Neuroadaptive responses to citalopram in rats using pharmacological magnetic resonance imaging

• Published in: Psychopharmacology 2011-02, Vol.213 (2-3), p.521-531
• Main Authors: Sekar, Sakthivel, Verhoye, M., Van Audekerke, J., Vanhoutte, G., Lowe, Andrew S., Blamire, Andrew M., Steckler, Thomas, Van der Linden, A., Shoaib, Mohammed
• Format: Article
• Language: English
• Subjects: Animals; Antidepressants; Biomedical and Life Sciences; Biomedicine; Brain; Brain - drug effects; Brain - metabolism; Central nervous system; Chronic effects; citalopram; Citalopram - administration & dosage; Citalopram - pharmacology; Cortex (frontal); Dose-Response Relationship, Drug; Drug Administration Schedule; Functional magnetic resonance imaging; Hindbrain; Hippocampus; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Male; Mesencephalon; Neurosciences; NMR; Nuclear magnetic resonance; Original Investigation; Oxygen - blood; Pharmacology/Toxicology; Piperazines - pharmacology; Psychiatry; Psychopharmacology; Pyridines - pharmacology; Rats; Receptors, Serotonin - drug effects; Receptors, Serotonin - metabolism; Rodents; Serotonin; Serotonin - metabolism; Serotonin receptors; Serotonin S1 receptors; Serotonin uptake inhibitors; Serotonin Uptake Inhibitors - administration & dosage; Serotonin Uptake Inhibitors - pharmacology; Time Factors
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-010-2084-4

Rationale The majority of psychoactive compounds, including antidepressants in clinical practice, were discovered largely by serendipity. The underlying neuropharmacological mechanisms of action of these compounds leading to resolution of depressive symptomatology are targets of the current research. Pharmacological magnetic resonance imaging (phMRI), a rapidly developing advancement of blood oxygenation level dependent (BOLD) contrast offers the potential to localize the regional sites of action in the CNS. Objective Acute and chronic effects of the clinically effective selective serotonin reuptake inhibitor (SSRI) citalopram were examined for changes in BOLD contrast using phMRI in rats. To pharmacologically characterize the specific involvement of the 5-HT 1A receptors, citalopram was co-administered with a highly selective 5-HT 1A receptor antagonist WAY100635. Results Acute citalopram treatment (10 and 20 mg/kg i.p.) produced a widespread and dose-dependent activation throughout the whole brain. Following 14 days of chronic daily administration of citalopram (20 mg/kg i.p.), localized effects were observed; regions integral in the therapeutic antidepressant effects included the hypothalamus, hippocampus, and cortical regions, suggesting desensitization of serotonergic receptors in the midbrain contributing to elevated levels of 5-HT. Co-administration with WAY100635 (0.3 mg/kg s.c.) increased BOLD activation in the frontal cortex and decreased BOLD contrast in the hypothalamus, hippocampus, and hindbrain structures. Conclusion The present findings highlight the adaptive nature of responses to citalopram which exhibits regional and pharmacological specificity. These findings translate well to the clinical findings and suggest that this approach may offer the opportunity to develop more efficacious antidepressants with a faster clinical response.