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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

The bottom-up pathway of the hippocampus-VTA loop mediates positive place reinforcement learning following conditioning the VHC. (A and B) Total amount of time spent (30 min/session/day); (A) in the Ringer's-paired, and (B) in the METH-paired chambers following conditioning with either Ringer's (gray bars) or METH (white dotted bars). (C and D) Time deviation from baseline preference: (C) in the Ringer's-paired chambers, and (D) in the METH-paired chambers. Abbreviations: CS+, conditioned stimulus present; US+, unconditioned stimulus present; US−, the unconditioned stimulus, METH, absent. Hatched vertical line separates treatment days (US+, CS+) from no treatment days (US−, CS+). Data are shown as ± SEM, *P < 0.05.
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fig04: The bottom-up pathway of the hippocampus-VTA loop mediates positive place reinforcement learning following conditioning the VHC. (A and B) Total amount of time spent (30 min/session/day); (A) in the Ringer's-paired, and (B) in the METH-paired chambers following conditioning with either Ringer's (gray bars) or METH (white dotted bars). (C and D) Time deviation from baseline preference: (C) in the Ringer's-paired chambers, and (D) in the METH-paired chambers. Abbreviations: CS+, conditioned stimulus present; US+, unconditioned stimulus present; US−, the unconditioned stimulus, METH, absent. Hatched vertical line separates treatment days (US+, CS+) from no treatment days (US−, CS+). Data are shown as ± SEM, *P < 0.05.

Mentions: After we finished our assessments on intra-VTA-METH-induced CPP learning, the same groups of rats from “METH produced positive place learning following conditioning the VTA” were conditioned with either METH or Ringer's intra-VHC, for the first time (refer Fig. 1B). There was a significant interaction between treatments (Base [n = 11], Ringer's [n = 9], METH [n = 10]) and test (Test 4, Test 5, Test 6) (F [6, 49] = 3.39, P < 0.01). Following the first-time intra-VHC exposure, the two groups did not statistically differ from one another, but both groups showed significant positive CPP toward the drug-paired chambers compared to the baseline condition (P < 0.005). The time deviation for the METH-paired chambers following the second conditioning session was significantly reduced to a negative value below baseline (P < 0.005), however, there were no significant differences between METH-paired and Ringer's-paired groups on time deviation from the baseline condition (P = 0.67). To our surprise, 24 h following conditioning, METH rats, but not Ringer's rats, spent a significantly greater amount of time in METH-paired chambers compared to both the Ringer's group (P < 0.05) and the baseline condition (P < 0.05) (Fig. 4B–D). In addition, METH groups spent a significantly more time in METH-paired chambers compared to Ringer's-paired chambers (P < 0.01).


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

Keleta YB, Martinez JL - Brain Behav (2012)

The bottom-up pathway of the hippocampus-VTA loop mediates positive place reinforcement learning following conditioning the VHC. (A and B) Total amount of time spent (30 min/session/day); (A) in the Ringer's-paired, and (B) in the METH-paired chambers following conditioning with either Ringer's (gray bars) or METH (white dotted bars). (C and D) Time deviation from baseline preference: (C) in the Ringer's-paired chambers, and (D) in the METH-paired chambers. Abbreviations: CS+, conditioned stimulus present; US+, unconditioned stimulus present; US−, the unconditioned stimulus, METH, absent. Hatched vertical line separates treatment days (US+, CS+) from no treatment days (US−, CS+). Data are shown as ± SEM, *P < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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

fig04: The bottom-up pathway of the hippocampus-VTA loop mediates positive place reinforcement learning following conditioning the VHC. (A and B) Total amount of time spent (30 min/session/day); (A) in the Ringer's-paired, and (B) in the METH-paired chambers following conditioning with either Ringer's (gray bars) or METH (white dotted bars). (C and D) Time deviation from baseline preference: (C) in the Ringer's-paired chambers, and (D) in the METH-paired chambers. Abbreviations: CS+, conditioned stimulus present; US+, unconditioned stimulus present; US−, the unconditioned stimulus, METH, absent. Hatched vertical line separates treatment days (US+, CS+) from no treatment days (US−, CS+). Data are shown as ± SEM, *P < 0.05.
Mentions: After we finished our assessments on intra-VTA-METH-induced CPP learning, the same groups of rats from “METH produced positive place learning following conditioning the VTA” were conditioned with either METH or Ringer's intra-VHC, for the first time (refer Fig. 1B). There was a significant interaction between treatments (Base [n = 11], Ringer's [n = 9], METH [n = 10]) and test (Test 4, Test 5, Test 6) (F [6, 49] = 3.39, P < 0.01). Following the first-time intra-VHC exposure, the two groups did not statistically differ from one another, but both groups showed significant positive CPP toward the drug-paired chambers compared to the baseline condition (P < 0.005). The time deviation for the METH-paired chambers following the second conditioning session was significantly reduced to a negative value below baseline (P < 0.005), however, there were no significant differences between METH-paired and Ringer's-paired groups on time deviation from the baseline condition (P = 0.67). To our surprise, 24 h following conditioning, METH rats, but not Ringer's rats, spent a significantly greater amount of time in METH-paired chambers compared to both the Ringer's group (P < 0.05) and the baseline condition (P < 0.05) (Fig. 4B–D). In addition, METH groups spent a significantly more time in METH-paired chambers compared to Ringer's-paired chambers (P < 0.01).

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