Evaluation of the Brain 5-HT2A Receptor Binding Index in Dogs with Anxiety Disorders, Measured with <sup>123</sup>I-5I-R91150 and SPECT

Vermeire, Simon; Audenaert, Kurt; Dobbeleir, André; Meester, Rudy H. De; Vos, Filip J. De; Peremans, Kathelijne

doi:10.2967/jnumed.108.055731

Cited by 48 publications

(36 citation statements)

References 40 publications

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“…Dogs with anxiety disorders were previously used in another SPECT study in which serotonin receptor alterations similar to humans with anxiety disorders were noticed, proving the value of the dog as model for human anxiety (Vermeire et al 2009). Other abnormal canine behavior, such as impulsive aggressive behavior, revealed results concordant with the those found in human studies investigating the same behavior (Peremans et al 2003).…”

Section: Introductionmentioning

confidence: 98%

Regional Cerebral Blood Flow Changes in Dogs with Anxiety Disorders, Measured with SPECT

Vermeire

Audenaert

Dobbeleir

et al. 2009

Brain Imaging and Behavior

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Alterations of regional brain activity in the prefrontal cortex and in limbic areas have been reported in humans with anxiety disorders. This animal study reports the results of brain perfusion imaging with single photon emission computed tomography (SPECT) in dogs with anxiety disorders. Based on the human literature, we hypothesized altered prefrontal and higher temporal brain perfusion. SPECT acquisitions were performed using the 99m Tc-labelled tracer ethyl cysteinate dimer (ECD). Eighteen dogs with pathological anxiety were compared with 18 normally behaving reference dogs. We found, in the group of dogs with anxiety disorders, lower perfusion in the left frontal cortex (p=0.003), in the subcortical region (p= 0.007) and increased perfusion in the right (p=0.05) temporal cortex. Taken together, our rCBF findings are suggestive for a dysfunction of the prefrontal cortex and the limbic system in canine anxiety disorders.

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Section: Introductionmentioning

confidence: 98%

Regional Cerebral Blood Flow Changes in Dogs with Anxiety Disorders, Measured with SPECT

Vermeire

Audenaert

Dobbeleir

et al. 2009

Brain Imaging and Behavior

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“…In the frontal cortex, 5-HT 2A is well represented as well (28,29). Frontocortical 5-HT 2A has been shown to play a role in several mood disorders, such as anxiety, aggression, and depression, not only in humans (10,11) but also in dogs (19,21). These are mood disorders that often arise during opioid addiction and dependence, and a 5-HTergic dysfunction is suggested to represent a main mechanism contributing to mood disorders in opiate abstinence (30).…”

Section: Discussionmentioning

confidence: 99%

“…The visualization of the brain 5-HT 2A system in dogs with SPECT and the radioligand 123 I-5I-R91150 was proven to be efficacious in several studies. Studies regarding the role of the 5-HT 2A system in canine anxiety, aggression, and aging supported the application of a dog model as a suitable model for human disease (19)(20)(21).…”

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confidence: 99%

The Influence of Morphine on Cerebral 5-HT_2A Availability in Dogs: a SPECT Study

et al. 2012

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The opioid and serotonergic systems are closely involved in pain processing and mood disorders. The aim of this study was to assess the influence of systemic morphine on cerebral serotonin 2A receptor (5-HT 2A ) binding in dogs using SPECT with the 5-HT 2A radioligand 123 I-5I-R91150. Methods: 5-HT 2A binding was estimated with and without morphine pretreatment in 8 dogs. The 5-HT 2A binding indices in the frontal, parietal, temporal, and occipital cortex and in the subcortical region were obtained by semiquantification. Results: A significantly decreased 5-HT 2A binding index was found in the morphine group for the right (morphine, 1.41 6 0.06; control, 1.52 6 0.10) and left (morphine, 1.44 6 0.08; control, 1.55 6 0.11) frontal cortices, with P 5 0.012 and P 5 0.040, respectively. No significant differences were noted for the other regions. Conclusion: Morphine decreased the frontocortical 5-HT 2A availability, confirming an interaction between the 5-HTergic and the opioid systems. Whether this interaction is caused by decreased receptor density due to direct internalization or is the result of indirect actions, such as increased endogenous serotonin release, remains to be elucidated.Key Words: serotonin (5-HT); 5-HT 2A ; morphine; SPECT; frontal cortex Nucl Med 2012; 53:1969 53: -1973 53: DOI: 10.2967 It is well documented that there is a close interaction between the brain opioid and serotonin (5-hydroxytryptamine [5-HT]) neurotransmitter systems (1-3). Activation of the m-opioid receptor system leads to 5-HTergic changes, including increased release of synaptic 5-HT, as was shown in several brain regions and in the spinal cord in various in vivo microdialysis studies (1,2). Furthermore, pharmacologic and behavioral studies pointed out that the 5-HTergic system is implicated in spinal pain transmission, modulation, and control and particularly in the mediation of opioid analgesia (3,4). Morphine-induced analgesia is thought to rely in part on the indirect activation of descending inhibitory 5-HTergic pathways (3). Consequently, antidepressants that inhibit 5-HT reuptake, such as fluvoxamine and fluoxetine, are also known to have analgesic properties, especially in chronic pain states (5,6). JBeside its role in pain modulation (7-9), 5-HT 2A receptor (5-HT 2A ) gained interest over the last few decades due to its involvement in several neurologic disorders in humans, including anxiety (10), depression (11), schizophrenia (12), and obsessive-compulsive disorder (13). More specifically, atypical antipsychotic drugs acting as 5-HT 2A antagonists and inverse agonists were seen to be effective in reducing the symptoms of these diseases (10,14). Because the opioid system has been shown to be involved in several of these mood disorders as well (15), the interaction between m-opioid receptors and 5-HT 2A at an emotional or cognitive level gained interest, partly with regard to common opioid side effects such as tolerance and addiction that are thought to have a 5-HTergic component as well. Consequently, several in v...

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“…An increased or decreased binding potential of the 5-HT 2A receptor antagonist 123 I-5-I-R91150 was also reported in dogs with, respectively, impulsive aggression or pathologic anxiety (9,10). In humans as well as in dogs, the frontal, temporal, and parietal cortices are the regions mostly involved (5,9,10). Hyperthyroidism has been associated with alterations in serotonergic neurotransmission in humans and rats (11,12).…”

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confidence: 95%

5-HT_2AReceptors in the Feline Brain:¹²³I-5-I-R91150 Kinetics and the Influence of Ketamine Measured with Micro-SPECT

et al. 2013

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Subanesthetic doses of ketamine can be used as a rapid-acting antidepressant in patients with treatment-resistant depression. Therefore, the brain kinetics of 123 I-5-I-R91150 (4-amino-N-[1-[3-(4-fluorophenyl)propyl]-4-methylpiperidin-4-yl]-5-iodo-2-methoxybenzamide) and the influence of ketamine on the postsynaptic serotonin-2A receptor (5-hydroxytryptamine-2A, or 5-HT 2A ) status were investigated in cats using micro-SPECT. Methods: This study was conducted on 6 cats using the radioligand 123 I-5-I-R91150, a 5-HT 2A receptor antagonist, as the imaging probe. Anesthesia was induced and maintained with a continuous-rate infusion of propofol (8.4 6 1.2 mg kg 21 followed by 0.22 mg kg 21 min 21 ) 75 min after tracer administration, and acquisition of the first image began 15 min after induction of anesthesia. After this first acquisition, propofol (0.22 mg kg 21 min 21 ) was combined with ketamine (5 mg kg 21 followed by 0.023 mg kg 21 min 21 ), and the second acquisition began 15 min later. Semiquantification, with the cerebellum as a reference region, was performed to calculate the 5-HT 2A receptor binding indices (parameter for available receptor density) in the frontal and temporal cortices. The binding indices were analyzed with Wilcoxon signed ranks statistics. Results: The addition of ketamine to the propofol continuous-rate infusion resulted in decreased binding indices in the right frontal cortex (1.25 6 0.22 vs. 1.45 6 0.16; P 5 0.028), left frontal cortex (1.34 6 0.15 vs. 1.49 6 0.10; P 5 0.028), right temporal cortex (1.30 6 0.17 vs. 1.45 6 0.09; P 5 0.046), and left temporal cortex (1.41 6 0.20 vs. 1.52 6 0.20; P 5 0.046). Conclusion: This study showed that cats can be used as an animal model for studying alterations of the 5-HT 2A receptor status with 123 I-5-I-R91150 micro-SPECT. Furthermore, an interaction between ketamine and the 5-HT 2A receptors resulting in decreased binding of 123 I-5-I-R91150 in the frontal and temporal cortices was demonstrated. Whether the decreased radioligand binding resulted from a direct competition between ketamine and 123 I-5-I-R91150 or from a decreased affinity of the 5-HT 2A receptor caused by ketamine remains to be elucidated.

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Evaluation of the Brain 5-HT2A Receptor Binding Index in Dogs with Anxiety Disorders, Measured with ¹²³I-5I-R91150 and SPECT

Cited by 48 publications

References 40 publications

Regional Cerebral Blood Flow Changes in Dogs with Anxiety Disorders, Measured with SPECT

Regional Cerebral Blood Flow Changes in Dogs with Anxiety Disorders, Measured with SPECT

The Influence of Morphine on Cerebral 5-HT_2A Availability in Dogs: a SPECT Study

5-HT_2AReceptors in the Feline Brain:¹²³I-5-I-R91150 Kinetics and the Influence of Ketamine Measured with Micro-SPECT

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Evaluation of the Brain 5-HT2A Receptor Binding Index in Dogs with Anxiety Disorders, Measured with 123I-5I-R91150 and SPECT

Cited by 48 publications

References 40 publications

Regional Cerebral Blood Flow Changes in Dogs with Anxiety Disorders, Measured with SPECT

Regional Cerebral Blood Flow Changes in Dogs with Anxiety Disorders, Measured with SPECT

The Influence of Morphine on Cerebral 5-HT2A Availability in Dogs: a SPECT Study

5-HT2AReceptors in the Feline Brain:123I-5-I-R91150 Kinetics and the Influence of Ketamine Measured with Micro-SPECT

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Evaluation of the Brain 5-HT2A Receptor Binding Index in Dogs with Anxiety Disorders, Measured with ¹²³I-5I-R91150 and SPECT

The Influence of Morphine on Cerebral 5-HT_2A Availability in Dogs: a SPECT Study

5-HT_2AReceptors in the Feline Brain:¹²³I-5-I-R91150 Kinetics and the Influence of Ketamine Measured with Micro-SPECT