The role of α2‐adrenoceptor antagonism in the anti‐cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat

  title={The role of $\alpha$2‐adrenoceptor antagonism in the anti‐cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat},
  author={Hans Otto Kalkman and V Neumann and D. Hoyer and Mark David Tricklebank},
  journal={British Journal of Pharmacology},
1 The mechanism underlying the anticataleptic properties of the atypical neuroleptic agent, clozapine, has been investigated in the rat. 2 The close structural analogues of clozapine, loxapine (0.1 mg kg−1 s.c.) and iso‐clozapine (1 and 3 mg kg−1 s.c.) induced catalepsy in rats. In contrast, clozapine and the regio‐isomer of loxapine, iso‐loxapine (up to 10 mg kg−1 s.c.) did not produce catalepsy, but at a dose of 1 mg kg−1 significantly inhibited catalepsy induced by loxapine (0.3 mg kg−1 s.c… 
The effect of the α2-adrenoreceptor antagonist idazoxan against 6-hydroxydopamine-induced Parkinsonism in rats: multiple facets of action?
It is indicated that systemic administration of idazoxan counteracts 6-OHDA-induced Parkinsonian symptoms in rats and that both dopaminergic and serotonergic mechanisms could contribute to its anti-Parkinsonian effect.
Clozapine reversal of the deficits in coordinated movement induced by D2 receptor blockade does not depend upon antagonism of α2 adrenoceptors
Results indicate that the anticholinergic rather than the α2 antagonistic properties of clozapine may mediate the reversal of the motor deficit induced by D2 antagonism in a rotating rod test.
The α2-Adrenoceptor Antagonist Idazoxan Reverses Catalepsy Induced by Haloperidol in Rats Independent of Striatal Dopamine Release: Role of Serotonergic Mechanisms
The results suggest that idazoxan reversed haloperidol-induced catalepsy by a mechanism involving blockade of α2-adrenoceptors and, at least in part, 5-HT neurons.
Haloperidol, but not clozapine, produces dramatic catalepsy in Δ9‐THC‐treated rats: possible clinical implications
It was suggested that the different effects on rat catalepsy induced by Δ9‐THC following HP or CLOZ administration may depend on the receptor‐binding profiles of the two antipsychotics.
Clozapine-Induced Locomotor Suppression is Mediated by 5-HT2A Receptors in the Forebrain
It is confirmed that haloperidol and risperidone caused catalepsy in rodents, driven by strong antagonism of D2, and it is shown that it is the cortical population of 5-HT2A that mediate the locomotor-suppressing effects of clozapine.
Anticataleptic properties of α2 adrenergic antagonists in the crossed leg position and bar tests: differential mediation by 5-HT1A receptor activation
Serotonin 5-HT1A receptors play a prominent role in anticataleptic effects of certain α2 adrenergic antagonists in the CLP test, whereas α2-adrenergic mechanisms are likely to be primarily responsible for the anticatalesptic effects of these ligands in the bar test.


Characterization of the 5-HT2 receptor antagonist MDL 100907 as a putative atypical antipsychotic: behavioral, electrophysiological and neurochemical studies.
The data indicate that MDL 100,907 has a clozapine-like profile of potential antipsychotic activity with low extrapyramidal sid-effect liability.
Clozapine inhibits catalepsy induced by olanzapine and loxapine, but prolongs catalepsy induced by SCH 23390 in rats
The mechanism by which clozapine exerts this anti-cataleptic effect remains unknown, but it is unlikely that muscarinic blockade, NMDA ion channel blockade and 5-HT1A receptor agonism are involved in clozAPine’s action.
5-HT1A receptors are not involved in clozapine's lack of cataleptogenic potential
Do Central Antiadrenergic Actions Contribute to the Atypical Properties of Clozapine?
Clozapine is only weakly antidopaminergic but is a potent antagonist at brain α1-adrenergic, 5-HT2-serotonergic, and muscarinic receptors, and its apparent limbic-over-extrapyramidal neuro-physiological selectivity can be mimicked by combining a typical neuroleptic with a central α1 antagonist.
Putting the 'A' in atypical: does α2-adrenoceptor antagonism account for the therapeutic advantage of new antipsychotics?
  • D. Nutt
  • Psychology, Medicine
    Journal of psychopharmacology
  • 1994
These ’atypical’ antipsychotic drugs appear to have significant advantages over older drugs, such as haloperidol and chlorpromazine, in particular, they induce significantly less extrapyramidal side effects (EPS), produce less mood impairment and may directly attenuate negative as well as positive symptoms of schizophrenia.
Genetic Alteration of α2C-Adrenoceptor Expression in Mice: Influence on Locomotor, Hypothermic, and Neurochemical Effects of Dexmedetomidine, a Subtype-Nonselective α2-Adrenoceptor Agonist
The effects of dexmedetomidine, a subtype-nonselective α 2 -AR agonist, on monoamine turnover in brain and on locomotor activity were similar in mice with targeted inactivation of the α 2C -AR gene, but the hypothermic effect was significantly attenuated by the receptor gene inactivation.
Behavioural effects of serotonin agonists and antagonists in the rat and marmoset
Behavioral Effects of Clozapine and Dopamine Receptor Subtypes
Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons
  • L. Chiodo, B. Bunney
  • Psychology, Biology
    The Journal of neuroscience : the official journal of the Society for Neuroscience
  • 1983
It is suggested that the time-dependent development of A9 DA neuron inactivation induced by repeated neuroleptic treatment may provide a mechanism for understanding the delayed onset of extrapyramidal side effects often observed with antipsychotic drugs.