Brain substrates of methamphetamine place reinforcement learning




Keleta, Yonas B.

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Addiction is a learning process and it is one major health problem in the United States. The reinforcing effects of addictive drugs involve the midbrain ventral tegmental area (VTA) which is the primary source of dopamine (DA) to the nucleus accumbens (NAc) and the ventral hippocampus (VHC). These three brain regions make a behaviorally functional connection called the VHC-VTA loop. There are two major neural pathways within this loop: the bottom-up link; VTA projections directly into cortical and subcortical areas, and the top-down link; indirect VHC projection via the NAc en route to the ventral pallidum into the VTA. Therefore, it is likely that the hippocampus (especially the VHC) is involved in learning processes subserving addiction. I addressed the role in conditioned place preference (CPP) learning of these two pathways by sequentially conditioning each of the three nuclei in either the bottom-up order; VTA, followed by VHC, followed by NAc, or the top-down order; VHC, followed by VTA, and followed by NAc. Following familiarization to the apparatus to establish baseline place preference, rats underwent experimental modules consisting of two conditioning trials each followed by immediate testing (day 1, test 1; and day 2, test 2), then a third testing 24 h following conditioning (day 3, test 3). This module was repeated three times for each nucleus. For the top-down order an additional test was performed a week following conditioning (day 10, test 4). The results showed that METH, but not ACSF, produced positive place reinforcement learning following conditioning each brain area in the bottom-up order, however, in the top-down order METH, but not ACSF, produced aversive place conditioning. In addition, METH place aversion was antagonized by co-administration of the NMDA antagonist MK801 suggesting the aversion learning was an NMDA receptor activation dependent process. I conclude that the hippocampus, more specifically the VHC, is critically important structure in the reward circuit. I suggest that target specific development of pharmacotherapy for the control of addiction focus on the VHC-VTA top-down connection.


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Methamphetamine, Midbrain Dopamine, Nucleus Accumbens, Reinforcement Learning, Ventral Hippocampus, Ventral Tegmental Area



Integrative Biology