ABSTRACT
BACKGROUND: Major depressive disorder is a common illness that severely decreases psychosocial functioning. Due to the major limitations of current treatments including response failure, it is crucial to develop better therapy strategies. Evidence suggests that dopamine dysregulation might play a major role in major depressive disorder physiopathology. AIMS: This study investigates whether the dopamine D1 receptor agonist A77636 modulates antidepressant-like activity in rats. METHODS: Rats were injected with an acute single dose of A77636 (0.75, 1.5 or 3 mg/kg), a potent and selective dopamine D1-like receptor agonist. Their locomotor activity, social interactions and behavioural response to the forced swim test were analysed 30 min after the injection. RESULTS: During the forced swim test, the D1 agonist dose dependently reduced the immobility while the time of bursting was increased. Social interactions were significantly increased in the animals exposed to 3 mg/kg of A77636 whereas no significant changes were measured in general motor activity. CONCLUSIONS: The present results provide evidence that pharmacological modulation of D1 receptor by the selective agonist A77636 induces antidepressant-like effects in rats, which encourages further studies regarding D1-specific modulation in major depressive disorder treatment.
Subject(s)
Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Dopamine Agonists/pharmacology , Locomotion/drug effects , Receptors, Dopamine D1/agonists , Social Interaction , Adamantane/analogs & derivatives , Adamantane/pharmacology , Animals , Antidepressive Agents/administration & dosage , Benzopyrans/pharmacology , Dopamine Agonists/administration & dosage , Male , Rats , Rats, Sprague-DawleyABSTRACT
RATIONALE: The basis of the unique clinical profile of the antipsychotic clozapine is not yet elucidated. Brain histamine receptors may play a role in schizophrenia and its treatment, but their involvement in the profile of clozapine remained unknown. OBJECTIVES: We explored the properties of clozapine and its two metabolites, N-desmethylclozapine (NDMC) and clozapine N-oxide, at the four human histaminergic receptors. We compared their active concentrations with their blood concentrations in patients treated by clozapine. We investigated the changes in receptor densities induced in rat brain by repeated administration of a therapeutic dose of clozapine. RESULTS: Clozapine and NDMC behaved as very potent, and partial, H(1)-receptor inverse agonists, weak, and full, H(2)-receptor inverse agonists, moderate, and protean, H(3)-receptor agonists, and moderate, and partial, H(4)-receptor agonists. Taking into account their micromolar mean blood concentrations found in 75 treated patients, and assuming that they are enriched in human brain as they are in rat brain, a full occupation of H(1)-, H(3)-, and H(4)-receptors, and a partial occupation of H(2) receptors, is expected. In agreement, repeated administration of clozapine at a therapeutic dose (20 mg/kg/day for 20 days) induced an up-regulation of H(1)- and H(2)-receptors in rat brain. CONCLUSIONS: Clozapine and its active metabolite NDMC interact with the four human histamine receptors at clinically relevant concentrations. This interaction may substantiate, at least in part, the atypical antipsychotic profile of clozapine, as well as its central and peripheral side effects such as sedation and weight gain.
Subject(s)
Antipsychotic Agents/pharmacology , Clozapine/pharmacology , Receptors, Histamine/drug effects , Animals , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/pharmacokinetics , Brain/drug effects , Brain/metabolism , Clozapine/administration & dosage , Clozapine/analogs & derivatives , Clozapine/pharmacokinetics , Drug Inverse Agonism , Histamine Agonists/administration & dosage , Histamine Agonists/pharmacokinetics , Histamine Agonists/pharmacology , Humans , Male , Rats , Rats, Wistar , Receptors, Histamine/genetics , Receptors, Histamine/metabolism , Retrospective Studies , Up-Regulation/drug effectsABSTRACT
The central effects of histamine are mediated by H(1), H(2) and H(3) receptors. The H(3) receptor inhibits histamine release in brain. Therefore, H(3) receptor inverse agonists, by suppressing this brake, enhance histamine neuron activity. The histaminergic system plays a major role in cognition and H(3) receptor inverse agonists are expected to be a potential therapeutics for cognitive deficits of Alzheimer's disease (AD). They are eagerly awaited inasmuch as other treatments of the disease, such as tacrine or memantine, also enhance, through different mechanisms, histaminergic neurotransmission. An important loss of histaminergic neurons has been observed in AD. In contrast, levels of the histamine metabolite in the CSF of AD patients show that their global activity is decreased by only 25%. This indicates that activating histamine neurons in AD can be envisaged.
