The high affinity dopamine uptake inhibitor, JHW 007, blocks cocaine-induced reward, locomotor stimulation and sensitization
Introduction
Cocaine addiction is a chronic neuropsychiatric disorder that poses a severe burden for the individuals affected and society. The pharmacological treatment of cocaine addiction has relied thus far on dopamine (DA) agonists, antidepressants and GABA medications (Karila et al., 2008, Sofuoglu & Kosten, 2006, Minozzi et al., 2008), while other strategies, such as vaccination (Orson et al., 2009), remain to be fully developed and evaluated. There is substantial agreement that interference with the DA transporter (DAT) is required for cocaine to induce psychostimulant effects. The potency of cocaine-like drugs to sustain self-administration in animals was shown to correlate with their binding affinity at the DAT (Ritz et al., 1987). Further, a correlation was found between DAT occupancy by cocaine and the magnitude of self-reported “high” in humans (Volkow et al., 1997). Another factor deemed important was the rate of DAT occupancy, as uptake inhibitors with slow DAT occupancy, such as methylphenidate, do not uniformly evoke euphorogenic effects despite producing significant DAT blockade (Volkow et al., 1996, Volkow et al., 1999). Moreover, several DAT blockers, including bupropion and nomifensine, have not been reported to induce euphoria or possess significant abuse liability. Taken together, these findings fuelled the concept of agonist or replacement treatment in cocaine addiction by means of slow-onset, long-acting DAT inhibitors (Rothman, 1990, Grabowski et al., 2004).
The design of compounds with low abuse potential that could block the actions of cocaine is hindered by the fact that dopamine, cocaine and amphetamine bind at extensively overlapping recognition sites at the DAT (Indarte et al., 2008, Beuming et al., 2008). However, binding to the DAT and subsequent transport inhibition does not invariably produce cocaine-like effects (Katz et al., 1997) (Newman and Katz, 2009). One of the most promising leads toward the development of effective substitute medications for cocaine addiction was the discovery of the benztropine (BZT) class of DAT inhibitors. Chemical substitutions of the parent BZT molecule generated a large number of analogues, some of which showed enhanced potency for inhibition of DA uptake and atypical pharmacokinetic/dynamic properties that are distinct from those of cocaine (Newman & Agoston, 1998, Newman & Kulkarni, 2002). Some BZT analogues exhibited rates of DAT occupancy slower than that of cocaine (Desai et al., 2005) and provoked long-lasting increases in striatal dopamine release (Raje et al., 2005, Tanda et al., 2009). Most remarkably, some BZT analogues, including AHN-1055 and JHW 007, appeared to be devoid of strong psychostimulant effects (Desai et al., 2005, Hiranita et al., 2009), thus supporting their candidacy as potential medications for cocaine addiction.
We showed previously that the N-substituted BZT analogue, AHN-1055, prevented cocaine-induced striatal early-gene expression, locomotor activity and conditioned reward (Velazquez-Sanchez et al., 2009), and displayed low abuse liability in self-administration and relapse assays (Ferragud et al., 2009). The antagonistic effects of AHN-1055 can be ascribed to DAT interference but also to its anticholinergic profile, as this BZT analogue readily antagonizes muscarinic M1 receptors. To gain insight into the relative contribution of these targets, we studied the behavioural effects of JHW 007, an N-substituted BZT analogue with 10-fold selectivity for DAT versus M1 receptors and > 50-fold versus serotonin and norepinephrine transporters. To characterize the behavioural profile of JHW 007, we used conditioned place preference (CPP), locomotor stimulation and anxiety-like behavioural assays in which the BZT analogue was administered alone and in combination with cocaine.
Section snippets
Subjects
Male Swiss OF1 mice (N = 188) purchased from Charles River (Barcelona, Spain) served as experimental subjects. Mice were 5–6 week of age upon arrival at the laboratories and were allowed 4–7 days to acclimatize to the animal facility before the experiments began. Mice were housed in groups of 4 subjects with food and water available ad libitum. The housing room was maintained under standard conditions of temperature (21 ± 2 °C) and humidity (45–55%) and was kept on a 12 h light–dark cycle (lights on at
Results
To investigate the ability of JHW 007 to influence cocaine-induced conditioned reward in the CPP paradigm, mice received different doses of BZT analogue as a pre-treatment and saline or cocaine as a post-treatment. Fig. 1 shows the results. ANOVA was carried out with one between-subject variable, Treatment, with eight levels (eight groups of treatment) and one within-subjects variable, Conditioning, with two levels (pre-conditioning and post-conditioning). ANOVA indicated a significant effect
Discussion
The general aim of the current experiments was to characterize the effects of the BZT analogue, JHW 007, a high affinity DAT inhibitor, in preclinical models of cocaine addiction. The specific objectives were three-fold. First, we studied the rewarding effects of JHW 007 in the CPP paradigm and the ability of the BZT analogue to influence cocaine-induced CPP. Second, we examined locomotor activity in mice undergoing drug conditioning to determine the effects of JHW 007 treatment alone and the
Role of the funding source
Funding for this study was provided by Plan Nacional sobre Drogas (Spanish Ministry of Health) and the Instituto de Salud Carlos III (Network for Addictive Disorders, Spanish Ministry of Science and Technology). These institutions had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors
Authors Clara Velázquez-Sánchez and Juan J. Canales designed the study and wrote the manuscript. Authors Clara Velázquez-Sánchez and Antonio Ferragud performed the experiments and analyzed the data. Authors Juan Murga and Miguel Cardá synthesized the BZT analogue. All authors contributed to and have approved the final manuscript.
Conflict of interest
The authors declare that they have no conflicts of interest.
Acknowledgements
The study was supported by grants from Plan Nacional sobre Drogas (Spanish Ministry of Health) and the Instituto de Salud Carlos III (Network for Addictive Disorders, Red RTA, Spanish Ministry of Science and Technology). Clara Velázquez-Sánchez is a recipient of a graduate student contract from the Instituto de Salud Carlos III. The technical assistance of Agueda Ferrer, Gema Morant and Alexandra Arcusa is gratefully acknowledged.
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2018, Neuroscience LettersCitation Excerpt :Among other promising compounds, one of such N-substituted BZT analogues, JHW-007, showed nearly 10-fold higher affinity for the DAT (Ki = 25 nM) than cocaine and negligible activity at the NET (Ki = 1330 nM) and SERT (Ki = 1730 nM) [32], together with a slower rate of DAT occupancy and receptor offset [16,12]. Moreover, JHW-007 was able to block cocaine stimulant effects [16,33], cocaine place preference [33], amphetamine sensitization [18] and METH self-administration [19,20], while not sustaining responding in a self-administration task [17]. These findings strongly suggest that JHW-007 could be an effective substitute treatment for METH.
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