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Calcium antagonists in the olfactory bulbectomy animal model of depression: effect on the cortical NMDA receptor
1Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson 39216-4505, USA.
Abstract:
Voltage-dependent calcium channel (VDCC) antagonists are active in the forced swim test and in learned helplessness behavioral paradigms, suggesting their antidepressant efficacy. In fact, some clinical reports show that VDCC antagonists are useful in a treatment of affective disorders. Because none of the VDCC antagonists has been tested in the olfactory bulbectomy (OB) model of depression, we examined the efficacy of chronic treatment with verapamil and diltiazem to reduce OB-induced hyperactivity. We also observed the effect of these treatments on OB-induced alterations in the NMDA receptor complex in rat cortex. We report that chronic administration of verapamil (20 mg/kg) and diltiazem (10 mg/kg) did not reduced OB-induced hyperactivity, although these drugs reduced the potency of glycine to inhibit [3H]5,7-dichlorokynurenic acid (DCKA) binding to strychnine-insensitive glycine sites of the NMDA receptor complex. OB also reduced the potency of glycine to inhibit [3H]5,7-DCKA binding, and this reduction was slightly attenuated by chronic treatment with both drugs. These data indicate that: 1) verapamil and diltiazem are not effective in OB model of depression, 2) VDCC antagonists'-induced effect in the glycine sites of the NMDA receptor complex is not species-specific, and 3) there is no direct relationship between OB-induced hyperactivity and alterations in strychnine-insensitive glycine sites of the NMDA receptor complex.
Insights
Voltage-dependent calcium channel (VDCC) antagonists, like verapamil and diltiazem, did not reduce depression-like hyperactivity in rats. However, they did affect NMDA receptor glycine sites, suggesting no direct link to hyperactivity.
Area of Science:
- Neuropharmacology
- Behavioral Neuroscience
- Molecular Psychiatry
Background:
- Voltage-dependent calcium channel (VDCC) antagonists show antidepressant potential in behavioral tests and some clinical reports.
- The olfactory bulbectomy (OB) model is a recognized animal model for studying depression.
- The efficacy of VDCC antagonists in the OB model and their effects on the NMDA receptor complex remained uninvestigated.
Purpose of the Study:
- To evaluate the antidepressant efficacy of chronic verapamil and diltiazem administration in the olfactory bulbectomy (OB) rat model of depression.
- To investigate the impact of these VDCC antagonists on OB-induced alterations within the NMDA receptor complex in rat cortical tissue.
Main Methods:
- Chronic administration of verapamil (20 mg/kg) and diltiazem (10 mg/kg) to olfactory bulbectomized (OB) rats.
- Assessment of OB-induced hyperactivity.
- Measurement of glycine's potency to inhibit [3H]5,7-dichlorokynurenic acid (DCKA) binding to strychnine-insensitive glycine sites of the NMDA receptor complex.
Main Results:
- Neither verapamil nor diltiazem treatment reduced OB-induced hyperactivity in rats.
- Both drugs decreased the potency of glycine in inhibiting [3H]5,7-DCKA binding to NMDA receptor glycine sites.
- Olfactory bulbectomy itself reduced glycine's inhibitory potency, an effect partially attenuated by verapamil and diltiazem treatment.
Conclusions:
- Verapamil and diltiazem are ineffective in mitigating hyperactivity in the OB model of depression.
- The observed effects of VDCC antagonists on NMDA receptor glycine sites are not species-specific.
- There is no direct correlation between OB-induced hyperactivity and changes in the NMDA receptor's strychnine-insensitive glycine sites.