Abstract
The antidepressant desipramine inhibits the reuptake of norepinephrine (NE), leading to activation of both pre- and postsynaptic adrenergic receptors, including α-1, α-2, β-1, and β-2 subtypes. However, it is not clear which adrenergic receptors are involved in mediating its antidepressant effects. Treatment of mice with desipramine (20 mg/kg, i.p.) produced an antidepressant-like effect, as evidenced by decreased immobility in the forced-swim test; this was antagonized by pretreatment with the α-2 adrenergic antagonist idazoxan (0.1-2.5 mg/kg, i.p.). Similarly, idazoxan, administered peripherally (0.5-2.5 mg/kg, i.p.) or centrally (1-10 μg, i.c.v.), antagonized the antidepressant-like effect of desipramine in rats responding under a differential-reinforcement-of-low-rate (DRL) 72-s schedule, ie, decreased response rate and increased reinforcement rate. By contrast, pretreatment with the β-adrenergic antagonists propranolol and CGP-12177 or the α-1 adrenergic antagonist prazosin did not alter the antidepressant-like effect of desipramine on DRL behavior. The lack of involvement of β-adrenergic receptors in mediating the behavioral effects of desipramine was confirmed using knockout lines. In the forced-swim test, the desipramine-induced decrease in immobility was not altered in mice deficient in β-1, β-2, or both β-1 and β-2 adrenergic receptors. In addition, desipramine (3-30 mg/kg) produced an antidepressant-like effect on behavior under a DRL 36-s schedule in mice deficient in both β-1 and β-2 adrenergic receptors. As antagonism of presynaptic α-2 adrenergic receptors facilitates NE release, which potentiates the effects of desipramine, the present results suggest that postsynaptic α-2 adrenergic receptors play an important role in its antidepressant effects.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1067-1077 |
| Number of pages | 11 |
| Journal | Neuropsychopharmacology |
| Volume | 34 |
| Issue number | 4 |
| DOIs | |
| State | Published - Mar 2009 |
| Externally published | Yes |
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Keywords
- α-2 adrenergic receptors
- β-adrenergic receptors
- Antidepressant
- Desipramine
- DRL behavior
- Forced-swim behavior
ASJC Scopus subject areas
- Pharmacology
- Psychiatry and Mental health
Cite this
Postsynaptic α-2 adrenergic receptors are critical for the antidepressant-like effects of desipramine on behavior. / Zhang, Han Ting; Whisler, Lisa R.; Huang, Ying; Xiang, Yang Kevin; O'Donnell, James M.
In: Neuropsychopharmacology, Vol. 34, No. 4, 03.2009, p. 1067-1077.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Postsynaptic α-2 adrenergic receptors are critical for the antidepressant-like effects of desipramine on behavior
AU - Zhang, Han Ting
AU - Whisler, Lisa R.
AU - Huang, Ying
AU - Xiang, Yang Kevin
AU - O'Donnell, James M.
PY - 2009/3
Y1 - 2009/3
N2 - The antidepressant desipramine inhibits the reuptake of norepinephrine (NE), leading to activation of both pre- and postsynaptic adrenergic receptors, including α-1, α-2, β-1, and β-2 subtypes. However, it is not clear which adrenergic receptors are involved in mediating its antidepressant effects. Treatment of mice with desipramine (20 mg/kg, i.p.) produced an antidepressant-like effect, as evidenced by decreased immobility in the forced-swim test; this was antagonized by pretreatment with the α-2 adrenergic antagonist idazoxan (0.1-2.5 mg/kg, i.p.). Similarly, idazoxan, administered peripherally (0.5-2.5 mg/kg, i.p.) or centrally (1-10 μg, i.c.v.), antagonized the antidepressant-like effect of desipramine in rats responding under a differential-reinforcement-of-low-rate (DRL) 72-s schedule, ie, decreased response rate and increased reinforcement rate. By contrast, pretreatment with the β-adrenergic antagonists propranolol and CGP-12177 or the α-1 adrenergic antagonist prazosin did not alter the antidepressant-like effect of desipramine on DRL behavior. The lack of involvement of β-adrenergic receptors in mediating the behavioral effects of desipramine was confirmed using knockout lines. In the forced-swim test, the desipramine-induced decrease in immobility was not altered in mice deficient in β-1, β-2, or both β-1 and β-2 adrenergic receptors. In addition, desipramine (3-30 mg/kg) produced an antidepressant-like effect on behavior under a DRL 36-s schedule in mice deficient in both β-1 and β-2 adrenergic receptors. As antagonism of presynaptic α-2 adrenergic receptors facilitates NE release, which potentiates the effects of desipramine, the present results suggest that postsynaptic α-2 adrenergic receptors play an important role in its antidepressant effects.
AB - The antidepressant desipramine inhibits the reuptake of norepinephrine (NE), leading to activation of both pre- and postsynaptic adrenergic receptors, including α-1, α-2, β-1, and β-2 subtypes. However, it is not clear which adrenergic receptors are involved in mediating its antidepressant effects. Treatment of mice with desipramine (20 mg/kg, i.p.) produced an antidepressant-like effect, as evidenced by decreased immobility in the forced-swim test; this was antagonized by pretreatment with the α-2 adrenergic antagonist idazoxan (0.1-2.5 mg/kg, i.p.). Similarly, idazoxan, administered peripherally (0.5-2.5 mg/kg, i.p.) or centrally (1-10 μg, i.c.v.), antagonized the antidepressant-like effect of desipramine in rats responding under a differential-reinforcement-of-low-rate (DRL) 72-s schedule, ie, decreased response rate and increased reinforcement rate. By contrast, pretreatment with the β-adrenergic antagonists propranolol and CGP-12177 or the α-1 adrenergic antagonist prazosin did not alter the antidepressant-like effect of desipramine on DRL behavior. The lack of involvement of β-adrenergic receptors in mediating the behavioral effects of desipramine was confirmed using knockout lines. In the forced-swim test, the desipramine-induced decrease in immobility was not altered in mice deficient in β-1, β-2, or both β-1 and β-2 adrenergic receptors. In addition, desipramine (3-30 mg/kg) produced an antidepressant-like effect on behavior under a DRL 36-s schedule in mice deficient in both β-1 and β-2 adrenergic receptors. As antagonism of presynaptic α-2 adrenergic receptors facilitates NE release, which potentiates the effects of desipramine, the present results suggest that postsynaptic α-2 adrenergic receptors play an important role in its antidepressant effects.
KW - α-2 adrenergic receptors
KW - β-adrenergic receptors
KW - Antidepressant
KW - Desipramine
KW - DRL behavior
KW - Forced-swim behavior
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UR - http://www.scopus.com/inward/citedby.url?scp=59949089339&partnerID=8YFLogxK
U2 - 10.1038/npp.2008.184
DO - 10.1038/npp.2008.184
M3 - Article
C2 - 18923403
AN - SCOPUS:59949089339
VL - 34
SP - 1067
EP - 1077
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
IS - 4
ER -