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.
ABSTRACT
The goal of this study was to assess the interactive effects of chronic anabolic androgenic steroid (AAS) exposure and brain serotonin (5-hydroxytryptamine, 5-HT) depletion on behavior of pubertal male rats. Serotonin was depleted beginning on postnatal day 26 with parachlorophenylalanine (PCPA 100 mg/kg, every other day); controls received saline. At puberty (P40), half the PCPA-treated rats and half the saline-treated rats began treatment with testosterone (T, 5 mg/kg, 5 days/week). Behavioral measures included locomotion, irritability, copulation, partner preference, and aggression. Animals were tested for aggression in their home cage, both with and without physical provocation (mild tail pinch). Brain levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were determined using HPLC. PCPA significantly and substantially depleted 5-HT and 5-HIAA in all brain regions examined. Chronic T treatment significantly decreased 5-HT and 5-HIAA in certain brain areas, but to a much lesser extent than PCPA. Chronic exposure to PCPA alone significantly decreased locomotor activity and increased irritability but had no effect on sexual behavior, partner preference, or aggression. T alone had no effect on locomotion, irritability, or sexual behavior but increased partner preference and aggression. The most striking effect of combining T+PCPA was a significant increase in attack frequency as well as a significant decrease in the latency to attack, particularly following physical provocation. Based on these data, it can be speculated that pubertal AAS users with low central 5-HT may be especially prone to exhibit aggressive behavior.
