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Abstract
The hippocampus is a brain region that has long been known to be critical in learning and memory processes. Over the past several years, there has been increased recognition of the hippocampus’ role in addiction and addiction as a disease of learning and memory. Functionally and anatomically the hippocampal formation can be divided along its septotemporal axis into two main sectors: the dorsal hippocampus and the ventral hippocampus (vH). The vH plays an important role in responses to stress and motivational factors through its connection with the brain’s mesolimbic reward circuitry. One of the most prevalently used models of addiction, the conditioned place preference assay, relies heavily on hippocampal-dependent learning. This method, however, also relies on researcher administration of drugs which fails to mimic the voluntary intake seen in both the self-administration model of addiction and human usage. To better study the effects of cocaine addiction, we developed an escalating conditioning protocol that resulted in changes of vH synaptic plasticity observable on withdrawal day (WD) 28. We found on WD28, cocaine-treated animals exhibited impaired long-term potentiation (LTP) and increased basal synaptic plasticity. Mice treated with this cocaine conditioning also exhibited impairments in working memory during withdrawal, a behavioral consequence of these alterations to vH synaptic plasticity.Furthermore, we investigated the temporal nature of the changes in vH synaptic transmission and found progressive changes throughout cocaine withdrawal. We recorded excitatory postsynaptic currents on either WD2, WD9, or WD28 following cocaine conditioning. Our results showed that there is increased excitatory transmission throughout withdrawal in the vH, but the increase is mediated by different types and, consequently, ratios of AMPA receptors. Early in withdrawal, excitatory transmission is increased in the vH due to an increase in canonical, calcium-impermeable AMPARs. As withdrawal progresses, calcium-permeable AMPARs are inserted into the synapse and by WD28 they account for a significant portion excitatory transmission in the vH. The presence of these calcium-permeable AMPARs after cocaine conditioning may increase responsiveness to contexts associated with cocaine use and drive cocaine craving. Additionally, they may create neurons that do not respond to normal plasticity events resulting in impaired memory ability.