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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

Intra-VTA METH induces positive place reinforcement learning. (A) Baseline place preference as defined by the amount of time per session prior to the commencement of IC-CPP. The rats were allowed to freely access the entire CPP runway to establish the baseline preference (base, day 3). Three consecutive days into the training (30 min/session/day), rats showed an increasing trend of place preference toward the black chambers (preferred) and a declining trend for the white chambers (nonpreferred). (B) The total time spent in the Ringer's-paired (gray bars) and METH-paired chambers (white dotted bars) following conditioning with either Ringer's or METH, and (C) the time deviation from baseline preference, in the Ringer's-paired chambers (gray bars) and in the METH-paired chambers (white dotted bars) normalized to the baseline. 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 standard error of the mean ± SEM, *0.005 < P < 0.05.
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fig02: Intra-VTA METH induces positive place reinforcement learning. (A) Baseline place preference as defined by the amount of time per session prior to the commencement of IC-CPP. The rats were allowed to freely access the entire CPP runway to establish the baseline preference (base, day 3). Three consecutive days into the training (30 min/session/day), rats showed an increasing trend of place preference toward the black chambers (preferred) and a declining trend for the white chambers (nonpreferred). (B) The total time spent in the Ringer's-paired (gray bars) and METH-paired chambers (white dotted bars) following conditioning with either Ringer's or METH, and (C) the time deviation from baseline preference, in the Ringer's-paired chambers (gray bars) and in the METH-paired chambers (white dotted bars) normalized to the baseline. 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 standard error of the mean ± SEM, *0.005 < P < 0.05.

Mentions: The VTA is functionally involved in the early stages (acquisition) of reinforcement learning. We previously reported that intra-VTA application of METH produced positive CPP in subjects that self administered cocaine, intravenously (n = 5; Society for Neuroscience conference, Keleta et al., 2009). In an extension and replication of the data, we used another set of rats that had no previous cocaine exposure (cocaine naïve). We hypothesized that METH applied intra-VTA would produce positive CPP learning even in subjects that had no previous cocaine experience. We used an “all-in-all-out” method of conditioning and testing by alternating METH with Ringer's every other day, for four consecutive days. On the last day of testing, all subjects were tested for CPP without any intra-VTA treatment (Fig. 1A). Based on criteria described in “Behavioral Assay,” the rats satisfied the requirement for baseline place preference (Fig. 2A). There was a significant interaction between treatment (METH, Ringer's) and Test (test 1, test 2) (F [4, 48] = 5.03, P < 0.005, n = 13). In agreement with our previous findings, METH reverse dialyzed into the VTA produced a markedly significant positive CPP. Compared to the baseline, a single (first time; METH1) intra-VTA conditioning session significantly increased the time deviation values in favor of the drug-paired chambers (P < 0.05). The METH1 groups, but not the Ringer's1 groups, showed a positive CPP toward the METH-paired chambers compared to the baseline condition (P < 0.05) and compared to the Ringer's group (P < 0.05). On repeated exposure with METH (METH2), however, the place conditioning effect was not different from that of Ringer's and that of the baseline (Fig. 2 B–D). Following the second conditioning session with Ringer's (Ringer's2), rats showed positive bias toward the drug-paired chambers compared to that of the nonpaired chambers (P < 0.05), suggesting that METH-seeking behavior or withdrawal induced METH-seeking behavior. This later observation furthermore suggests that the novelty component of the reinforcer diminishes with repeated exposure and that the VTA primarily involves the detection of the novelty component of the METH. When tested 24 h following conditioning, without intra-VTA treatment, greater amount of time deviation values were found in the METH-paired chambers compared to the Ringer's-paired chambers (P < 0.05). Overall, the observed deviation in place preference in favor of the drug-paired chambers can suggest that environmental cues (the conditioned stimulus, CS+) paired with the METH (unconditioned stimulus, US+) produce stronger effect on drug-seeking behavior even in the absence of the reinforcer (US−).


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

Keleta YB, Martinez JL - Brain Behav (2012)

Intra-VTA METH induces positive place reinforcement learning. (A) Baseline place preference as defined by the amount of time per session prior to the commencement of IC-CPP. The rats were allowed to freely access the entire CPP runway to establish the baseline preference (base, day 3). Three consecutive days into the training (30 min/session/day), rats showed an increasing trend of place preference toward the black chambers (preferred) and a declining trend for the white chambers (nonpreferred). (B) The total time spent in the Ringer's-paired (gray bars) and METH-paired chambers (white dotted bars) following conditioning with either Ringer's or METH, and (C) the time deviation from baseline preference, in the Ringer's-paired chambers (gray bars) and in the METH-paired chambers (white dotted bars) normalized to the baseline. 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 standard error of the mean ± SEM, *0.005 < P < 0.05.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3345357&req=5

fig02: Intra-VTA METH induces positive place reinforcement learning. (A) Baseline place preference as defined by the amount of time per session prior to the commencement of IC-CPP. The rats were allowed to freely access the entire CPP runway to establish the baseline preference (base, day 3). Three consecutive days into the training (30 min/session/day), rats showed an increasing trend of place preference toward the black chambers (preferred) and a declining trend for the white chambers (nonpreferred). (B) The total time spent in the Ringer's-paired (gray bars) and METH-paired chambers (white dotted bars) following conditioning with either Ringer's or METH, and (C) the time deviation from baseline preference, in the Ringer's-paired chambers (gray bars) and in the METH-paired chambers (white dotted bars) normalized to the baseline. 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 standard error of the mean ± SEM, *0.005 < P < 0.05.
Mentions: The VTA is functionally involved in the early stages (acquisition) of reinforcement learning. We previously reported that intra-VTA application of METH produced positive CPP in subjects that self administered cocaine, intravenously (n = 5; Society for Neuroscience conference, Keleta et al., 2009). In an extension and replication of the data, we used another set of rats that had no previous cocaine exposure (cocaine naïve). We hypothesized that METH applied intra-VTA would produce positive CPP learning even in subjects that had no previous cocaine experience. We used an “all-in-all-out” method of conditioning and testing by alternating METH with Ringer's every other day, for four consecutive days. On the last day of testing, all subjects were tested for CPP without any intra-VTA treatment (Fig. 1A). Based on criteria described in “Behavioral Assay,” the rats satisfied the requirement for baseline place preference (Fig. 2A). There was a significant interaction between treatment (METH, Ringer's) and Test (test 1, test 2) (F [4, 48] = 5.03, P < 0.005, n = 13). In agreement with our previous findings, METH reverse dialyzed into the VTA produced a markedly significant positive CPP. Compared to the baseline, a single (first time; METH1) intra-VTA conditioning session significantly increased the time deviation values in favor of the drug-paired chambers (P < 0.05). The METH1 groups, but not the Ringer's1 groups, showed a positive CPP toward the METH-paired chambers compared to the baseline condition (P < 0.05) and compared to the Ringer's group (P < 0.05). On repeated exposure with METH (METH2), however, the place conditioning effect was not different from that of Ringer's and that of the baseline (Fig. 2 B–D). Following the second conditioning session with Ringer's (Ringer's2), rats showed positive bias toward the drug-paired chambers compared to that of the nonpaired chambers (P < 0.05), suggesting that METH-seeking behavior or withdrawal induced METH-seeking behavior. This later observation furthermore suggests that the novelty component of the reinforcer diminishes with repeated exposure and that the VTA primarily involves the detection of the novelty component of the METH. When tested 24 h following conditioning, without intra-VTA treatment, greater amount of time deviation values were found in the METH-paired chambers compared to the Ringer's-paired chambers (P < 0.05). Overall, the observed deviation in place preference in favor of the drug-paired chambers can suggest that environmental cues (the conditioned stimulus, CS+) paired with the METH (unconditioned stimulus, US+) produce stronger effect on drug-seeking behavior even in the absence of the reinforcer (US−).

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