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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 top-down pathway of the hippocampus-VTA loop attenuates place preference learning following conditioning the VHC, which was reversed by inhibiting NMDA receptors using MK801. (A) Baseline place preference as defined by the amount of time per session prior to the commencement of IC-CPP testing. The rats were allowed to freely access the entire CPP runway to establish the baseline following habituation. After four consecutive days the rats showed an increasing trend of preference toward the black chambers (preferred) but a declining trend for the white chambers (nonpreferred). (B and C) The total amount of time spent (30 min/session/day); (B) in the Ringer's-paired, and (C) in the drug-paired chambers following conditioning with either Ringer's (gray bars), METH (white dotted bars), or METH+MK801 (black dotted bars). (D and E) The time deviation from baseline preference: (D) in the Ringer's-paired chambers, and (E) in the drug-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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fig06: The top-down pathway of the hippocampus-VTA loop attenuates place preference learning following conditioning the VHC, which was reversed by inhibiting NMDA receptors using MK801. (A) Baseline place preference as defined by the amount of time per session prior to the commencement of IC-CPP testing. The rats were allowed to freely access the entire CPP runway to establish the baseline following habituation. After four consecutive days the rats showed an increasing trend of preference toward the black chambers (preferred) but a declining trend for the white chambers (nonpreferred). (B and C) The total amount of time spent (30 min/session/day); (B) in the Ringer's-paired, and (C) in the drug-paired chambers following conditioning with either Ringer's (gray bars), METH (white dotted bars), or METH+MK801 (black dotted bars). (D and E) The time deviation from baseline preference: (D) in the Ringer's-paired chambers, and (E) in the drug-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: Based on criteria described in “Behavioral Assay”, these rats (new batch of rats) satisfied the requirement for baseline place preference (Fig. 6A). The rats underwent intra-VHC conditioning against their initial place preference followed by immediate IC-CPP testing (30 min/session/day), while the controls (Ringer's group, n = 6) were conditioned within their preferred chambers. After two consecutive days of treatment (test 1 and test 2), no significant interaction between treatments was detected (F [5, 22] = 0.43, P > 0.05), however 24 h following conditioning, the METH+MK801 group (n = 5), but not the Ringer's (n = 6) and or the METH-treated groups (n = 5), showed positive CPP toward the drug-paired chambers (P < 0.001). In addition, METH+MK801 rats showed a statistically greater increase in time deviation toward the drug-paired chambers compared to the controls (P < 0.001). One week following conditioning, only the previously METH-treated rats showed positive bias toward Ringer's-paired chambers compared to both the METH+MK801 groups (P < 0.001) and the Ringer's groups (P < 0.05) (Fig. 6D and 6E). Our observation overall indicated that blocking the NMDA receptors reversed the diminished place learning following intra-VHC-METH. This attenuation in place learning could therefore be an NMDA receptor activation-mediated process. The observation could also be METH-induced place aversion. Alternatively, because the initial place preference was negative relative to the positively conditioned side of the apparatus, the finding could be a block of CPP and that the data may reflect a block of learning rather than an aversion.


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

Keleta YB, Martinez JL - Brain Behav (2012)

The top-down pathway of the hippocampus-VTA loop attenuates place preference learning following conditioning the VHC, which was reversed by inhibiting NMDA receptors using MK801. (A) Baseline place preference as defined by the amount of time per session prior to the commencement of IC-CPP testing. The rats were allowed to freely access the entire CPP runway to establish the baseline following habituation. After four consecutive days the rats showed an increasing trend of preference toward the black chambers (preferred) but a declining trend for the white chambers (nonpreferred). (B and C) The total amount of time spent (30 min/session/day); (B) in the Ringer's-paired, and (C) in the drug-paired chambers following conditioning with either Ringer's (gray bars), METH (white dotted bars), or METH+MK801 (black dotted bars). (D and E) The time deviation from baseline preference: (D) in the Ringer's-paired chambers, and (E) in the drug-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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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3345357&req=5

fig06: The top-down pathway of the hippocampus-VTA loop attenuates place preference learning following conditioning the VHC, which was reversed by inhibiting NMDA receptors using MK801. (A) Baseline place preference as defined by the amount of time per session prior to the commencement of IC-CPP testing. The rats were allowed to freely access the entire CPP runway to establish the baseline following habituation. After four consecutive days the rats showed an increasing trend of preference toward the black chambers (preferred) but a declining trend for the white chambers (nonpreferred). (B and C) The total amount of time spent (30 min/session/day); (B) in the Ringer's-paired, and (C) in the drug-paired chambers following conditioning with either Ringer's (gray bars), METH (white dotted bars), or METH+MK801 (black dotted bars). (D and E) The time deviation from baseline preference: (D) in the Ringer's-paired chambers, and (E) in the drug-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: Based on criteria described in “Behavioral Assay”, these rats (new batch of rats) satisfied the requirement for baseline place preference (Fig. 6A). The rats underwent intra-VHC conditioning against their initial place preference followed by immediate IC-CPP testing (30 min/session/day), while the controls (Ringer's group, n = 6) were conditioned within their preferred chambers. After two consecutive days of treatment (test 1 and test 2), no significant interaction between treatments was detected (F [5, 22] = 0.43, P > 0.05), however 24 h following conditioning, the METH+MK801 group (n = 5), but not the Ringer's (n = 6) and or the METH-treated groups (n = 5), showed positive CPP toward the drug-paired chambers (P < 0.001). In addition, METH+MK801 rats showed a statistically greater increase in time deviation toward the drug-paired chambers compared to the controls (P < 0.001). One week following conditioning, only the previously METH-treated rats showed positive bias toward Ringer's-paired chambers compared to both the METH+MK801 groups (P < 0.001) and the Ringer's groups (P < 0.05) (Fig. 6D and 6E). Our observation overall indicated that blocking the NMDA receptors reversed the diminished place learning following intra-VHC-METH. This attenuation in place learning could therefore be an NMDA receptor activation-mediated process. The observation could also be METH-induced place aversion. Alternatively, because the initial place preference was negative relative to the positively conditioned side of the apparatus, the finding could be a block of CPP and that the data may reflect a block of learning rather than an aversion.

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