Neuroadaptive responses to citalopram in rats using pharmacological magnetic resonance imaging

TY - JOUR

T1 - Neuroadaptive responses to citalopram in rats using pharmacological magnetic resonance imaging

AU - Sekar, Sakthivel

AU - Verhoye, M

AU - Van Audekerke, J

AU - Vanhoutte, G

AU - Lowe, Andrew S

AU - Blamire, Andrew M

AU - Steckler, Thomas

AU - Van der Linden, A

AU - Shoaib, Mohammed

PY - 2011/2

Y1 - 2011/2

N2 - 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. 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-HT1A receptors, citalopram was co-administered with a highly selective 5-HT1A receptor antagonist WAY100635. 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. 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.

AB - 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. 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-HT1A receptors, citalopram was co-administered with a highly selective 5-HT1A receptor antagonist WAY100635. 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. 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.

KW - Magnetic Resonance Imaging

KW - Animals

KW - Drug Administration Schedule

KW - Dose-Response Relationship, Drug

KW - Brain

KW - Receptors, Serotonin

KW - Pyridines

KW - Serotonin Uptake Inhibitors

KW - Citalopram

KW - Serotonin

KW - Rats

KW - Oxygen

KW - Piperazines

KW - Time Factors

KW - Male

U2 - 10.1007/s00213-010-2084-4

DO - 10.1007/s00213-010-2084-4

M3 - Article

C2 - 21103865

SN - 1432-2072

VL - 213

SP - 521

EP - 531

JO - Psychopharmacology

JF - Psychopharmacology

IS - 2-3

ER -