Scopolamine Impairs Appetitive But Not Aversive Trace Conditioning: Role of the Medial Prefrontal Cortex

Abstract

The muscarinic acetylcholine receptor is an important modulator of medial prefrontal cortex (mPFC) functions, such as the working memory required to bridge a trace interval in associative leaning. Aversive and appetitive trace conditioning procedures were used to examine the effects of scopolamine (0.1 and 0.5 mg/kg, i.p.) in male rats. Follow-up experiments tested the effects of microinfusion of 0.15 μg of scopolamine (0.075 μg of in 0.5 μl/side) in infralimbic (IL) versus prelimbic regions of rat mPFC, in appetitive trace and locomotor activity (LMA) procedures. Systemic scopolamine was without effect in an aversive trace conditioning procedure, but impaired appetitive conditioning at a 2 s trace interval. This effect was demonstrated as reduced responding during presentations of the conditioned stimulus (CS) and during the interstimulus interval (ISI). There was no such effect on responding during food (unconditioned stimulus, US) responding or in the intertrial interval (ITI). In contrast, systemic scopolamine dose-relatedly increased LMA. Trace conditioning was similarly impaired at the 2 s trace (shown as reduced responding to the CS and during the ISI, but not during US presentations or in the ITI) after infusion in mPFC, whereas LMA was increased (after infusion in IL only). Therefore, our results point to the importance of cholinergic modulation in mPFC for trace conditioning and show that the observed effects cannot be attributed to reduced activity.SIGNIFICANCE STATEMENT Events are very often separated in time, in which case working memory is necessary to condition their association in “trace conditioning.” The present study used conditioning variants motivated aversively with foot shock and appetitively with food. The drug scopolamine was used to block muscarinic acetylcholine receptors involved in working memory. The results show that reduced cholinergic transmission in medial prefrontal cortex (mPFC) impaired appetitive trace conditioning at a 2 s trace interval. However, scopolamine was without effect in the aversive procedure, revealing the importance of procedural differences to the demonstration of the drug effect. The finding that blockade of muscarinic receptors in mPFC impaired trace conditioning shows that these receptors are critical modulators of short-term working memory.

Infusions of scopolamine in dorsal hippocampus reduce anticipatory responding in an appetitive trace conditioning procedure

“…Locomotor activity was measured in a dimly lit (50–70 Lux) room in 12 clear Perspex chambers (39.5 cm long × 23.5 cm wide × 24.5 cm deep) with metal grid lids. The chambers were surrounded by frames containing two levels of photobeams (Photobeam Activity System, San Diego Instruments, USA) as described previously (Jones, Brown, Auer, & Fone, ; Pezze, Marshall, Fone, & Cassaday, ; Pezze et al, ).…”

“…Rats were placed in a recovery incubator before being reintroduced to their cages. Because of the previous incidence of meningitis (Pezze et al, , ), the antibiotic Synulox (Ready‐To‐Use, Pfizer Ltd; 0.05 ml kg ‐1 day ‐1 , s.c.) was administered as a prophylactic measure.…”

“…Specifically, we examined the effects of scopolamine infused into dorsal hippocampus (30 µg/side; Pang et al, ) in an appetitive procedure identical to that which we have used previously to compare conditioning at 2 s and 10 s trace intervals following microinfusions in prefrontal cortex (mPFC) sub‐regions (Pezze, Marshall, & Cassaday, ). We also tested the effects of the same scopolamine treatment on locomotor activity (LMA).…”

“…As noted above, the replication of the effects of hippocampal lesions, reliably shown in aversive trace conditioning, has been challenging when appetitive procedures are used (Chan et al, ; Tam & Bonardi, ; Thibaudeau et al, , ). We therefore sought to test the generality of the finding that intra‐hippocampal scopolamine impairs trace conditioning (Pang et al, ), using the same appetitive procedure which previously showed sensitivity to scopolamine administered systemically (as well as in mPFC; Pezze, et al, ).…”

“…Other appetitive trace studies (e.g., Chan et al, ; Thibaudeau et al, ) have compared short and long trace intervals similar to those used in the present experiment. Moreover, we also routinely examine the distribution of responding within the longer 10 s trace interval (Pezze et al, ; Tam & Bonardi, ). Extinction tests were conducted drug‐free as a further control measure, for scopolamine effects on motor responding.…”