Phosphodiesterase type 1 inhibition improves learning in rats exposed to alcohol during the third trimester equivalent of human gestation

Abstract

Deficits in learning and memory have been extensively observed in animal models of fetal alcohol spectrum disorders (FASD). Here we use the Morris maze to test whether vinpocetine, a phosphodiesterase type 1 inhibitor, restores learning performance in rats exposed to alcohol during the third trimester equivalent of human gestation. Long Evans rats received ethanol (5g/kg i.p.) or saline on alternate days from postnatal day (P) 4 to P10. Two weeks later (P25), the latency to find a hidden platform was evaluated (2 trials per day spaced at 40-min inter-trial intervals) during 4 consecutive days. Vinpocetine treatment started on the first day of behavioral testing: animals received vinpocetine (20mg/kg i.p.) or vehicle solution every other day until the end of behavioral procedures. Early alcohol exposure significantly affected the performance to find the hidden platform. The average latency of ethanol-exposed animals was significantly higher than that observed for the control group. Treatment of alcohol-exposed animals with vinpocetine restored their performance to control levels. Our results show that inhibition of PDE1 improves learning and memory deficits in rats early exposed to alcohol and provide evidence for the potential therapeutic use of vinpocetine in FASD.

Figure 1

Body weight gain (in grams) from Postnatal Day (PD) 4 to PD10 (A), and from PD 25 to PD 29 (B). Values represent means (±SEM) from males and females combined. Note that ethanol exposure from PD4 to PD10 resulted in a significant body weight reduction, which persisted until P29. VINP = ethanol-exposed rats treated with vinpocetine; ETOH = ethanol-exposed rats treated with vehicle solution; CONT = saline-exposed rats treated with vehicle solution. ***P < 0.001 saline-exposed vs. ethanol-exposed; **P < 0.01 CONT vs. VINP; # P < 0.05 CONT vs. ETOH.

Figure 2

Mean (±SEM) latencies to find the hidden platform (A and B) and swimming speeds (C and D) for all groups in the Morris water maze. In A and C, data represents averaged values by trial. In B and D, data represents averaged values from all trials in all testing days. Note that ethanol exposed animals took significantly more time to find the hidden platform than control animals and that vinpocetine treatment was able to restore the latency of ethanol-exposed animals to control levels. The swimming speed did not differ between groups. VINP = ethanol-exposed rats treated with vinpocetine; ETOH = ethanol-exposed rats treated with vehicle solution; CONT = saline-exposed rats treated with vehicle solution. **P<0.01, * P <0.05.

Figure 3

Mean (±SEM) of percentage of time spent in each quadrant along sessions for the CONT (A), ETOH (B) and VINP (C) groups. In D, E and F are represented the respective mean differences between the second and the fourth sessions for each quadrant. The platform was positioned in the quadrant NE. Values were collapsed across trials over the training days. Note that the increase in time spent in the quadrant NE from the second to the fourth session was more pronounced in the CONT and VINP as compared to the ETOH group. VINP = ethanol-exposed rats treated with vinpocetine; ETOH = ethanol-exposed rats treated with vehicle solution; CONT = saline-exposed rats treated with vehicle solution. *P<0.05, comparisons with NE quadrant.

Figure 4

Mean (±SEM) of percentage of time spent in the outer ring along sessions. Values were collapsed across trials over the training days. In A, values were collapsed across trials over the training days. In B, values were collapsed across both trials and day. Note that the CONT group spent less time in the center than that ETOH and VINP groups. VINP = ethanol-exposed rats treated with vinpocetine; ETOH = ethanol-exposed rats treated with vehicle solution; CONT = saline-exposed rats treated with vehicle solution. **P<0.01, * P <0.05: CONT vs. ETOH; # #P < 0.01, # P < 0.05: CONT vs. VINP.