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. 2019 Nov 29;12:292.
doi: 10.3389/fnmol.2019.00292. eCollection 2019.

Amphetamine and the Smart Drug 3,4-Methylenedioxypyrovalerone (MDPV) Induce Generalization of Fear Memory in Rats

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Free PMC article

Amphetamine and the Smart Drug 3,4-Methylenedioxypyrovalerone (MDPV) Induce Generalization of Fear Memory in Rats

Paola Colucci et al. Front Mol Neurosci. .
Free PMC article

Abstract

Human studies have consistently shown that drugs of abuse affect memory function. The psychostimulants amphetamine and the "bath salt" 3,4-methylenedioxypyrovalerone (MDPV) increase brain monoamine levels through a similar, yet not identical, mechanism of action. Findings indicate that amphetamine enhances the consolidation of memory for emotional experiences, but still MDPV effects on memory function are underinvestigated. Here, we tested the effects induced by these two drugs on generalization of fear memory and their relative neurobiological underpinnings. To this aim, we used a modified version of the classical inhibitory avoidance task, termed inhibitory avoidance discrimination task. According to such procedure, adult male Sprague-Dawley rats were first exposed to one inhibitory avoidance apparatus and, with a 1-min delay, to a second apparatus where they received an inescapable footshock. Forty-eight hours later, retention latencies were tested, in a randomized order, in the two training apparatuses as well as in a novel contextually modified apparatus to assess both strength and generalization of memory. Our results indicated that both amphetamine and MDPV induced generalization of fear memory, whereas only amphetamine enhanced memory strength. Co-administration of the β-adrenoceptor antagonist propranolol prevented the effects of both amphetamine and MDPV on the strength and generalization of memory. The dopaminergic receptor blocker cis-flupenthixol selectively reversed the amphetamine effect on memory generalization. These findings indicate that amphetamine and MDPV induce generalization of fear memory through different modulations of noradrenergic and dopaminergic neurotransmission.

Keywords: behavior; dopamine; inhibitory avoidance discrimination task; memory accuracy; norepinephrine; rat.

Figures

Figure 1
Figure 1
Schematic representation of the experimental design.
Figure 2
Figure 2
Amphetamine and 3,4-methylenedioxypyrovalerone (MDPV) induce memory generalization of inhibitory avoidance discrimination task. On the 48-h retention test, rats were sequentially tested in all three contextually modified inhibitory avoidance apparatuses in a random order and their retention latencies were analyzed. (A) Retention latencies of amphetamine and saline-treated rats. Saline-treated animals showed longer retention latencies in the Shock box and Non-Shock box compared to those induced in the Novel box. In all three boxes, amphetamine 3 mg/kg induced higher retention latencies than saline-treated rats. ##P < 0.01 saline group latencies in the Shock box or Non-Shock box vs. saline group latencies in the Novel box; *P < 0.05, **P < 0.01 amphetamine 3 mg/kg latencies in the Shock box, Non-Shock box or Novel box vs. saline group in the Shock box, Non-Shock box or Novel box; NS, no significant differences (n = 9–13 rats). (B) Retention latencies of MDPV and saline-treated rats. Saline-treated animals showed longer retention latencies in the Shock box and Non-Shock box compared to those induced in the Novel box. In the Novel box retention latencies induced by MDPV 1 mg/kg were significantly longer than those induced by saline-treated rats in the same box. #P < 0.05 saline group latencies in the Shock box or Non-Shock box vs. saline group latencies in the Novel box; *P < 0.05 MDPV 1 mg/kg treated group latencies in the Novel box vs. saline group latencies in the Novel box; NS, no significant differences (n = 10–12 rats).
Figure 3
Figure 3
Noradrenergic activation mediates amphetamine and MDPV effects on memory generalization. On the 48-h retention test, rats were sequentially tested in all three contextually modified inhibitory avoidance apparatuses in a random order and their retention latencies were analyzed. (A) Retention latencies of rats treated with propranolol or saline 30 min prior to training together with amphetamine or saline administered immediately after training. Saline alone-treated animals showed longer retention latencies in the Shock box and Non-Shock box compared to those induced in the Novel box, the same happens for the propranolol alone-treated animals. In all three boxes, amphetamine alone-treated rats showed higher retention latencies than saline alone-treated rats and then those exerted by rats given propranolol alone. Retention latencies of the group treated with propranolol together with amphetamine in all three boxes were significantly lower compared to those of amphetamine alone-treated rats. #P < 0.05 saline group latencies in the Shock box or Non-Shock box vs. saline group latencies in the Novel box; P < 0.05 propranolol alone latencies in the Shock box or Non-Shock box vs. propranolol alone latencies in the Novel box; *P < 0.05, **P < 0.01 amphetamine alone-treated group latencies in the Shock box, Non-Shock box or Novel box vs. saline group latencies in the Shock box, Non-Shock box or Novel box; §P < 0.05, §§P < 0.01 amphetamine alone-treated group latencies in the Shock box, Non-Shock box or Novel box vs. propranolol alone group latencies in the Shock box, Non-Shock box or Novel box; °P < 0.05, °°P < 0.01 propranolol and amphetamine-treated group latencies in the Shock box, Non-Shock box or Novel box vs. amphetamine alone-treated group latencies in the Shock box, Non-Shock box or Novel box; NS, no significant differences (n = 9–13 rats). (B) Retention latencies of rats treated with propranolol or saline 30 min prior to training together with MDPV or saline administered immediately after training. Saline alone-treated animals showed longer retention latencies in the Shock box and Non-Shock box compared to those induced in the Novel box, the same happens for the propranolol together with MDPV-treated animals. In the Novel box retention latencies induced by MDPV alone treatment were significantly longer than those exerted by rats treated with saline alone and propranolol alone. Retention latencies of the group treated with propranolol together with MDPV in the Novel box were significantly lower compared to those of MDPV alone-treated rats. #P < 0.05 saline group latencies in the Shock box or Non-Shock box vs. saline group latencies in the Novel box; P < 0.05 propranolol together with MDPV latencies in the Shock box or Non-Shock box vs. propranolol together with MDPV latencies in the Novel box; **P < 0.01, MDPV alone-treated group latencies in the Novel box vs. saline group latencies in the Novel box; §P < 0.05, MDPV alone-treated group latencies in the Novel box vs. propranolol alone-treated group latencies in the Novel box; °P < 0.05, propranolol and MDPV-treated group latencies in the Novel box vs. MDPV alone-treated group in the Novel box; NS, no significant differences (n = 8–11 rats).
Figure 4
Figure 4
Dopaminergic activation mediates the effects induced by amphetamine, but not MDPV, on memory generalization. On the 48-h retention test, rats were sequentially tested in all three contextually modified inhibitory avoidance apparatuses in a random order and their retention latencies were analyzed. (A) Retention latencies of rats treated with cis-flupenthixol or saline 30 min prior to training together with amphetamine or saline administered immediately after training. Saline alone-treated animals showed longer retention latencies in the Shock box and Non-Shock box compared to those induced in the Novel box. Cis-flupenthixol alone-treated animals showed higher retention latencies in Shock box compared only to those showed in the Novel box. Cis-flupenthixol together with amphetamine treated-rats showed longer retention latencies in the Shock box and Non-Shock box compared to those induced in the Novel box. In all three boxes, amphetamine alone-treated rats showed higher retention latencies than saline alone-treated rats and cis-flupenthixol alone-treated rats. Retention latencies of rats treated with cis-flupenthixol together with amphetamine were significantly lower than those of amphetamine alone-treated rats, only in the Novel box. #P < 0.05 saline group latencies in the Shock box or Non-Shock box vs. saline group latencies in the Novel box; P < 0.05 cis-flupenthixol alone latencies in the Shock box vs. cis-flupenthixol alone latencies in the Novel box; +P < 0.05, cis-flupenthixol together with amphetamine latencies in the Shock or Non-Shock box vs. cis-flupenthixol together with amphetamine latencies in the Novel box; *P < 0.05, **P < 0.01, amphetamine alone-treated group latencies in the Shock box, Non-Shock box or Novel box vs. saline group latencies in the Shock box, Non-Shock box or Novel box; §P < 0.05, §§P < 0.01, amphetamine alone group latencies in the Shock box, Non-Shock box or Novel box vs. cis-flupenthixol alone-treated group latencies in the Shock box, Non-Shock box or Novel box; °°P < 0.01, cis-flupenthixol and amphetamine-treated group latencies in the Novel box vs. amphetamine alone-treated group in the Novel box; NS, no significant differences (n = 9–10 rats). (B) Retention latencies of rats treated with cis-flupenthixol or saline 30 min prior to training together with MDPV or saline administered immediately after training. Saline alone-treated animals showed longer retention latencies in the Shock box and Non-Shock box compared to those induced in the Novel box, the same happens to cis-flupenthixol alone-treated animals. In the Novel box, MDPV alone-treated rats showed higher latencies with respect to saline-treated rats and cis-flupenthixol alone-treated rats; cis-flupenthixol and MDPV-treated rats showed higher latencies with respect to cis-flupenthixol alone-treated rats and with respect to cis-flupenthixol alone-treated. #P < 0.05 saline group latencies in the Shock box or Non-Shock box vs. saline group latencies in the Novel box; P < 0.05, ∧∧P < 0.01, cis-flupenthixol alone latencies in the Shock box or Non-shock box vs. cis-flupenthixol alone latencies in the Novel box; **P < 0.01, MDPV alone-treated group latencies in the Novel box vs. saline group latencies in the Novel box; §§P < 0.01, MDPV alone-treated group latencies in the Novel box vs. cis-flupenthixol alone-treated group in the Novel box; &P < 0.05, cis-flupenthixol together with MDPV retention latencies in the Novel box vs. cis-flupenthixol alone latencies in the Novel box; NS, no significant differences (n = 8–11 rats).

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