for AMPH with increases in the length of den- drites of NAc neurons and layer III neurons of medial PFC (Robinson and Kolb, 1997). Several other forms of experience-dependent plasticity, Progress in Neuro-Psychopharmacology & Biological Psychiatry 44 (2013) 73–80 Abbreviations: AMPH, Amphetamine; BZT, Benztropine; DAT, Dopamne trans- porter; MSNs, Medium spiny neurons; FADD, Fas-associated death domain; JHW 007, [(N-(n-butyl)-3α-[bis(4′-fluorophenyl)methoxy]-tropane)]; AHN 1055, [3α-[bis(4'-fluorophenyl)methoxy]-tropane]; NAc, Nucleus accumbens; VTA, Ven- tral tegmental area; PFC, Prefrontal cortex; EM, Electron microscopy; PB, Phosphate buffer; N-K, Newman–Keuls. ⁎ Corresponding author at: Behavioural Neuroscience, Department of Psychology, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand. Tel.: +64 3 364 2987x7005. E-mail address: juan.canales@canterbury.ac.nz (J.J. Canales). 0278-5846/$ – see front matter © 2013 Elsevier Inc. 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