These experiments focus on the neurobiological mediators of motivation to seek offspring versus cocaine during the postpartum period, a unique period in the life of the female, critical for the survival of her offspring. A foremost goal of my preclinical model is to explore the neural circuitry and neurochemistry supporting motivational responses in the postpartum female rat. I posit that these behavioral and neurobiological data will provide information that usefully generalizes to processes related to the human condition. These experiments will use conditioned place preference (CPP) as a measure of stimulus seeking because CPP does not require the presence of the stimulus during motivation testing, so the neural substrates active exclusively during seeking of the stimulus can be targeted.
Specific Aim Revealing the network of neurons and their neurotransmitters necessary for the choice of pup-associated versus cocaine-associated environments. A. Is the medial preoptic area (mPOA) necessary to determining the choice of environments associated with pups versus cocaine presented in a dual choice paradigm? I will test this using neuroanatomical site specific and transient inactivation (with bupivacaine a local anesthetic) of the mPOA during CPP test. B. Which additional components of the circuit are necessary to determining the choice of environments associated with pups versus cocaine presented in a dual choice paradigm? I will using methods used in the experiments in A, test the hypothesis that the ventral tegmental area, nucleus accumbens and the medial prefrontal cortex are necessary to the manifestation of CPP for either pup or cocaine-associated environments. C. What is the causal contribution of dopamine and glutamate mediated neurotransmission within key components of the neural circuit necessary for the choice of environments associated with pups versus cocaine? I will inject dopaminergic or glutametergic antagonists via site specifically directed cannulae into limited regions of this circuit at CPP test. It is likely that the incentive value and choice to seek each individual stimulus is established in a distributed neural network that underlies the components of motivated response, and that neuronal activation in this network is state-dependent, and that the postpartum state is a unique one that must be studied specifically. I posit that the different stimuli (pups versus cocaine) may recruit certain components of this network more strongly than others, providing a likely mechanism explaining why an individual attributes different incentive values to different stimuli. Exploring the specific circuitry mediating the choice between the two particular stimuli in my paradigm is likely to reveal neural substrate particular to this highly state dependent and functionally incompatible set of choices, seeking and caring for offspring or seeking cocaine.
Pregnancy and the nursing period are unique in the natural history of the human, or of any mammal, because during this period the child can be uniquely harmed or uniquely helped, each with life-long consequences. From the complex nexus of biology, education, and culture, the human female must choose her behavior to be optimal to protect her offspring during this period. Maternal motivation to initiate care is a universal mammalian phenomena that extends to robust maternal motivation in many women. However, a mother's world is full of choices. One choice that faces the human mother is whether or not to use of cocaine which can be an initial step toward a devastating condition of chronic relapsing drug dependency. Such a choice can have devastating consequences on maternal care giving, and hence life-long consequences for their offspring. There is insufficient scientific understanding of the brain processes that mediate the complex motivational forces at work in females cause them to initiate care for their offspring or to initiate choices that are harmful to their offspring such as use of cocaine. The experiments in this application will examine the behavioral neurobiology of a preclinical model of maternal motivation which we fully expect will uncover principles of function that will generalize informatively to the human condition. These experiments examine how the motivation to seek cocaine might hijack the motivation to care for offspring using a well established laboratory model, the postpartum rat. Both the behavior of the rat, using a well established tool to measure motivation, the conditioned place preference procedure, and the brain structures that mediate choice behaviors will be endpoints of these experiments. While the human condition is vastly more complex than can be modeled in any preclinical models, we can very usefully determine the basic biological and neural mechanisms at work in mammals with the sure knowledge that all we learn about the biological fundamentals will usefully generalize to the basic neurobiology of maternal humans. PHS 398/2590 (Rev. 11/07) Page PAGE ?1?Continuation Format Page
Showing the most recent 10 out of 18 publications
