Diazepam dependence prevented by glutamate antagonists.

Abstract

Long-term treatment leads to tolerance to and dependence on benzodiazepines. Abrupt termination of benzodiazepine administration triggers the expression of signs of dependence. Mice withdrawn from chronic treatment with diazepam showed a time-related evolution of anxiety, muscle rigidity, and seizures between days 4 and 21 after treatment discontinuation. A period between withdrawal days 1 and 3 was symptom-free. Surprisingly, during this "silent phase" the susceptibility of mice to a-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionate (ATPA) and kainate seizures and the magnitude of monosynaptic reflexes mediated by non-N-methyl-Daspartate (NMDA) mechanisms were enhanced. In apparent contrast, the "active phase", between withdrawal days 4 and 21, was characterized by increased susceptibility to NMDA seizures and enhanced magnitude of polysynaptic reflexes, which are NMDA dependent. Treatment ofmice with a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonists 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466) or 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline but not with the NMDA antagonist 3-[(+)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP) during the silent phase prevented signs of dependence. In contrast, treatment with CPP but not with GYKI 52466 during the active phase prevented the symptoms. The development of tolerance to and dependence on diazepam was prevented by concurrent treatment of mice with CPP but was not prevented by GYKI 52466. These data indicate that NMDA-dependent mechanisms contribute to the development of tolerance to diazepam and to the expression of signs of dependence in mice after termination of long-term treatment with diazepam.

Transient Plasticity of Hippocampal CA1 Neuron Glutamate Receptors Contributes to Benzodiazepine Withdrawal-Anxiety

“…Similarly, following chronic ethanol administration, fast AMPA/kainate receptor-mediated CA1 neuron synaptic potentials progressively increase from 2 to 6 h after cessation of ethanol consumption (Molleman and Little, 1995). In the present study, AMPAR changes preceded NMDAR changes (Figure 3), a temporal pattern, which parallels that observed following chronic diazepam (Steppuhn and Turski, 1993). Systemic GYKI-52466 prevented both increased AMPAR-mediated excitation in CA1 neurons and withdrawal-anxiety when injected at the onset of FZP withdrawal (Figure 7a and b), while MK-801 blocked downregulation of NMDAR-mediated currents in 2-day FZP-withdrawn rats.…”

“…Moreover, these changes correlated with localized increases in AMPAR-antagonist binding and decreases in NR2B subunit mRNA and protein levels in the CA1, but not CA3 or DG, region, the latter observation consistent with a decreased efficacy of NMDA applied to isolated CA1 neurons . Modulation of hippocampal glutamatergic function may be important in BZ withdrawal behaviors, as the hippocampus is an integral component of several neural circuits implicated in the expression of anxiety (Andrews et al, 1997;File et al, 1996;McNaughton and Gray, 2000;Menard and Treit, 2001;Millan, 2003) and seizures can originate in the hippocampus during BZ withdrawal (Steppuhn and Turski, 1993). In support of this possibility, Izzo et al (2001) demonstrated increased AMPAR subunit GluR1 protein in rat hippocampus, which corresponded with anxiety-like behavior in an elevated plus-maze during withdrawal from chronic diazepam.…”

“…Since glutamate receptors have been implicated in the development and expression of behaviors indicative of BZ withdrawal (Steppuhn and Turski, 1993), a behavioral correlate for the observed temporal pattern of the regulation of hippocampal AMPAR and NMDAR function was sought. The elevated plus-maze was used to assess temporal changes in anxiety-like behavior in rats during withdrawal from 1-week FZP treatment (average FZP dose per each of four groups: 130.572.8-133.774.1 mg/kg/day, n ¼ 7-8 rats/ group).…”

“…Moreover, increased CA1 neuron AMPAR-mediated excitatory postsynaptic potentials correlate with withdrawal hyperexcitability following chronic ethanol (Molleman and Little, 1995), and NMDAR binding and subunit expression in hippocampus are regulated in pentobarbital-withdrawn rats (Jang et al, 1998;Oh et al, 1997). The observations that pharmacologic antagonism of AMPARs and NMDARs modifies behavioral manifestations of BZ withdrawal (Steppuhn and Turski, 1993;Tsuda et al, 1998) and that AMPAR binding increases in the hippocampus and frontal cortex following withdrawal from diazepam provide evidence that glutamate receptors are also important in BZ withdrawal. Nevertheless, the neural mechanisms fundamental to the expression of BZ withdrawal remain to be clearly identified.…”

Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit

“…The number of interruptions of horizontal sensors was taken as a measure of horizontal activity, whereas that of vertical sensors was taken as a measure of vertical activity. Furthermore, the time spent by mice moving in close proximity to the walls (Ͻ1 cm) or in the center (Ͼ1 cm), indicating fear, was monitored (10), and the center-time͞margin-time ratio was used as a measure of anxiety (11). Locomotor activity and movement tracking were monitored every 4 weeks in independent groups of mice for 2 min between 9 and 10 a.m. Motor Disturbances.…”