Methamphetamine enhances memory of operantly conditioned respiratory behavior in the snail Lymnaea stagnalis

Abstract

SUMMARYAmphetamines have been used as cognitive enhancers to promote learning and memory. Amphetamines are also drugs of abuse that may promote the initiation of strong memories that ultimately lead to addiction. To understand how methamphetamine (Meth) may be augmenting learning and memory, we chose a relatively simple system, the pond snail, Lymnaea stagnalis. We studied the effects of Meth exposure on the long-term memory (LTM), extinction and reinstatement of operantly conditioned aerial respiratory behavior in Lymnaea. We first determined doses of Meth that would acutely alter respiratory behavior. Next, we measured the impact of training snails in Meth solution or water (control group) using a training procedure that produces LTM (>6h) in control conditions. Meth exposure impaired the expression of LTM 21h after two training sessions, but this appeared to be a context-dependent effect only. However, snails exposed to 3.3mmoll -1 Meth during training had a decreased rate of extinction of the operantly conditioned memory. We then tested whether this decreased ability of snails to extinguish memory was due to enhanced LTM or impaired extinction of that memory. Snails were operantly conditioned in water and exposed to Meth 16h after their last trial but 4-5h prior to extinction. Meth produced an increase rather than a decrease in extinction rate. Thus, Meth impaired extinction only when snails were exposed to Meth during training. Last, we tested the effect of Meth on the ability to form LTM using a single training procedure that is suboptimal for LTM formation. Control snails did not demonstrate LTM, as expected, but pre-exposure of snails to 3.3mmoll -1 Meth 24h prior to the single training session produced LTM 24h later, indicating that Meth pre-exposure primed snails for LTM formation. Taken together, our studies suggest that LTM is strengthened by Meth such that extinction training is less effective. Lymnaea provides a simple and useful model system to dissect the cellular and/or molecular mechanisms of how Meth may initiate the formation of stronger memories.

A flavonol present in cocoa [(−)epicatechin] enhances snail memory

“…Additionally, yoked control snails trained in epi-PW do not exhibit LTM; therefore, the decrease in breathing attempts in trained snails was not due to prolonged effects of drug exposure or a generalised sensitization to a physical stimulus. Enhancement of LTM following exposure to methamphetamine has also been shown to occur at a concentration that did not alter homeostatic aerial respiratory behaviour (Kennedy et al, 2010). Thus, we strongly conclude that epi directly affects the activity of neurons that are necessary for LTM formation.…”

“…We have previously demonstrated extinction in Lymnaea (McComb et al, 2002), and we further demonstrated that extinction can be extended or enhanced by a number of different means, including blocking newer memory formation (Sangha et al, 2003e;Sangha et al, 2005;Knezevic et al, 2011). Additionally, animals that have apparently forgotten exhibit re-instatement of the original training following a protocol that does not typically result in LTM formation (Sangha et al, 2003b;Carter et al, 2006;Parvez et al, 2006;Kennedy et al, 2010). We chose to assess the effects of (-)epicatechin (epi), as it has been identified as a bioactive molecule in vivo (Schroeter et al, 2006) and is also commonly consumed through cocoa, green tea, blueberries and red wine (Spencer, 2008).…”

“…Similarly to other species studied (Barondes and Jarvik, 1964;Cohen and Barondes, 1966;Flood et al, 1975;Squire et al, 1975), in our model system, the pond snail L. stagnalis, ITM is dependent on the translation of existing RNA transcripts whilst LTM involves the formation of new RNA transcripts and protein synthesis (Sangha et al, 2003d). Extinction is considered a specific type of learning process (Pavlov, 1927;Lattal et al, 2006;Kennedy et al, 2010). During extinction, the behavioural phenotype is similar to 'forgetting'; however, extinction is, in fact, new learning and memory formation that occludes, but does not erase, previously learned behaviour (Bouton, 1994;Eisenberg et al, 2003).…”

Enhanced memory persistence is blocked by a DNA methyltransferase inhibitor in the snail Lymnaea stagnalis

“…Fig. 2 Our previous study demonstrated that pre-exposure to Meth 24 h prior to training enhanced the ability to form 24 h LTM after a single training session (Kennedy et al, 2010). We conducted additional pilot studies (not shown) to assess the time interval during which Meth pre-exposure produced maximal effects on memory persistence, which was 4 h. Fig.…”

“…First, we tested the impact of 5-HT because of previous work describing enhanced memory in Aplysia via changes in DNA methylation status (Rajasethupathy et al, 2012). Second, we previously reported that the psychostimulant drugs cocaine (Carter et al, 2006) and Meth (Kennedy et al, 2010) enhanced long-term memory (LTM) in snails. We also demonstrated that pre-exposure to Meth prior to weak training produced LTM of respiratory behavior that was not found in controls.…”