The results from the present study revealed that repeated administration of 0.1 mg/kg reserpine impaired recognition memory, as monitored in the Morris water maze and novel object recognition test. The preference for exploring new objects was shown by reserpine-injected animals (Fig. 1), indicating that repeated reserpine administration impaired this memory in animals. Others have also reported reserpine-induced memory impairment. However, they have reported such memory impairing effects of reserpine after single administration of higher dose (0.5 mg/kg) of the drug. However, we monitored a ‘progressive’ animal model of memory impairment, and although a novel object recognition test was performed at the end of the study, we monitored the Morris water maze test on a weekly basis to monitor the progression of memory impairment.
In comparison with others, we used a relatively low dose of reserpine, which does not usually produce an impairment of memory upon acute administration (Fernandes et al., 2008). We also did not find any effect of reserpine injections on the memory of animals until the first week. However, after week 2, long-term memory was impaired only without affecting short-term memory. An interesting finding of the present study was that in the Morris water maze test, short-term memory was impaired after long-term memory (Fig. 2), suggesting an earlier loss of long-term memory followed by short-term memory loss. Cammarota et al. (2005) have also reported that short-term memory is more resistant to extinction than long-term memory. However, both of these forms of memories are linked not only by mechanisms in the hippocampus that require NMDA receptors and protein synthesis but also by other mechanisms requiring protein synthesis in the prefrontal cortex (Santini et al., 2004). A comparison of short- and long-term memories (Fig. 3) indicated that long-term memories were impaired earlier than short-term memories. Long-term memories of both vehicle- and reserpine-injected rats were comparable to short-term memories of the same.
In the present study, we did not find memory impairment until after the first week. Thus, we hypothesize a progressive effect of reserpine, resulting in memory impairment. Although reserpine does not induce neuronal depletion, which is reported to be the most common underlying cause of the dementia observed in AD (McCarty, 2006), it produces monoamine depletion, which is the final common feature in naturally progressing dementia. Although very unlikely, the possibility of context-dependent memory impairment (if any), similar to any other behavioral sensitization (Ikram and Haleem, 2011), or context-dependent learning and memory, could not be ruled out. Others have also reported context-dependent potentiation of memory deficits by the blockade of dopaminergic neurotransmission (Schwartz et al., 2003). To rule out this possibility, we also performed the novel object recognition test at the end of the experiment to cross check the memory impairment, as the novel object recognition task for rodents is a nonspatial, nonaversive memory test (Ennaceur and Delacour, 1988).
Animals spent more time exploring new objects in the test session during the novel object recognition task because they easily recognized a previously presented (old) object (Fig. 1). Reserpine-injected animals presented a preference for the new object, indicating that it could not affect this type of memory. In addition, the test animals spent comparatively more time recognizing the old object than the vehicle-injected animals (Fig. 1). Different classes of dopaminergic receptors exert distinct effects on recognition memory (Nagai et al., 2007); activation of D1 receptors can enhance recognition memory consolidation. Importantly, pharmacological activation of D1 receptors enhances novel object recognition memory even under conditions in which control rats show significant retention (de Lima et al., 2011).
A focus of current research is whether short-term memory is merely a step towards long-term memory or whether both are separate entities (Izquierdo et al., 2006). However, an important role of the serotonergic system has been suggested in short- and long-term memory (Meneses, 1999; 2007). 5-HT can affect memory directly and/or indirectly by modulating neurotransmitters such as acetylcholine and glutamate (Madjid et al., 2006; Hu et al., 2007). Although it is possible to separately study short- and long-term memory, both mostly function in a serial manner (Meneses, 2007). Apart from serotonin, dopamine is also important for working memory functions, mainly within the prefrontal cortex (PFC), and depletion of dopamine in the PFC induces severe impairment in the classic working memory task in nonhuman primates (Brozoski et al., 1979). A depletion of 5-HT, dopamine and metabolites was observed in the present study (Fig. 4), confirming that these neurochemical deficits are the underlying reason for memory impairment.