Effects of M-amphetamine on Neural Circuit Development

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DESCRIPTION (provided by applicant): Abuse of amphetamine and its derivatives, including methamphetamine (METH), is a great socio-medical problem. The biochemical and behavioral effects of these compounds are well-documented for the mature and developing brains but their effects on developing neuronal circuitry and the subsequent recovery from those effects, are not well-studied. Because the pattern of neural circuitry is a major determinant of function, this creates a crucial hiatus in understanding the neurobiological basis of the postnatal behavioral deficits that result from fetal drug exposure. Data on METH-induced changes in neural circuitry are also important for guiding investigations of the cellular and molecular actions of METH, that are aimed at devising therapies to ameliorate its functional effects. In adult animals, the amphetamines are neurotoxic to dopaminergic (DAergic) axons and selectively destroy the terminal arbors of fme serotonergic (5HTergic) axons originating from the dorsal raphe (DR), whereas beaded 5HTergic axons originating from the median raphe remain intact. The somata and axon trunks of the DAergic and 5HTergic neurons do not degenerate. This permits a slow partial regeneration of the damaged 5HTergic axons. Comparable studies in developing brains are lacking. Therefore, we will study the effects of METH on the development of 5HTergic and DAergic circuitry. Our experiments include another innovative feature: 5HT or DA secreted by aminergic axon terminals binds to receptors and transporters located on nonaminergic axon terminals and dendrites. Because neurotransmitters, including 5HT and DA, can modulate the development of axons and dendrites, METH-induced lesions of the 5HT or DA systems may cause abnormalities in the development of other axons or dendrites within the targets of those systems. This could produce permanent abnormalities in neural circuitry. Thus, we study the effects of METH on the development of paradigmatic, non-aminergic axons and dendrites in the targets of 5HTergic or DAergic axons. We will also study the cellular mechanisms by which METH produces its effects on the preceding features of neural circuitry. Abusers of METH include pregnant women. Thus, it is crucial to assess potential neurological damage to their fetuses and to develop therapeutic strategies. Our experiments advance this goal in 2 innovative ways: We study the actions of METH 1) in developing brains and 2) in non-aminergic neurons whose development is likely to be modulated by aminergic neurons that are a direct target of METH. Our experiments will also advance knowledge of 1) how aminergic axons normally modulate the development of neural circuitry and 2) the cellular mechanisms of METH neurotoxicity and of the actions of METH on developing neural circuitry.