Medial prefrontal cortex ERK and conditioning: Evidence for the association of increased medial prefrontal cortex ERK with the presence/absence of apomorphine conditioned behavior using a unique post-trial conditioning/extinction protocol.

Increases in medial prefrontal cortex ERK have been linked to learning and memory processes. In the present study separate groups of rats initially underwent testing in an open-field paired with either 2.0 mg/kg apomorphine or vehicle injections. Subsequently, in a brief conditioning 5 min. test the paired apomorphine group manifested a conditioned hyperactivity response. The vehicle/apomorphine groups were then subdivided into two vehicle and two apomorphine subgroups matched for their activity scores in this conditioning test. Following another apomorphine/vehicle pairing in the test environment the groups received 3 additional 5 min. non-drug conditioning tests in which the groups received post-trial vehicle/apomorphine treatments. The vehicle groups received vehicle either immediately or 15 min. after the first two of the three conditioning tests and the apomorphine groups received 2.0 mg/kg either immediately or 15 min. after the first two of the three conditioning tests. In the first conditioning test both of the apomorphine groups exhibited equivalent conditioned responses. By the third test, the conditioned response of the immediate post-trial apomorphine group remained robust whereas conditioned response of the 15 min. apomorphine post-trial group was extinguished. Immediately following the third conditioning test, the animals were euthanized and ERK was measured in the medial prefrontal cortex and the nucleus accumbens. ERK was enhanced in both brain areas, selectively in the immediate apomorphine post-trial group. Increased ERK activity linked to the presence of the apomorphine conditioned response coupled with the absence of increased ERK activity following extinction of the apomorphine conditioned response suggests that ERK activity immediately following a conditioning test is an indicator of activity in brain systems with substantial dopaminergic input that are important in learning and memory. The facilitative effects of the immediate post-trial apomorphine treatment on the conditioned response are also consistent with the proposition that immediate post-trial dopaminergic drug treatments can modify the re-consolidation of conditioned behavior.

Increase in medial frontal cortex ERK activation following the induction of apomorphine sensitization.

Repeated high dose injections of the direct acting D1/D2 agonist apomorphine (APO) induces context specific behavioral sensitization. We assessed the effects of 2.0 mg/kg APO on open-field locomotor responses of rats over a 30 min period following either single or five daily APO injections. Acute injections increased locomotor activity, which was markedly increased in rats given 5 daily APO injections. This progressive increase in locomotion during the repeated APO treatments is indicative of behavioral sensitization. Immediately following the open-field test for the acute and the fifth apomorphine injection, the animals were euthanized and their brain tissue was prepared for immunohistochemistry. ERK immunoreactive nuclei in the medial prefrontal cortex (PFC), nucleus accumbens (NAcc), amygdala (AMYG) and lateral hypothalamus (LH) were quantified. The acute apomorphine injections increased ERK in all brain areas as compared to vehicle. Following the fifth apomorphine injection, ERK significantly increased in the PFC, decreased in the amygdala but was unchanged in the LH and NAcc. The selective increase in ERK activity in the PFC associated with behavioral sensitization, points to a possible pivotal role of the dopamine projection to the medial frontal cortex in the mediation of neural plasticity, considered to underlie the sensitization processes induced by dopaminergic drugs.