Low-dose systemic scopolamine disrupts context conditioning in rats

Abstract

Cholinergic neurotransmission plays a key role in learning and memory. Prior research with rats indicated that a low dose of pre-training scopolamine (0.1 mg/kg), a cholinergic receptor antagonist, did not affect cued fear conditioning, but did block renewal when injected before extinguishing a conditioned tone, opening up opportunities to pharmacologically improve exposure therapy for anxiety patients. Before translating these findings to the clinic, it is important to carefully examine how scopolamine affects contextual fear memories. Here, we investigated the effects of scopolamine on encoding of contextual anxiety and its generalization in male Wistar rats. We found a profound disruption of context conditioning, suggesting that, even at a low dose, systemic scopolamine may influence contextual encoding in the hippocampus, particularly when the context is the best predictor for the presence of shocks.

Keywords: Context conditioning; anxiety; contextual fear; generalization; rats; scopolamine.

Fig. 1. The effects of 0.1 mg/kg pre-training scopolamine in a contextual generalization procedure.

(A) Study design. N = 12 per group, 48 rats in total. (B) %Freezing (mean ± SD) after each shock during the Training session in rats that received an intraperitoneal pre-training saline (SAL) or 0.1 mg/kg scopolamine (SCOP) injection, *significantly higher than after the first shock in SAL rats, ^#significantly higher than after the first shock in SCOP rats, ^§significantly different between SAL and SCOP rats (p ≤ .01). (C) %Freezing (median + interquartile range) during the 8-minute Test 1 session, *significantly lower than A SAL rats (p < .01). (D) %Freezing after shocks for A SAL and A SCOP rats. Colored circles indicate animals that were included in the subset of rats with postshock freezing scores close to the average of saline rats. (E) %Freezing (median + interquartile range) during the 8-minute Test 1 in the subset of six A SAL and five A SCOP rats with ‘average’ postshock freezing scores, *significantly lower than A SAL rats (p < .01). (F) %Freezing (median) during the 8-minute Test 1 and subsequent 16-minute Extinction phase. (G) %Freezing (median + interquartile range) during the 8-minute Test 2.

Fig. 2. The effects of 0.1 mg/kg scopolamine in the open field test and on the accelerating rotarod.

(A) %Time (mean + SD) spent in the center of the open field during a 10-minute test, *significantly shorter than SAL rats (p = .03). (B) Distance travelled (mean + SD) during the 10-minute open field test. (C) Average time (mean ± SD) until falling off the rotarod on three drug-free training days and a subsequent test day when rats were given saline (SAL) or scopolamine (SCOP), *significantly different between SAL and SCOP rats (p < .01). N = 8 per group.