The perinatal domoate rat model: Alterations in behaviors mediated by the mesocorticolimbic pathway

Glutamate is the primary excitatory amino acid neurotransmitter in the mammalian central nervous system. Glutamate is also critically important in the development of the central nervous system, and in order for normal development to occur, an optimal level of glutamate signalling is needed. Previous studies in our lab have demonstrated that an alteration in the glutamatergic system, through low non-convulsive doses of domoic acid (DOM) and kainic acid (KA) (selective for kainate receptors, a distinct class of glutamate receptors), administered chronically (s.c.) to rats during a critical period of brain development, caused permanent neuroanatomical, neurochemical and behavioural alterations. Such changes include an altered response to a novel, spatial environment, and alterations in hippocampal morphology. The altered response in a novel environment suggests that the rats treated with DOM in these studies had an alteration in systems modulating response to novelty. The dopaminergic system is important in modulating response to both novelty and reward. Glutamate signalling, through kainate receptors, has been shown to modulate dopamine release in the mesocorticolimbic dopamine pathway, and if expression of these receptors is altered by administering DOM, then the result could be alterations in response to novelty and reward. Therefore, the objective of this thesis was to examine the effects of similar low doses of DOM (20μg/kg), administered during a critical period of brain development when the system is undergoing rapid change (postnatal day 8-14), on behaviours specifically designed to assess responses to reward and novelty. It is known that systems undergoing rapid change are the most susceptible to insult, therefore such treatment could result in permanent change to the functional integrity of the nervous system, rather than just producing transient effects.

The first set of experiments involved the administration of 20μg/kg of DOM to rat pups, over PND 8-14. The rats were then assessed as juveniles and adolescents in the open field. During adulthood, rats were tested in an open field, a sucrose consumption task, the playground maze and in a nicotine-induced conditioned place preference (CPP) paradigm. Activity levels were altered in the DOM-treated rats in open field behavior at each time point assessed. In the playground maze the DOM-treated male rats had an altered response to novelty, as indicated by an increase in time spent exploring objects during the novelty trial of the playground maze. This was not found in DOM-treated female or control rats. The DOM-treated female rats had an increased sensitivity to nicotine in the nicotine-induced CPP paradigm, with a conditioning to nicotine as indicated by a preference for the nicotine-paired compartment of the test arena. This preference was maintained for at least a month following the final drug-compartment pairing.

In the second set of experiments, 20 μg/kg of DOM was administered to rat pups over PND 8-14. The rats were assessed in the nicotine-induced CPP paradigm, during late adolescence. Peri-adolescence is a period of increased sensitivity to the rewarding properties of nicotine, and a period of maturation for the mesocorticolimbic pathway. In the DOM-treated rats, there was a decrease in the sensitivity to nicotine in the nicotine-induced CPP, compared to the saline control rats. The DOM-treated rats failed to manifest the age-appropriate preference for the nicotine-paired compartment.

The results of these studies demonstrate the effects of early DOM exposure on the emergence of behaviors mediated by the mesocorticolimbic pathway, specifically activity levels, response to the rewarding properties of nicotine and response to novelty. These differences are also gender related, and manifested differently at differing stages of development. These results are discussed in light of the putative mechanism of initial KA receptor mediated activation and the link to the DA mesocorticolimbic system.