(-)-OSU6162 reduces freezing elicited by context-conditioned fear in rats

(-)-OSU6162 is an antagonist at dopaminergic D₂ receptors which - like other D₂ antagonists - dampens spontaneous activity in animals exploring a novel environment. However, unlike other D₂ antagonists, (-)-OSU6162 has unexpectedly been found to stimulate locomotor activity in inactive, habituated rodents. To what extent the compound may increase activity also in other situations characterised by reduced locomotion is unknown, and it has also not been clarified whether two other receptors also targeted by (-)-OSU6162 - serotonergic 5-HT_2A receptors and sigma-1 receptors - are involved in its unusual behavioural profile. The objective of the present study was to investigate the possible impact of (-)-OSU6162 on the pronounced inactivity in the form of freezing displayed by rats exposed to context-conditioned fear. For comparison, the effect of amphetamine - another dopamine-augmenting and activating compound - was also explored in the same paradigm.

The impact of (-)-OSU6162 and amphetamine on the expression of freezing was assessed in rats exposed to contextual fear conditioning using electrical foot shocks. It was also assessed whether the increase in activity observed in animals treated with (-)-OSU6162 could be countered by pretreatment with a D₂/D₃ antagonist (raclopride), a 5-HT_2A inverse agonist (MDL100907), or a sigma-1 receptor antagonist (BD1063).

While (-)-OSU6162 markedly reduced freezing behaviour, amphetamine abolished it completely. The effect of (-)-OSU6162 was countered by raclopride but neither by MDL100907 nor by BD1063.

(-)-OSU6162 reduces the expression of context-conditioned fear displayed as freezing by a mechanism involving D₂ but not 5-HT_2A or sigma-1 receptors.