Enhancement and depression of spinal reflexes by 8-hydroxy-2-(di-n-propylamino)tetralin in the decerebrated and spinalized rabbit: involvement of 5-HT1A- and non-5-HT1A-receptors.
1. In decerebrated, spinalized and paralyzed rabbits, intravenous administration of the 5-HT1A-receptor agonists (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 3-300 nmol kg(-1), cumulative) and flesinoxan (22-2200 nmol kg(-1), cumulative) significantly increased the short latency reflex evoked in gastrocnemius medialis motoneurones by electrical stimulation of all myelinated afferents (Abeta and Adelta fibres) of the sural nerve. Reflexes increased to median values of 198% (inter-quartile range (IQR) 148-473%) and 296% (IQR 254-522%) of pre-drug values with the highest doses of 8-OH-DPAT and flesinoxan, respectively. The enhancement of reflexes induced by 5-HT1A-receptor agonists was not reversed by the selective 5-HT1A-receptor antagonist (S)WAY-100135 (2.05 micromol kg[-1]). 2. The effects of 8-OH-DPAT were tested after pretreatment with (S)WAY-100135 (2.05 micromol kg[-1]), its more potent analogue WAY-100635 (185 nmol kg[-1]), and the 5-HT2/5-HT1D-/5-HT7-receptor ligand ritanserin (1.67 micromol kg[-1]). 8-OH-DPAT (300 nmol kg(-1) single dose) significantly increased gastrocnemius reflex responses in the presence of (S)WAY-100135 and WAY-100635, to median values of 260% (IQR 171-295%) and 165% (IQR 136-170%) of pre-drug levels, respectively. These values were not significantly different from each other, or from the effects of 8-OH-DPAT given alone. When 8-OH-DPAT was given after ritanserin, reflexes were a median of 102% (IQR 76-148%) of pre-drug values: i.e. there was no significant increase in responses. Neither WAY-100635 nor ritanserin had any effects on reflexes per se. 3. WAY-100635 (185 nmol kg[-1]) and ritanserin (1.67 micromol kg[-1]) were given after 8-OH-DPAT (300 nmol kg[-1]). The agonist increased reflexes to a median value of 184% (IQR 135-289%), after which WAY-100635 significantly reduced responses to 165% (IQR 130-254%) and ritanserin further decreased reflexes to a median of 107% (IQR 100-154%) of pre-drug levels, i.e. not significantly different from controls. 4. Previous studies have shown that reflexes evoked by large myelinated axons tend to be suppressed, rather than enhanced, by 5-HT1A-receptor agonists. When tested against reflexes evoked by stimulation of the sural nerve at strengths between 1.5 and 2.5 times threshold, 8-OH-DPAT (3-300 nmol kg(-1), cumulative) and flesinoxan (22-2200 nmol kg(-1), cumulative) significantly reduced gastrocnemius responses to median values of 36% (IQR 15-75%) and 17% (IQR 12-38%) of pre-drug levels, respectively. This inhibition was fully reversed by (S)WAY-100135 (2.05 micromol kg[-1]). 5. These data show that drugs that are agonists at 5-HT1A-receptors increase polysynaptic spinal reflexes evoked by moderate to high stimulus intensities and depress responses to very low intensity stimuli. The inhibitory effects of these drugs were mediated through 5-HT1A-receptors as they were abolished by a selective antagonist for these sites. However, the facilitatory effects of 8-OH-DPAT could be completely blocked only by a combination of ritanserin, which has no significant affinity for 5-HT1A-receptors, with WAY-100635. It appears that the enhancement of reflexes by 8-OH-DPAT arises from a combined action at 5-HT1A-receptors and other, ritanserin-sensitive, sites which could be 5-HT1D- or 5-HT7-receptors.
Clarke
R W
RW
School of Biology, University of Nottingham, Sutton Bonington Campus, Loughborough.
Ogilvie
J
J
Houghton
A K
AK
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000818:Animals; D003655:Decerebrate State; D004558:Electric Stimulation; D005260:Female; D008297:Male; D011817:Rabbits; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D044263:Receptors, Serotonin, 5-HT1; D012018:Reflex / Q000187:drug effects* / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology; D013497:Sural Nerve / Q000502:physiology
D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin