Methylenedioxypyrovalerone (MDPV) impairs working memory and alters patterns of dopamine signaling in mesocorticolimbic substrates

Abstract

Knowledge remains limited about how chronic cathinone exposure impacts dopamine systems in brain reward circuits. In the present study, a binge-like MDPV exposure that impaired novel object recognition (NOR) dysregulated dopamine markers in mesocorticolimbic substrates of rats, with especially profound effects on D1 and D2 receptor's and VMAT gene expression. Our data suggested that dopamine receptivity was reduced in the NAc but increased in the PFC and dopamine-producing VTA. The MDPV-induced impairment of NOR was prevented by a D1 receptor antagonist, suggesting that chronic MDPV exposure produces site-specific dysregulation of dopamine markers in the mesocorticolimbic circuit and memory deficits in the NOR test that are influenced by D1 receptors.

Keywords: Addiction; Cathinones; Dopamine; Methylenedioxypyrovalerone; Neurotransmitters.

Figure 1.. Single injection of MDPV affects dopamine-related gene expression in the NAc, VTA and PFC regions of rat’s brain.

qRT-PCR quantification of the mRNA levels for DRD1 (A), DRD2 (B), DAT1 (C) and VMAT2 (D), genes in brain tissue obtained from rats treated with single injection of MDPV (1 mg/kg) (brains extracted 120 min after last MDPV injection). Gene expression level in control group was set as 1. Data are presented as fold-change in gene expression normalized to GAPDH, represented as ±SEM. N=4–6. *p < 0.05 or **p < 0.01 versus saline control (MDPV 0 mg/kg).

Figure 2.. Repeated MDPV exposure affects dopamine-related gene expression in the NAc, VTA and PFC regions of rat’s brain.

qRT-PCR quantification of the mRNA levels for DRD1 (A), DRD2 (B), DAT1 (C) and VMAT2 (D) genes in brain tissue obtained from rats treated with MDPV (1 mg/kg) 3 times/day for 10 consecutive days (brains extracted 120 min after last MDPV injection). Gene expression level in control group was set as 1. Data are presented as fold-change in gene expression normalized to GAPDH, represented as ±SEM. N=4–6. *p < 0.05 or **p < 0.01 versus saline control (MDPV 0 mg/kg).

Figure 3.. Repeated MDPV exposure produces deficit in NOR that is prevented by a D1 receptor antagonist.

(A) Rats were treated with MDPV (1 mg/kg) or saline 3x/day for 10 days. Rats from both treatment groups were pretreated with a D1 antagonist (SCH 23390) (0.3 mg/kg), D2 antagonist (eticlopride) (0.1 mg/kg), or saline 30 min before the first daily injections of MDPV. Data are presented as discrimination index + S.E.M., N=8 rats/group. **p < 0.05 versus SAL + MDPV group. (Insert) Rats injected once with MDPV (1 mg/kg) or saline were tested for NOR. N=4–6 rats/group.