Depletion of brain norepinephrine: differential influence on anxiolyic treatment effects |
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Authors: | David J Fontana Love V McMiller Jr R L Commissaris |
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Institution: | (1) Department of Pharmaceutical Sciences, College of Pharmacy & AHP, Wayne State University, Detroit, MI 48202, USA, US;(2) Department of Psychiatry, School of Medicine, Wayne State University, Detroit, MI 48202, USA e-mail: rlc@wizard.pharm.wayne.edu, Fax: +1-313-577-2033, US |
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Abstract: | Rationale: Previous studies have demonstrated that anxiolytic-like anticonflict effects can be produced by either (1) acute administration
of traditional anti-anxiety compounds (benzodiazepines or barbiturates) or (2) chronic administration of tricyclic (TCA) or
monoamine oxidase inhibitor (MAOI) antidepressants. Objective: The present study determined the effects of noradrenergic neuronal depletion on these distinct anticonflict treatments.
Methods: After 3 weeks of training in a repeated measures drink suppression conflict paradigm, water-restricted rats consumed 11–14 ml
water/session (unpunished responding) and accepted 25–40 shocks/session (punished responding) during control (i.e., non-drug)
10-min test sessions. The noradrenergic neurotoxin DSP4 N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride; 65 mg/kg, IP] or its vehicle (saline; 1 ml/kg) was administered after 3 weeks of
conflict testing. Conflict behavior was then evaluated for 8 weeks post-treatment. In separate groups of DSP4- and vehicle-pretreated
subjects, the effects of acute administration (10-min pretreatment) of phenobarbital (5–40 mg/kg) or alprazolam (0.3–2.5 mg/kg)
were determined. In a third experiment, the effects of chronic treatment with the TCA desipramine (DMI; 5 mg/kg, twice daily
for 8 weeks) or the non-selective MAOI phenelzine (4.0 mg/kg, twice daily for 8 weeks) on conflict behavior were determined
in additional groups of DSP4- or vehicle-pretreated subjects. Results: DSP4 treatment produced a modest yet statistically significant decrease in punished responding (i.e., anxiogenic-like effect)
relative to vehicle controls. DSP4 pretreatment did not alter the anticonflict effects of acute alprazolam or phenobarbital
treatment. In contrast, DSP4 treatment completely abolished the anticonflict effects produced by chronic DMI or chronic phenelzine
treatment. Conclusions: Thus, noradrenergic neuronal integrity appears to be required for the anxiolytic-like effects of chronic antidepressant
treatment, but not for the anxiolytic-like effects of acute treatment with barbiturates and benzodiazepines.
Received: 6 August 1998/Final version: 16 October 1998 |
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Keywords: | Anxiety Anxiolytics Antidepressants Barbiturates Benzodiazepines Conflict behavior Desipramine Norepinephrine Phenelzine DSP4 Phenobarbital Alprazolam Panic disorder Generalized anxiety disorder |
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