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Previous studies suggest that noradrenaline may regulate serotonergic (5-HT) neurotransmission at the serotonin cell body and noradrenaline nerve terminal. Using microdialysis coupled to HPLC, we investigated the effects of alpha 1-adrenoceptor manipulation on extracellular serotonin levels in the ventral hippocampus, prefrontal cortex, and raphe nuclei in the presence or absence of the serotonin reuptake inhibitor (SSRI), citalopram. Extracellular 5-HT levels from prefrontal cortex, ventral hippocampus and raphe nuclei were markedly increased following citalopram administration (3.0 mg/kg s.c.). In the prefrontal cortex and ventral hippocampus, local blockade of the alpha 1-adrenoceptor (3.0 mu M prazosin infusion) significantly decreased this citalopram-induced increase in serotonin, while cirazoline (alpha 1-adrenoceptor agonist) and reboxetine (noradrenaline reuptake inhibitor) further increased extracellular serotonin levels when administered systemically (0.02 mg/kg i.p. and 5.0 mg/kg s.c. respectively) or locally infused (10.0 mu M and 1.0 mu M respectively). Moreover, prazosin pre-infusion into terminal areas prevented the increase in citalopram-induced increase in serotonin levels with systemic cirazoline or reboxetine administration. Prazosin also decreased the citalopram-induced increase in serotonin levels in the raphe nuclei; however no enhancement of the SSRI response was observed with systemic or local administration of cirazoline or reboxetine, suggesting that alpha 1-adrenoceptors may already be maximally activated under these conditions. These data provide strong evidence that after acute citalopram administration, the alpha 1-adrenoceptor exerts a modulatory role on serotonin levels. (C) 2009 Published by Elsevier Ltd.

Clozapine and the novel putative, antipsychotic S 16924 ((1-(benzodioxane-5-yl)-3-[3-(4-fluorophenacyl)pyrrolidine]-1-o xapropane HCl) share significant affinity for alpha1-adrenoceptors and 5-HT1A autoreceptors in vitro and display an 'atypical' behavioural profile in in vivo models used for detecting potential neuroleptic effects. In the present study, in vivo microdialysis was used to examine the effect of clozapine and S 16924 on 5-HT overflow in the rat ventral hippocampus, and to assess the relative role of putative alpha1-adrenoceptor antagonist and 5-HT1A autoreceptor agonist properties of the drugs in this regard. S 16924 (0.1-3 mg/kg, s.c.) reduced dialysate 5-HT in a dose- and time-dependent fashion by maximally approximately 70% from baseline 40-60 min after injection. Clozapine (0.1-10 mg/kg, s.c.) reduced 5-HT overflow in the same manner, with a maximum effect of approximately 60% from baseline, obtained after 60-80 min. The 5-HT decrease elicited by S 16924 (1.0 mg/kg, s.c.) was significantly, though only partially, antagonized by pretreatment with the selective 5-HT1A receptor antagonist WAY 100635 (0.3 mg/kg, s.c.). The selective alpha1-adrenoceptor agonist cirazoline (0.02 mg/kg, i.p.) alone did not significantly attenuate the effect of S 16924 (1.0 mg/kg, s.c.) on 5-HT overflow. Combined treatment with both WAY 100635 and cirazoline, however, totally reversed the 5-HT-suppressing effect of S 16924 (1.0 mg/kg, s.c.). By comparison, when given separately, neither WAY 100635 (0.3 mg/kg, s.c.) nor cirazoline (0.02 mg/kg, i.p.) antagonized the clozapine (0.3 mg/kg, s.c.)-induced decrease of 5-HT in ventral hippocampus dialysates. In the presence of both WAY 100635 and cirazoline, the response to this dose of clozapine was however significantly, though modestly, attenuated. In contrast, the WAY 100635/cirazoline combination failed to antagonise the 5-HT decrease resulting from a higher dose (3.0 mg/kg, s.c.) of clozapine. We conclude that both alpha1-adrenoceptor antagonist and 5-HT1A receptor agonist properties of clozapine and S 16924 contribute to the 5-HT release-reducing action of these drugs. Whereas these factors apparently explain the effect of S 16924 fully, additional mechanism(s) appear to be involved in the case of clozapine. With regard to the interplay between alpha1-adrenoceptor and 5-HT1A (auto)receptor mechanisms in the control of 5-HT release in the rat forebrain, the present data suggest that an excitation mediated by the former is outweighed by the simultaneous activation of the latter-inhibitory-receptors.

The novel spiroimidazoline, S18616, a potent and efficacious agonist at alpha2-adrenoceptors (ARs), shows>100-fold selectivity versus alpha1-ARs, imidazoline receptors and all other sites examined. Herein, we characterized its discriminative stimulus (DS) properties in rats trained to recognise S18616 (0.01 mg/kg, s.c.) from saline. S18616 dose-dependently (0.0063-0.01) and "fully" (>or=80% "S18616" lever selection) substituted for itself. Full substitution was also acquired for the agonist, UK14,304 (0.04-0.16), while the partial agonist, clonidine (0.01-0.08), yielded sub-maximal substitution (67%). Guanfacine (0.16-1.25) and guanabenz (0.00063-0.04), preferential agonists at alpha2A-ARs, revealed full substitution for S18616. In contrast, the alpha1-AR agonists, cirazoline and ST587 (both 0.04-0.63), did not substitute. The alpha2-AR antagonists, RX821,002, atipamezole (both 0.0025-0.04) and idazoxan (0.04-0.63) blocked the S18616 DS, whereas the alpha1-AR antagonists, prazosin (0.16-0.63) and WB4101 (0.04-0.63), were inactive. Prazosin is also a preferential antagonist at alpha2B/2C- versus alpha2A-ARs and a further preferential alpha2B/2C-AR antagonist, BRL41,992 (0.63-2.5), was likewise ineffective. In contrast, the alpha2A-AR antagonist, BRL44,408 (0.04-0.16), dose-dependently abolished the S18616 DS. Finally, the "atypical" antidepressants, mirtazapine (0.16-10.0) and mianserin (0.63-10.0), which behave as antagonists at alpha2A-ARs, dose-dependently blocked the S18616 DS. In conclusion, S18616 elicits a robust DS in rats that principally reflects engagement of alpha2A-ARs. This novel procedure should prove useful in the characterisation of psychoactive drugs which interact with alpha2-ARs.

The role of the alpha-1 adrenoceptor in prepulse inhibition (PPI) was evaluated in rats. The alpha-1 adrenergic agonist cirazoline disrupted PPI; this effect was reversed by the alpha-1 adrenergic antagonist prazosin or the atypical antipsychotic quetiapine. Alpha-1 adrenoceptors may thus be involved in the regulation of PPI and in the psychotherapeutic actions of certain antipsychotics.

The porphyrin precursor, delta-aminolaevulinic acid (ALA) at concentrations of 0.23-7.6 mM caused dose-dependent inhibition of spontaneous contractions in isolated preparations of rabbit small intestine, suspended in Ringer-Locke solution. Contractions which returned after inhibition from 3.8 and 7.6mM ALA showed increased amplitude and from 7.6 mM ALA a reduction in rate. Pretreatment with prazosin (10(-7) M) significantly reduced the duration of inhibition exerted by 3.8 and 7.6 mM ALA and also the amplitude of contractions returning after this inhibition. Pretreatment with yohimbine (10(-6) M) and propranolol (7 X 10(-6) M) had no significant effects. Blocking of the release of noradrenaline in preparations by incubation with 6-hydroxydopamine (10(-3) M) or guanethidine (1.5 X 10(-5) M) did not prevent the inhibitory effects of ALA. The alpha 1 agonist, cirazoline (10(-5) M), inhibited contractile activity. This effect was blocked by prazosin (10(-7) M). The alpha 2 agonist, guanoxabenz (10(-5) M) had no detectable effect, in the presence of prazosin, to block any residual alpha 1 actions. It is concluded that alpha 1 receptors mediate inhibitory effects in this preparation and that ALA appears to have direct effects upon these receptors.

A lipid soluble α 1 -adrenoceptor agonist 2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587) antagonized the hypnotic effect of ethanol in C57B1/6 and CD-1 mice. In Swiss-Webster mice the effect of St 587 was weak and in BALB/c mice this drug potentiated ethanol hypnosis. St 587 did not enhance the elimination of ethanol. Cirazoline, an α 1 -adrenoceptor agonist which is more potent than St 587, was relatively more effective in antagonizing the ethanol-induced hypnosis. Though it appears that St 587 exerted its ethanol antagonism by virtue of its α 1 -adrenoceptor agonistic effect, other contributing factors may also have to be considered. St 587 may prove to be of value in understanding the mechanism of action of ethanol and in the treatment of acute ethanol intoxication.

A new in vivo pharmacological method for the quantitative evaluation of alpha 1-adrenoceptor agonists and antagonists has been developed. It consists of recording the myoclonic twitch activity (MTA) of the suprahyoideal muscle of rats anesthetized with urethane. In these animals, the isomers of amphetamine elicited myoclonic twitch activity; their effects were dose-related and the d-isomer was approximately 3.5 times more effective than the l-isomer. While pimozide did not block this response, the postsynaptic alpha 1-antagonist prazosin fully blocked the myoclonic twitch activity induced by d-amphetamine. Other postsynaptic alpha 1-antagonists, such as haloperidol, phenoxybenzamine and clozapine, were also effective in blocking this response to d-amphetamine. Since d-amphetamine elicited myoclonic twitch activity in rats pretreated with reserpine and alpha-methyl-p-tyrosine, it was concluded that d-amphetamine exerted a direct alpha 1-adrenoceptor stimulation. In rats pretreated with nialamide and pimozide, l-DOPA elicited myoclonic twitch activity which was dose-related. This effect of l-DOPA was promptly and fully blocked by prazosin. It was concluded that this response to l-DOPA resulted from stimulation of alpha 1-adrenoceptors. The relative potencies of four alpha 1-adrenoceptor stimulants, namely, cirazoline, St-587, (-)SKF 89748A and Sgd 101/75 were determined using this method. The results correlated very well with their relative potencies to increase the diastolic blood pressure of pithed rats. Evidence that myoclonic twitch activity is a centrally-mediated response has also been presented. It appears that the method is a simple, sensitive, versatile and easily quantifiable procedure for the evaluation of the central effects of alpha 1-adrenoceptor agonists and antagonists.