The neurophysiological mechanisms underlying withdrawal syndromes reflecting physical dependence on a variety of drugs of abuse, including the benzodiazepines (BZs), are unknown. Using a well-established rat model of chronic BZ treatment, we have identified changes in hippocampal excitatory amino acid receptors temporally associated with anxiety-like behavior, a sign of withdrawal. CA1 neuron changes include increases in alpha-amino-3-hydroxy-5-methyl-4-isozaxolepropionic acid receptor (AMPAR) current amplitude and conductance, and increases in AMPAR binding and GluR1 subunit levels. When AMPAR currents increase, N-methyl-D-aspartate receptor (NMDAR)-evoked currents, NMDA efficacy and NR2B subunit levels are reduced. NMDA antagonist treatment during withdrawal reverses NMDAR down regulation, allowing more prolonged expression of anxiety-like behavior. AMPAR antagonist treatment prevents subsequent AMPAR upregulation. These findings suggest that enhanced AMPAR function contributes to BZ-induced withdrawal through NMDAR-dependent hippocampal pathways, and are reminiscent of well-described mechanisms underlying activity-dependent plasticity of hippocampal excitatory synapses. Similar mechanisms may be involved in behavioral plasticity during BZ withdrawal. The working hypothesis is that localized remodeling of hippocampal CA1 neuron excitatory synapses is a central feature underlying BZ physical dependence, expressed as withdrawal-induced anxiety-like behavior, and has essential characteristics analogous to those associated with activity-dependent synaptic plasticity. Three specific hypotheses focus on the subunit dependence of the functional and structural alterations that occur at CA1 neuron EAAR synapses after withdrawal from 1-week flurazepam treatment. AMPA and NMDAR function will be studied at selected time-points after drug removal, when anxiety-like behavior is expressed, using whole-cell and outside-out patch techniques in hippocampal slices and acutely dissociated CA1 neurons.
The first aim will be to explore AMPAR channel properties using GluR1 subunit-selective neurophysiological and pharmacological tools.
The second aim will use a similar approach to study the NR2B-subunitdependence of decreased NMDAR function at CA1 synapses.
The third aim i s to use light microscopic and electron microscopic immunohistochemical approaches to investigate the structural changes in AMPARs and NMDARs at CA1 synapses that contribute to changes in hippocampal excitatory function and to anxiety-like behavior. Rational approaches to the treatment of physical dependence on drugs of abuse can emerge from a better understanding of the neurophysiological mechanisms underlying withdrawal phenomena.
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