Functional supersensitivity to adrenergic agonists in the rat after DSP-4, a selective noradrenergic neurotoxin

We found previously that the beta-agonist clenbuterol and the alpha-agonist clonidine produced hyperthermia in rats kept at high ambient temperature, which effects were mediated by beta- and alpha 2-adrenoceptors, respectively. In the present paper this observation was used for testing the responsiveness of beta- or alpha 2-adrenoceptors, changed by a pharmacological manipulation, i.e., by chronic treatment with antidepressants. The animals were pretreated with desipramine, imipramine or amitriptyline twice a day for 1 or 2 weeks. All antidepressants significantly attenuated the clenbuterol-induced hyperthermia after 2 weeks of treatment. The effect of desipramine was stronger than that of the other antidepressants and appeared as little as 1 week after the treatment. The hyperthermic effect of clonidine was significantly reduced by repeated treatment with desipramine, increased after 2 weeks administration of imipramine, whereas amitriptyline produced no significant changes. In conclusion, these data suggest that, after repeated treatment, the antidepressants tested produce an adaptive decrease in function of beta-adrenoceptors while the same drugs exert differential effects on alpha 2-receptors. Moreover, clenbuterol induced hyperthermia may be a useful test for examining possible functional changes in beta-adrenoceptor sensitivity.

Section: Discussionmentioning

confidence: 96%

Adaptive and differential changes on ?- and ?2-adrenoreceptors mediated hyperthermia after chronic treatment with antidepressant drugs in the rat kept at high ambient temperature

Mogilnicka

Klimek

Nowak

et al. 1985

“…Our findings lead to similar conclusions: the hyperthermic effect of CLON is mediated by postsynaptic a2-adrenoceptors, since damage to central noradrenergic terminals with a new neurotoxin, DSP-4, does not inhibit the CLON-induced hyperthermia. In fact, an increase in CLONhyperthermic action was observed in DSP-4 lesioned rats, suggesting a supersensitivity of the central a2-receptor in DSP-4-treated rats (Dooley et al, 1983 b).…”

Section: Discussionmentioning

confidence: 98%

Clonidine and a ?-agonists induce hyperthermia in rats at high ambient temperature

Mogilnicka

Klimek

Nowak

et al. 1985

The effects of the alpha-agonist clonidine and the beta-agonist clenbuterol on body temperature of rats kept at high ambient temperature (28 degrees C) were studied. Both drugs induced a dose-dependent significant increase in temperature. The clonidine-induced hyperthermia was blocked by various alpha 2-antagonists, yohimbine, rauwolscine and RX 781094 and the alpha 1-antagonists, prazosin and corynanthine but not by 1-propranolol, spiperone, metergoline. The hyperthermic effect of clonidine was potentiated in rats after a lesion of the central noradrenergic terminals by DSP-4. The clenbuterol-induced hyperthermia was counteracted by 1-propranolol, yohimbine and rauwolscine but not by atenolol, prazosin, spiperone, metergoline. These observations indicate that clonidine- and clenbuterol-induced hyperthermia is mediated by alpha 2-(postsynaptic) and beta-adrenoceptors, respectively. Moreover, in the latter effect alpha 2-adrenoceptors are involved. The simple temperature measurement can thus be used as a preliminary indicator of central alpha 2- or beta-agonistic properties of the screened drug.

“…ClenbuteroMnduced hypoactivity is known to be centrally mediated, since it is abolished after destruction of brain noradrenergic neurons (Dooley et al, 1983) and [32 receptors are known to utilize adenylate cyclase as a second messenger. Since lithium treatment does not affect adrenergic receptor number (Gross et al, 1985), the results of Givant et al (1990) are likely to be due to lithium inhibition of adenylate cyclase, as more directly demonstrated in the present experiment.…”

Section: Discussionmentioning

confidence: 99%

The effect of acute and chronic lithium on forskolin-induced reduction of rat activity

Bersudsky

Patishi

Jensen

et al. 1997

Forskolin is a diterpene derivative that activates adenylate cyclase and raises cAMP levels in the cell. Both i.p. and i.c.v. forskolin cause behavioral hypoactivity. Lithium has been reported for many years to block cAMP accumulation, but the behavioral relevance of this biochemical effect is not clear. We studied the effect of acute and chronic lithium on icv forskolin-induced hypoactivity. Acute lithium had no effect, but chronic lithium significantly blocked forskolin-induced hypoactivity. The effect of chronic lithium occurred with both forskolin in DMSO and with a water-soluble forskolin derivative. These results suggest that this behavioral model can be used to investigate whether new inhibitors of adenylate cyclase possess lithium-like effects.