Repeated cocaine effects on learning, memory and extinction in the pond snail Lymnaea stagnalis

Abstract

SUMMARY The persistence of drug addiction suggests that drugs of abuse enhance learning and/or impair extinction of the drug memory. We studied the effects of repeated cocaine on learning, memory and reinstatement in the pond snail, Lymnaea stagnalis. Respiratory behavior can be operantly conditioned and extinguished in Lymnaea, and this behavior is dependent on a critical dopamine neuron. We tested the hypothesis that repeated cocaine exposure promotes learning and memory or attenuates the ability to extinguish the memory of respiratory behavior that relies on this dopaminergic neuron. Rotating disk electrode voltammetry revealed a Km and Vmax of dopamine uptake in snail brain of 0.9 μmol l-1 and 558 pmol s-1 g-1 respectively, and the IC50 of cocaine for dopamine was approximately 0.03 μmol l-1. For operant conditioning, snails were given 5 days of 1 h day-1 immersion in water (control) or 0.1 μmol l-1cocaine, which was the lowest dose that maximally inhibited dopamine uptake,and snails were trained 3 days later. No changes were found between the two groups for learning or memory of the operant behavior. However, snails treated with 0.1 μmol l-1 cocaine demonstrated impairment of extinction memory during reinstatement of the behavior compared with controls. Our findings suggest that repeated exposure to cocaine modifies the interaction between the original memory trace and active inhibition of this trace through extinction training. An understanding of these basic processes in a simple model system may have important implications for treatment strategies in cocaine addiction.

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

“…Alternatively, training in Meth may have activated downstream pathways within RPeD1 or other neurons that actively inhibit subsequent extinction learning. This result is similar to what we previously found for the effects of cocaine pre-exposure, in which reinstatement of operantly conditioned breathing behavior was enhanced compared with controls (Carter et al, 2006). In that study, however, animals were exposed for 5days to cocaine and then trained 3days after the last cocaine exposure.…”

“…Based on our previous results with cocaine pre-treatment of snails (Carter et al, 2006) and previous work showing that psychostimulants enhance memory (see Introduction), we predicted that Meth used during initial training would enhance LTM such that extinction would be impaired and/or reinstatement would be greater than that in the Water control snails. Meth exposure during training diminished the extinction rate of the trained behavior.…”

“…Thus, the circuitry involving RPeD1 may be susceptible to alteration by psychostimulant treatment, and these changes may in turn be assessed by examining basic mechanisms of learning and memory underlying operant conditioning of aerial respiration as well as extinction and reinstatement of this learned response. We previously reported that repeated cocaine exposure produced greater reinstatement of operantly conditioned respiratory behavior in Lymnaea (Carter et al, 2006). These studies suggested that initial molecular processes underlying long-term memory (LTM) formation were enhanced or that extinction was impaired by prior repeated cocaine treatment.…”

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

“…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).…”

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

“…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.…”