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Brain Circuits of Methamphetamine Place Reinforcement Learning: The Role of the Hippocampus-VTA Loop.

Keleta YB, Martinez JL - Brain Behav (2012)

Bottom Line: The reinforcing effects of addictive drugs including methamphetamine (METH) involve the midbrain ventral tegmental area (VTA).In the top-down order, METH, but not Ringer's, produced either an aversive CPP or no learning effect following conditioning each nucleus of interest.In addition, METH place aversion was antagonized by coadministration of the N-methyl-d-aspartate (NMDA) receptor antagonist MK801, suggesting that the aversion learning was an NMDA receptor activation-dependent process.

View Article: PubMed Central - PubMed

Affiliation: University of Texas at San Antonio, One UTSA Circle San Antonio, TX 78249 USA.

ABSTRACT
The reinforcing effects of addictive drugs including methamphetamine (METH) involve the midbrain ventral tegmental area (VTA). VTA is primary source of dopamine (DA) to the nucleus accumbens (NAc) and the ventral hippocampus (VHC). These three brain regions are functionally connected through the hippocampal-VTA loop that includes two main neural pathways: the bottom-up pathway and the top-down pathway. In this paper, we take the view that addiction is a learning process. Therefore, we tested the involvement of the hippocampus in reinforcement learning by studying conditioned place preference (CPP) learning by sequentially conditioning each of the three nuclei in either the bottom-up order of conditioning; VTA, then VHC, finally NAc, or the top-down order; VHC, then VTA, finally NAc. Following habituation, the rats underwent experimental modules consisting of two conditioning trials each followed by immediate testing (test 1 and test 2) and two additional tests 24 h (test 3) and/or 1 week following conditioning (test 4). The module was repeated three times for each nucleus. The results showed that METH, but not Ringer's, produced positive CPP following conditioning each brain area in the bottom-up order. In the top-down order, METH, but not Ringer's, produced either an aversive CPP or no learning effect following conditioning each nucleus of interest. In addition, METH place aversion was antagonized by coadministration of the N-methyl-d-aspartate (NMDA) receptor antagonist MK801, suggesting that the aversion learning was an NMDA receptor activation-dependent process. We conclude that the hippocampus is a critical structure in the reward circuit and hence suggest that the development of target-specific therapeutics for the control of addiction emphasizes on the hippocampus-VTA top-down connection.

No MeSH data available.


Related in: MedlinePlus

Hypothetical significance of the Hippocampus-VTA loop on place reinforcement learning: diagrammatic representation of neural pathways and neurotransmitters/modulators that potentially mediate the reinforcing properties of psychostimulants in the Hippocampus-VTA bottom-up and top-down connections (modified from [Floresco et al. 2001]).
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fig09: Hypothetical significance of the Hippocampus-VTA loop on place reinforcement learning: diagrammatic representation of neural pathways and neurotransmitters/modulators that potentially mediate the reinforcing properties of psychostimulants in the Hippocampus-VTA bottom-up and top-down connections (modified from [Floresco et al. 2001]).

Mentions: Decades of investigations on the behavior of midbrain DA neurons by Schultz and colleagues (Schultz W. 1998) assert that increases in the baseline firing rate of midbrain DA neurons are highly correlated with reward-related behaviors. If the DA hypothesis of reinforcement learning remains intact, we would have expected that blocking excitatory output of the VHC should have increased the firing rate of MSN neurons of the NAc, diminished the baseline firing rate of VTA DA neurons, and presumably reduced motivational behavior. However, unlike the expected behavioral outcome, rats that were treated with the combination of METH and MK801 spent more time in drug-paired chambers (enhanced motivation) as opposed to METH alone group, which implies that drug-seeking behavior can be potentially achieved by attenuating the baseline firing rate of VTA DA neurons. Alternatively, the observed finding could be MK801-mediated phenomenon rather than DA per se (Brown et al. 2008; Itzhak 2008). Furthermore, the enhanced positive CPP learning in rats that were treated with the combination of METH and MK801 could also be due to an increase in firing rate of MSN neurons of the NAc because of the attenuation of NMDA-mediated excitation followed by a decrease in VTA DA firing rate, which probably may increase the spontaneously active VTA DA neurons without increasing the baseline firing rate. In other words, the strengthening of accumbo-palidal inhibitory tone and attenuation of excitatory hippocampal GLUergic surge may result in the reduction of the firing rate of VTA DA neurons and thereby help recruit more of spontaneously active VTA DA neurons. Therefore, it is hypothesized that increases in the number of spontaneously active VTA DA neurons may subserve as a neural correlate of positive reinforcement learning (Fig. 9).


Brain Circuits of Methamphetamine Place Reinforcement Learning: The Role of the Hippocampus-VTA Loop.

Keleta YB, Martinez JL - Brain Behav (2012)

Hypothetical significance of the Hippocampus-VTA loop on place reinforcement learning: diagrammatic representation of neural pathways and neurotransmitters/modulators that potentially mediate the reinforcing properties of psychostimulants in the Hippocampus-VTA bottom-up and top-down connections (modified from [Floresco et al. 2001]).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3345357&req=5

fig09: Hypothetical significance of the Hippocampus-VTA loop on place reinforcement learning: diagrammatic representation of neural pathways and neurotransmitters/modulators that potentially mediate the reinforcing properties of psychostimulants in the Hippocampus-VTA bottom-up and top-down connections (modified from [Floresco et al. 2001]).
Mentions: Decades of investigations on the behavior of midbrain DA neurons by Schultz and colleagues (Schultz W. 1998) assert that increases in the baseline firing rate of midbrain DA neurons are highly correlated with reward-related behaviors. If the DA hypothesis of reinforcement learning remains intact, we would have expected that blocking excitatory output of the VHC should have increased the firing rate of MSN neurons of the NAc, diminished the baseline firing rate of VTA DA neurons, and presumably reduced motivational behavior. However, unlike the expected behavioral outcome, rats that were treated with the combination of METH and MK801 spent more time in drug-paired chambers (enhanced motivation) as opposed to METH alone group, which implies that drug-seeking behavior can be potentially achieved by attenuating the baseline firing rate of VTA DA neurons. Alternatively, the observed finding could be MK801-mediated phenomenon rather than DA per se (Brown et al. 2008; Itzhak 2008). Furthermore, the enhanced positive CPP learning in rats that were treated with the combination of METH and MK801 could also be due to an increase in firing rate of MSN neurons of the NAc because of the attenuation of NMDA-mediated excitation followed by a decrease in VTA DA firing rate, which probably may increase the spontaneously active VTA DA neurons without increasing the baseline firing rate. In other words, the strengthening of accumbo-palidal inhibitory tone and attenuation of excitatory hippocampal GLUergic surge may result in the reduction of the firing rate of VTA DA neurons and thereby help recruit more of spontaneously active VTA DA neurons. Therefore, it is hypothesized that increases in the number of spontaneously active VTA DA neurons may subserve as a neural correlate of positive reinforcement learning (Fig. 9).

Bottom Line: The reinforcing effects of addictive drugs including methamphetamine (METH) involve the midbrain ventral tegmental area (VTA).In the top-down order, METH, but not Ringer's, produced either an aversive CPP or no learning effect following conditioning each nucleus of interest.In addition, METH place aversion was antagonized by coadministration of the N-methyl-d-aspartate (NMDA) receptor antagonist MK801, suggesting that the aversion learning was an NMDA receptor activation-dependent process.

View Article: PubMed Central - PubMed

Affiliation: University of Texas at San Antonio, One UTSA Circle San Antonio, TX 78249 USA.

ABSTRACT
The reinforcing effects of addictive drugs including methamphetamine (METH) involve the midbrain ventral tegmental area (VTA). VTA is primary source of dopamine (DA) to the nucleus accumbens (NAc) and the ventral hippocampus (VHC). These three brain regions are functionally connected through the hippocampal-VTA loop that includes two main neural pathways: the bottom-up pathway and the top-down pathway. In this paper, we take the view that addiction is a learning process. Therefore, we tested the involvement of the hippocampus in reinforcement learning by studying conditioned place preference (CPP) learning by sequentially conditioning each of the three nuclei in either the bottom-up order of conditioning; VTA, then VHC, finally NAc, or the top-down order; VHC, then VTA, finally NAc. Following habituation, the rats underwent experimental modules consisting of two conditioning trials each followed by immediate testing (test 1 and test 2) and two additional tests 24 h (test 3) and/or 1 week following conditioning (test 4). The module was repeated three times for each nucleus. The results showed that METH, but not Ringer's, produced positive CPP following conditioning each brain area in the bottom-up order. In the top-down order, METH, but not Ringer's, produced either an aversive CPP or no learning effect following conditioning each nucleus of interest. In addition, METH place aversion was antagonized by coadministration of the N-methyl-d-aspartate (NMDA) receptor antagonist MK801, suggesting that the aversion learning was an NMDA receptor activation-dependent process. We conclude that the hippocampus is a critical structure in the reward circuit and hence suggest that the development of target-specific therapeutics for the control of addiction emphasizes on the hippocampus-VTA top-down connection.

No MeSH data available.


Related in: MedlinePlus