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Previously we reported that prenatal morphine exposure during embryonic days 5–8 can cause cognitive deficits of one-trial passive avoidance learning (PAL) in one-day old chicks. Because protein kinase C (PKC) has been associated with memory capacity, we investigated the effects of prenatal morphine exposure on PKC isoforms expression in the left intermediate medial mesopallium (IMM) of chick brain at a time when memory tests were performed at 30, 120 and 360 min respectively following training in PAL paradigm. We found that the level of PKCα in the membrane fractions in left IMM was decreased but that in the cytosol fractions showed a increased trend in prenatally morphine-exposed chicks with impaired long-term memory (120 and 360 min). Moreover, the translocation of PKC δ from cytosol to membrane in left IMM was shown in prenatal morphine group which had significantly impaired long-term memory at 360 min after training. Furthermore, there were no statistical differences between the two groups regarding the expressions of PKCα and PKC δ in the membrane fraction, although their levels in the cytosol fraction of prenatal morphine group which showed impaired intermediate-term memory at 30 min after training, were quite different from that of prenatal saline group. Taken together, these results indicate that PKCα and PKC δ in the left IMM are differentially involved in the impairments of long-term memory induced by prenatal morphine exposure. Neither PKCα nor PKC δ in left IMM may be associated with the disruption of intermediate-term memory of chicks prenatally exposed to morphine.

The susceptibility to drug abuse may be associated with the structural and/or functional changes in the reward-related brain regions induced by drug exposure during sensitive periods of embryonic development. Previously, we have found that prenatal morphine exposure during embryonic days 17–20 may be crucial for developing the susceptibility to morphine reward after hatching. However, the underlying structure and cellular mechanisms need further investigation. In the present study, the chicks of a few days old, which were prenatally exposed to morphine during E17-20, obviously showed higher preference for the morphine-paired chamber and hyperactivity during the expression of morphine conditioned place preference (CPP), and the reduction in membrane-bound of PKCα of the bilateral intermediate medial mesopallium (IMM) assayed immunologically. These results indicate that the decreased expression of PKCα in IMM may participate in the development of the susceptibility to the rewarding effects of morphine in chicks prenatally exposed to morphine, and provide further support for the cross-species evolutionary concordance among amniotes.

Prenatal exposure to morphine can alter the capacities for learning and memory and the sensitivity to drugs of abuse in progeny. In the present study, we examined the effects of morphine during chick embryonic period of 5–8, 9–12, 13–16 and 17–20 on cognitive function and the sensitivities to morphine reward in the post-hatch chick, using the one-trial passive avoidance learning task and the conditioned place preference paradigm. It was observed that the injection of morphine (1 mg/kg of egg weight) during E5–8, but not in other three periods, significantly impaired intermediate- and long-term memory in one-day-old chicks. On the other hand, the chicks prenatally exposed to morphine during E17–20 remarkably not only acquired but also maintained the conditioned place preference induced by morphine. The present results suggest that there are two time-windows during development, which in the chick are around E5–8 and E17–20, when prenatal morphine exposure is likely to confer maximal risks for vulnerabilities to breakdown of memory consolidation and to morphine-induced reward in day-old chicks respectively.

In the avian forebrain, the medial striatum and the intermediate medial mesopallium are thought to be important structures for associative learning in chicks, where the role of dopaminergic systems in learning processes has been verified in various behavioral paradigms, such as one-trial passive avoidance learning. However, it is not yet clear whether the dopaminergic system of these regions is responsible for associative learning underlying cue-elicited drug reward. In this study, a 6-day conditioning schedule in day-old chicks with i.p. morphine (2 mg/kg) was used to compare the effects of intracerebrally injected dopamine D(1) receptor antagonist, SCH23390, and D(2) antagonist, spiperone. The antagonists were injected bilaterally (3 mu g/site) into either the medial striatum or the intermediate medial mesopallium, and tests were conducted on morphine-induced conditioned place preference or locomotor activity. The acquisition of place preference was significantly inhibited by SCH23390 in either the medial striatum or the intermediate medial mesopallium, but not by spiperone. However, in the medial striatum, but not in the intermediate medial mesopallium, the locomotor activity was blocked by both SCH23390 and spiperone. These data suggest that the medial striatum and the intermediate medial mesopallium in birds are differentially involved in the rewarding effects of morphine, and similarly to mammals, the dopamine D(1) system may play an important role in the development of opiate reward. Crown Copyright (C) 2009 Published by Elsevier B.V. All rights reserved.

Based on our previous findings in day-old chicks with prenatal morphine-treated, embryonic days 5-8 is crucial for functional development of learning and memory, the underlying structure and cellular mechanisms were further explored. The prenatal morphine-exposed chicks showed deficits in passive avoidance learning and conditioned place preference, and attenuation in paired-pulse facilitation and heterosynaptic long-term potentiation in intermediate medial mesopallium (IMM) in vitro. These results suggest the altered synaptic plasticity of IMM by prenatal morphine exposure is involved in behavioral impairments.