Local hippocampal methamphetamine-induced reinforcement

Abstract

Drug abuse and addiction are major problems in the United States. In particular methamphetamine (METH) use has increased dramatically. A greater understanding of how METH acts on the brain to induce addiction may lead to better therapeutic targets for this problem. The hippocampus is recognized as an important structure in learning and memory, but is not typically associated with drug reinforcement or reward processes. Here, the focus is on the hippocampus which has been largely ignored in the addiction literature as compared to the nucleus accumbens (NAc), ventral tegmental area (VTA), and prefrontal cortex (PFC). The results show that METH administered unilaterally via a microdialysis probe to rats' right dorsal hippocampus will induce drug-seeking (place preference) and drug-taking (lever-pressing) behavior. Furthermore, both of these responses are dependent on local dopamine (DA) receptor activation, as they are impaired by a selective D(1)/D(5) receptor antagonist. The results suggest that the hippocampus is part of the brain's reward circuit that underlies addiction.

Keywords: hippocampus; methamphetamine; reward.

Figure 1

Intrahippocampal METH-induced CPP is spatially discrete and modulated via local D₁/D₅ receptors. (A) The effects of intrahippocampal METH 10 μg/μl (n = 12) or Ringer's (n = 10) on CPP Test 1 (white bars) and the effects of local SCH 23390 application (black bars) prior to Test 2 (to examine CPP Expression) of either Intrahippocampal METH trained rats for CPP (n = 7) or vehicle (n = 6). (B) The effects of intrahippocampal METH 10 μg/μl (n = 6) or Ringer's (n = 5) on CPP Test 1 (white bars) and the effects of local SCH 23390 co-application with METH (black bars) during conditioning (to examine CPP Acquisition) of either Intrahippocampal METH CPP (n = 6) or Ringer's (n = 6). The inset at the bottom left shows a coronal section of the brain of a representative rat that received multiple dialyses. Hippocampal sub regions (a, b and c) and cortical areas (CTXa) and (CTXb) used for the scintillation counter experiment are labeled. The inset at the bottom right shows scintillation counter measurements (CPM) of [³H] METH revealing limited diffusion within hippocampus during a 10-min dialysis where the microdialysis probe was located (1, 2, 3). Overlying tissue (CTXa) and lateral regions (CTXb) did not reflect any CPM revealing limited diffusion. The symbol * represents a statistical difference from all the other groups (P < 0.05).

Figure 2

Role of local D₁/D₅ receptors in the acquisition and expression of intrahippocampal METH CPP. (A) The effects of intrahippocampal METH μg/μl (n = 6) or Ringer's (n = 5) on CPP Test 1 and the effects of local SCH 23390 on CPP acquisition (Test 1) and CPP expression (Test 2) of intrahippocampal METH CPP (n = 6) or Ringer's vehicle (n = 6). (B) METH only induces CPP in the hippocampus and not the cortex (CTX). The effects of intracranial METH (hippocampus n = 13 or CTX n = 10) or Ringer's (hippocampus n = 11 or CTX n = 10) on CPP and local SCH 23390 on CPP acquisition (Test 1) and expression (Test 2) of intrahippocampal METH CPP. The symbol * represents a difference from all other groups (P < 0.05). (C) Local hippocampal D₁/D₅ antagonism does not affect locomotor activity. White bar represents crosses during pre conditioning test. The gray bar is activity during the first drug-free test while the black bar is activity in the presence of the D₁/D₅ antagonist (100 μM).

Figure 3

Intrahippocampal METH sustains self administration. (A) Cumulative lever presses per day on the active and inactive levers during the 30-min test sessions across 7 days. Rats in the Ringer's (n = 11) and METH 10 μg/μl (n = 12) groups were co-treated with 250 μM SCH during days 5–7. METH 10 μg/μl group active lever presses were significantly greater than Ringer's group active lever presses from day 3 onward. METH group: upside-down black triangles; METH inactive: light gray diamonds; Ringer's: dark gray triangles. (B) METH induces lever-pressing in the hippocampus and not the cortex (CTX). All groups were co-treated with 100 μM SCH 23390 during days 5–7. Intrahippocampal METH group active lever presses were significantly greater than CTX METH and Ringer's vehicle groups from day 2 onward. The symbol * represents a difference from all other groups (P < 0.05). Hippocampus METH group: upside-down black triangles; Hippocampus METH inactive: light gray diamonds; Hippocampus Ringer's: dark gray triangles; CTX METH: black filled circles.

Figure 4

Intrahippocampal METH self administration is modulated via local D₁/D₅ receptors. (A) Average lever presses on the active and inactive levers during the 30-min test sessions across 7 days. Rats in the Ringer's (n = 12) and METH 10 μg/μl (n = 17) groups were co-treated with 250 μM SCH 23390 during days 5–7 (black bars). METH group active lever presses were significantly greater than Ringer's group active lever presses. Local application of SCH 23390 impairs (black bars) impairs METH lever pressing behavior. (B) METH only induces lever-pressing in the hippocampus and not the cortex (CTX). All groups were co-treated with 100 μM SCH 23390 during days 5–7. Intrahippocampal METH group active lever presses were significantly greater than CTX METH and Ringer's vehicle groups from day 2 onward. The symbol * represents a difference from all other groups (P < 0.05).