Brain regional Fos expression elicited by the activation of mu- but not delta-opioid receptors of the ventral tegmental area: evidence for an implication of the ventral thalamus in opiate reward

Abstract

Both mu-opioid receptors (MORs) and delta-opioid receptors (DORs) are expressed in the ventral tegmental area (VTA) and are thought to be involved in the addictive properties of opiates. However, their respective contributions to opiate reward remain unclear. We used intracranial self-administration (ICSA) to study the rewarding effects of morphine microinjections into the VTA of male and female MOR-/- and DOR-/- mice. In brains of mice tested for intra-VTA morphine self-administration, we analyzed regional Fos protein expression to investigate the neural circuitry underlying this behavior. Male and female WT and DOR-/- mice exhibited similar self-administration performances, whereas knockout of the MOR gene abolished intra-VTA morphine self-administration at all doses tested. Naloxone (4 mg/kg) disrupted this behavior in WT and DOR mutants, without triggering physical signs of withdrawal. Morphine ICSA was associated with an increase in Fos within the nucleus accumbens, striatum, limbic cortices, amygdala, hippocampus, the lateral mammillary nucleus (LM), and the ventral posteromedial thalamus (VPM). This latter structure was found to express high levels of Fos exclusively in self-administering WT and DOR-/- mice. Abolition of morphine reward in MOR-/- mice was associated with a decrease in Fos-positive neurons in the mesocorticolimbic dopamine system, amygdala, hippocampus (CA1), LM, and a complete absence within the VPM. We conclude that (i) VTA MORs, but not DORs, are critical for morphine reward and (ii) the role of VTA-thalamic projections in opiate reward deserves to be further explored.