Heteromeric nicotinic receptors are involved in the sensitization and addictive properties of MDMA in mice

Abstract

We have investigated the effect of nicotinic receptor ligands in the behavioral sensitization (hyperlocomotion) and rewarding properties (conditioned place preference paradigm, CPP) of 3,4-methylenedioxy-methamphetamine (MDMA) in mice. Each animal received intraperitoneal pretreatment with either saline, dihydro-E-erythroidine (DHEE, 1 mg/Kg) or varenicline (VAR, 0.3 mg/Kg), 15 min prior to subcutaneous saline or MDMA (5 mg/Kg), for 10 consecutive days. On day 1, both DHEE and VAR inhibited the MDMA-induced hyperlocomotion. After 10 days of treatment, MDMA induced a hyperlocomotion that was not reduced (rather enhanced) in antagonistpretreated animals. This early hyperlocomotion was accompanied by a significant increase in heteromeric nicotinic receptors in cortex that was not blocked by DHEE or VAR. Behavioral sensitization to MDMA was highest 2 weeks after the discontinuation of MDMA treatment. This additional increase in sensitivity was prevented in animals pretreated with DHEE or VAR. At this time, MDMA-treated mice showed a significant increase in heteromeric receptors in cortex that was prevented by DHEE and VAR. An involvement of α7 nicotinic receptors in this effect is ruled out.MDMA (10 mg/Kg) induced positive CPP that was abolished by DHEE (2 mg/Kg) and VAR (2 mg/Kg). Moreover, chronic nicotine pretreatment (2 mg/Kg, ip, b.i.d., for 14 days) caused MDMA, administered at a low dose (3 mg/kg), to induce CPP, which would otherwise not occur. Finally, present results point out that heteromeric nicotinic receptors are involved in locomotor sensitization and addictive potential induced by MDMA. Thus, varenicline might be a useful drug to treat both tobacco and MDMA abuse at once.

Protracted treatment with MDMA induces heteromeric nicotinic receptor up-regulation in the rat brain: An autoradiography study

“…This is in agreement with our previous reports showing this effect in cultured PC 12 cells (Garcia-Ratés et al, 2007), in gross brain areas after the classical neurotoxic schedule (Pubill et al, 2013) or in mice after a sensitizing schedule (Ciudad-Roberts et al, 2013). MDMA has affinity for α4β2 nAChR (Garcia-Ratés et al, 2007;Chipana et al, 2008) as occurs with several nicotinic ligands, either agonists or antagonists, that have been reported to induce nAChR up-regulation (Peng et al, 1994;Gopalakrishnan et al, 1997).…”

“…Heteromeric nAChR play a role in the hyperlocomotion induced by amphetamine derivatives (Camarasa et al, 2009; Ciudad -1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Roberts et al, 2013), thus an increase in nAChR in these areas could account for sensitization to the locomotor effects and the addictive properties of MDMA. In fact, blockade of nAChR containing the α4 subunit with dihydro-β-erythroidine or varenicline inhibits the hyperlocomotion induced by MDMA in mice, as well as an increased delayed sensitization (Ciudad-Roberts et al, 2013). Moreover, in the same study it was demonstrated that pretreatment with nicotine inducing nAChR up-regulation reduced the dose threshold for MDMA-conditioned place preference.…”

“…Moreover, in recent in vivo studies (Pubill et al, 2013;Ciudad-Roberts et al, 2013), we have demonstrated that the classic neurotoxic treatment schedule of MDMA in rats (20 mg/kg b.i.d, 4 days) induces nAChR up-regulation in gross brain regions thus potentiating the up-regulation induced by nicotine; and that a sensitization schedule of MDMA in mice (5 mg/kg/day for 10 days) leads to heteromeric nAChR up-regulation in cortex. Changes in these receptors could have a role in drug addiction and explain some psychiatric effects of this drug, such as memory impairment and psychoses, among others in which nAChR have been found to play a role (Levin et al, 2002;Martin et al, 2004;Ripoll et al, 2004).…”

High affinity α3β4 nicotinic acetylcholine receptor ligands AT-1001 and AT-1012 attenuate cocaine-induced conditioned place preference and behavioral sensitization in mice

“…Among other neurotransmitter systems and circuitries that have been shown to directly or indirectly modulate cocaine-induced rewarding effects, the cholinergic system is of special interest. Activation of the nicotinic acetylcholine receptors (nAChRs), which are present throughout the mesocorticolimbic system, has been shown to play a major role in enhancing dopamine release in the mesolimbic reward circuitry [1–3], in neuroadaptive changes associated with cocaine abuse [4, 5] and in the rewarding and reinforcing effects of psychostimulants, including cocaine and amphetamines [1, 6, 7]. …”

Molecular basis of the selective binding of MDMA enantiomers to the alpha4beta2 nicotinic receptor subtype: Synthesis, pharmacological evaluation and mechanistic studies

“…Recently, Ciudad-Roberts et al [27] established that the α4β2 nAChR subtype modulates MDMA-mediated reinforcing properties. Previous studies [20,28] had also shown that MDMA has affinity for α4β2 nAChR and induced their up-regulation in PC12 cells following a similar mechanism than that of nicotine.…”