Central Alpha-Adrenoceptors and Behaviour

A range of agonists and antagonists were found to show selectivity peripherally for α1 and α2 receptors in vitro. Further studies showed that drugs showing elective effects at a2 receptors were able to modify the release of noradrenaline from central neurones. Behavioural studies were undertaken using all the drugs to determine whether central a1 and a2 receptors may mediate different effects. Agonists selective for α2 receptors clonidine, guanfacin and guanabenz, caused marked sedation, inhibited the pinna reflex, and were slightly analgesic. Clonidine also inhibited 5-HT-induced head twitches and haloperidol-induced catalepsy. In general, α1 agonists such as methoxamine, had the opposite effect on observed behaviour, producing a syndrome of hyperalertness, hyperalgesia and hyperreactivity which resembled fear. However, high doses did inhibit the pinna reflex and 5-HT-induced head twitches. Both clonidine and methoxamine also inhibited motor activity alone, but potentiated apomorphine-induced activity in reserpinised mice. Antagonists with selectivity for α2 receptors, yohimbine and piperoxane, had behaviourally opposite effects to clonidine (although, like clonidine, these drugs again reduced activity) and in general were able to reverse these effects. Alpha1 antagonists such as prazosin on the other hand, produced sedation and potentiated clonidine's actions. However, α1 antagonists did not inhibit the pinna reflex or produce analgesia alone. The results suggest that central a2 receptor stimulation leads to sedation, analgesia and inhibition of the pinna reflex, 5-HT head twitches, catalepsy and motor activity and also possibly to an anxiolytic-like effect. Stimulation of a1 receptors, on the other hand, appears to result in hyperalertness, hyperreactivity, hyperalgesia, potentiation of catalepsy and fearfulness; and, when α1 inhibitory effects are removed, increased activity and potentiation of 5-HT. The drug selectivity found between α1 and α2 receptors in vitro, thus appears to be retained in vivo and may be manifested in the different behavioural effects produced by drugs which display such selectivity for one or the other type of receptor.

Name dc:type.qualificationname

Ph.D.

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

Aston University

Year dc:date.issued

1980

Author dc:creator

• Brown, Janet