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Julie A Kauer

Publications and source records attributed to Julie A Kauer.

10 recordsLinked to original sources
PubMed2006

Amphetamine depresses excitatory synaptic transmission at prefrontal cortical layer V synapses.

Dopamine modulates the function of glutamatergic synapses in prefrontal cortex, modifying synaptic strength and influencing synaptic plasticity. Here we have explored the ability of endogenous dopamine, present in slices containing the prefrontal cortex, to influence excitatory synaptic transmission. We found that 10 microM amphetamine, which releases and blocks the reuptake of dopamine from dopaminergic nerve terminals, significantly depressed excitatory field potentials recorded in layer V during stimulation of layer II/III. The depression was reversible, dose dependent and correlated with increased paired pulse facilitation, suggesting that amphetamine inhibits the presynaptic release of glutamate. Pharmacological dissection of this response showed that dopamine D1 receptors are likely to mediate the effects of endogenous dopamine on excitatory synaptic transmission, with little effect of alpha2 adrenergic receptors, serotonin receptors, or D2 dopamine receptors. The time to peak amphetamine effect was longer than expected based on diffusion, suggesting that to raise dopamine levels in brain slices amphetamine may need to be transported into the presynaptic terminals. These results provide evidence that D1/D5 receptors depress glutamate release at this cortical synapse, and suggest that amphetamine will have profound and persistent effects on PFC functioning in vivo. Dysregulation of this mechanism could contribute to the impairment in cognitive performance associated with abnormal PFC dopamine receptor activation.

Adrenergic alpha-Antagonists↗
PubMed2004

Recycling endosomes supply AMPA receptors for LTP.

Long-term potentiation (LTP) of synaptic strength, the most established cellular model of information storage in the brain, is expressed by an increase in the number of postsynaptic AMPA receptors. However, the source of AMPA receptors mobilized during LTP is unknown. We report that AMPA receptors are transported from recycling endosomes to the plasma membrane for LTP. Stimuli that triggered LTP promoted not only AMPA receptor insertion but also generalized recycling of cargo and membrane from endocytic compartments. Thus, recycling endosomes supply AMPA receptors for LTP and provide a mechanistic link between synaptic potentiation and membrane remodeling during synapse modification.

Animals↗
PubMed2004

Repeated exposure to amphetamine disrupts dopaminergic modulation of excitatory synaptic plasticity and neurotransmission in nucleus accumbens.

The mesolimbic dopamine system is essential for reward-seeking behavior, and drugs of abuse perturb the normal functioning of this pathway. The nucleus accumbens (NAc) is a major terminal field of the mesolimbic dopamine neurons and modifications in neuronal structure and function in NAc accompany repeated exposure to psychomotor stimulants and other addictive drugs. Glutamatergic afferents to the NAc are thought to be crucial to the development of several aspects of addictive behavior, including behavioral sensitization and relapse to cocaine self-administration. Here we examine glutamatergic neurotransmission and synaptic plasticity in NAc neurons in vitro before and after repeated amphetamine treatment in vivo. We find that dopamine attenuates the response of NAc neurons to repetitive activation of glutamatergic afferents and thereby blocks long-term potentiation (LTP) induced by high-frequency afferent stimulation. Dopamine's effects are mimicked by dopamine receptor agonists and by amphetamine. In a second set of experiments, animals were treated with amphetamine daily for 6 days and brain slices were prepared after 8-10 days of withdrawal. In these slices, LTP in the NAc appears normal. However, acute exposure of such slices to amphetamine no longer modulates synaptic transmission or LTP induction. Thus, repeated exposure to amphetamine produces long-lasting changes in the modulation of glutamatergic synaptic transmission by amphetamine in the NAc. Our results support the notion that after psychostimulant exposure, excitatory synapses on NAc neurons alter their response to further psychostimulant for long periods of time.

Amphetamine↗
PubMed2004

Rapid synaptic plasticity of glutamatergic synapses on dopamine neurons in the ventral tegmental area in response to acute amphetamine injection.

Drugs of abuse activate the reward circuitry of the mesocorticolimbic system, and it has been hypothesized that drug exposure triggers synaptic plasticity of glutamatergic synapses onto dopamine (DA) neurons of the ventral tegmental area. Here, we show that just a 2 h in vivo exposure to amphetamine is sufficient to potentiate these synapses, measured as an increase in the synaptic AMPAR/NMDAR ratio. We tested the prediction that an increase in GluR1-containing AMPA receptors would result in an increase in GluR1 homomeric receptors at synapses, but were unable to observe any evidence of the predicted rectification in DA neurons from animals treated with amphetamine. We also examined the possibility of increased AMPA receptor insertion in the membrane, but did not detect a significant increase in biotinylated surface GluR1. We conclude that amphetamine induces rapid changes in synaptic AMPAR/NMDAR ratios, suggesting that potentiation of glutamatergic synapses is a relatively early event in the series of neuroadaptations in response to drugs of abuse.

2-Amino-5-phosphonovalerate↗
PubMed2004

Learning mechanisms in addiction: synaptic plasticity in the ventral tegmental area as a result of exposure to drugs of abuse.

One of the central questions in neurobiology is how experience modifies neural function, and how changes in the nervous system permit an animal to adapt its behavior to a changing environment. Learning and adaptation to a host of different environmental stimuli exemplify processes we know must alter the nervous system because the behavioral output changes after experience. Alterations in behavior after exposure to addictive drugs are a striking example of chemical alterations of nervous system function producing long-lasting changes in behavior. The alterations produced in the central nervous system (CNS) by addictive drugs are of interest because of their relationship to human substance abuse but also because these CNS alterations produce dramatic, easily observed alterations in behavior in response to discrete stimuli. Considerable study has been given to behavioral and biochemical correlates of addiction over the past 50 or more years; however, our understanding of the cellular physiological responses of affected CNS neurons is in its infancy. This review focuses on alterations in cellular and synaptic physiology in the ventral tegmental area (VTA) in response to addictive drugs.

Animals↗
PubMed2003

Addictive drugs and stress trigger a common change at VTA synapses.

In this issue of Neuron, Saal et al. find that exposure to any of five addictive drugs or exposure to a brief stressor produces a shared cellular modification of excitatory synapses in the ventral tegmental area (VTA). This common response may represent a starting point for dissecting early changes that underlie addiction.

Animals↗
PubMed2002

Novel protein kinase A-dependent long-term depression of excitatory synapses.

Dopamine neurons of the ventral tegmental area (VTA) are critically involved in processing novel and rewarding information, and mediate the addictive properties of many drugs of abuse. Excitatory synapses on these neurons, like those in other brain regions, exhibit long-term depression (LTD). Amphetamine or dopamine block LTD at VTA synapses, indicating that both pathological and local physiological stimuli regulate LTD. Here we show that in common with other forms of LTD, VTA LTD results from a selective decrease in AMPA receptor function accompanied by a decrease in cell surface AMPA receptors. However, unlike the case for any previously described form of LTD, activation of cyclic AMP-dependent protein kinase (PKA) is necessary and sufficient to trigger LTD at synapses on VTA dopamine neurons.

Animals↗