Alteration of Ethanol Reward by Prior Mephedrone Exposure: The Role of Age and Matrix Metalloproteinase-9 (MMP-9)

Abstract

Mephedrone, a synthetic cathinone, is widely abused by adolescents and young adults. The aim of this study was to determine: i) whether prior mephedrone exposure would alter ethanol reward and ii) whether age and matrix metalloproteinase-9 (MMP-9) are important in this regard. In our research, male Wistar rats at postnatal day 30 (PND30) received mephedrone at the dose of 10 mg/kg, i.p., 3 times a day for 7 days. To clarify the role of MMP-9 in the mephedrone effects, one mephedrone-treated group received minocycline, as an MMP-9 antagonist. Animals were then assigned to conditioned place preference (CPP) procedure at PND38 (adolescent) or at PND69 (adult). After the CPP test (PND48/79), expression of dopamine D1 receptors (D1R), Cav1.2 (a subtype of L-type calcium channels), and MMP-9 was quantified in the rat ventral striatum (vSTR). The influence of mephedrone administration on the N-methyl-D-aspartate glutamate receptors (NMDAR) subunits (GluN1, GluN2A, and GluN2B) was then assessed in the vSTR of adult rats (only). These results indicate that, in contrast with adolescent rats, adult rats with prior mephedrone administration appear to be more sensitive to the ethanol effect in the CPP test under the drug-free state. The mephedrone effect in adult rats was associated with upregulation of D1R, NMDAR/GluN2B, MMP-9, and Cav1.2 signaling. MMP-9 appears to contribute to these changes in proteins expression because minocycline pretreatment blocked mephedrone-evoked sensitivity to ethanol reward. Thus, our results suggest that prior mephedrone exposure differentially alters ethanol reward in adolescent and adult rats.

The L‐arginine‐NO‐cGMP pathway mediates the locomotor activity alterations during the expression of sensitization to mephedrone in mice

“…Furthermore, it was noticed that the enhanced locomotor activity of rats induced by mephedrone was inhibited by administration of a D 1 antagonist. 26 As for NR2B receptors, Grochecki et al 83,84 showed that a 10-day administration of 30 mg/kg of mephedrone and a 7-day administration of 10 mg/kg of this drug three times a day to adolescent rats resulted in a higher level of NR2B receptor subtype in the prefrontal cortex/ hippocampus and ventral striatum, respectively, during their adulthood. This small gaseous molecule facilitates the release of various monoamines (particularly dopamine) and it inhibits their reuptake via blockade of their transporters, which results in an increased monoaminergic neurotransmission.…”

Mephedrone – a synthetic derivative of cathinone

“…Mephedrone, moreover, also displays affinity for 5-HT2A, 5-HT2C, 5-HT1A, alpha-1A adrenergic receptor (α1A), alpha-2A adrenergic receptor (α2A), and trace amineassociated receptors (TAAR) [44,45,57,58]. There is also evidence that mephedrone interplays with the glutamatergic neurotransmission [59][60][61][62].…”

Impact of Mephedrone on Fear Memory in Adolescent Rats: Involvement of Matrix Metalloproteinase-9 (MMP-9) and N-Methyl-D-aspartate (NMDA) Receptor

“…The CPP unbiased paradigm was performed according to the method described earlier [18,83] with minor modifications. The apparatus designed to perform the CPP test consists of 6 cages divided into two compartments, 65 cm × 35 cm × 30 cm in size, differing in the color of the walls.…”

“…Our previous preclinical studies confirm that mephedrone possesses abuse potential and shows deleterious impact on memory processes. In these effects of mephedrone, both the matrix metalloproteinase-9 (MMP-9) and N-methyl-D-aspartate (NMDA) receptors are engaged [17,18]. The negative effect of mephedrone on memory processes is particularly strong when mephedrone is combined with ethanol [18,19].…”

“…In these effects of mephedrone, both the matrix metalloproteinase-9 (MMP-9) and N-methyl-D-aspartate (NMDA) receptors are engaged [17,18]. The negative effect of mephedrone on memory processes is particularly strong when mephedrone is combined with ethanol [18,19].…”