Altered responsiveness of serotonin receptor subtypes following long-term cannabinoid treatment

Hill, Matthew N.; Sun, Jiejie; Tse, Maric T.; Gorzalka, Boris B.

doi:10.1017/s1461145705005651

Cited by 88 publications

(78 citation statements)

References 64 publications

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“…The degree was correlated with subjective effects, and the pattern was consistent with CB 1 R localization (Volkow et al, 1991;Matthew et al, 2002). Third, CB 1 R agonism alters 5-HT 1A and 5HT 2A receptor-mediated behavioral responses (Hill et al, 2006) and inhibits 5-HT reuptake in vitro (Banerjee et al, 1975;Johnson et al, 1976). In this study, we therefore aimed at determining whether the CB 1 R agonist WIN55,212-2 (WIN) [R(ϩ)- [2,3-dihydro-5-methyl-3-[(morpholinyl)]pyrrolo [1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate] exhibits antidepressant-like effects in the forced swim test (FST), modulates 5-HT activity through a CB 1 R-mediated mechanism, and effects dose-dependent bidirectional modulations.…”

Section: Introductionmentioning

confidence: 53%

Cannabinoids Elicit Antidepressant-Like Behavior and Activate Serotonergic Neurons through the Medial Prefrontal Cortex

Bambico¹,

Katz²,

Debonnel³

et al. 2007

J. Neurosci.

288

213

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Preclinical and clinical studies show that cannabis modulates mood and possesses antidepressant-like properties, mediated by the agonistic activity of cannabinoids on central CB 1 receptors (CB 1 Rs). The action of CB 1 R agonists on the serotonin (5-HT) system, the major transmitter system involved in mood control and implicated in the mechanism of action of antidepressants, remains however poorly understood. In this study, we demonstrated that, at low doses, the CB 1 R agonist WIN55, 212-2 [R(ϩ)-[2,3-dihydro-5-methyl-3-[(morpholinyl)]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate] exerts potent antidepressant-like properties in the rat forced-swim test (FST). This effect is CB 1 R dependent because it was blocked by the CB 1 R antagonist rimonabant and is 5-HT mediated because it was abolished by pretreatment with the 5-HT-depleting agent parachlorophenylalanine. Then, using in vivo electrophysiology, we showed that low doses of WIN55,212-2 dose dependently enhanced dorsal raphe nucleus 5-HT neuronal activity through a CB 1 R-dependent mechanism. Conversely, high doses of WIN55,212-2 were ineffective in the FST and decreased 5-HT neuronal activity through a CB 1 R-independent mechanism. The CB 1 R agonist-induced enhancement of 5-HT neuronal activity was abolished by total or medial prefrontocortical, but not by lateral prefrontocortical, transection. Furthermore, 5-HT neuronal activity was enhanced by the local microinjection of WIN55,212-2 into the ventromedial prefrontal cortex (mPFCv) but not by the local microinjection of WIN55,212-2 into the lateral prefrontal cortex. Similarly, the microinjection of WIN55,212-2 into the mPFCv produced a CB 1 R-dependent antidepressantlike effect in the FST. These results demonstrate that CB 1 R agonists possess antidepressant-like properties and modulate 5-HT neuronal activity via the mPFCv.

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Section: Introductionmentioning

confidence: 53%

Cannabinoids Elicit Antidepressant-Like Behavior and Activate Serotonergic Neurons through the Medial Prefrontal Cortex

Bambico¹,

Katz²,

Debonnel³

et al. 2007

J. Neurosci.

288

213

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“…Twelve days of pretreatment with a cannabinoid receptor agonist resulted in an apparent upregulation of 5-HT 2A receptor activity and a downregulation of 5-HT 1A receptor activity. 277 The effects of THC on 5-HTergic functioning and receptor activity resemble the changes seen in depressed patients.…”

Section: 4-methylenedioxymethamphetamine (Mdma)mentioning

confidence: 95%

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

et al. 2006

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In recent years, the term serotonergic vulnerability (SV) has been used in scientific literature, but so far it has not been explicitly defined. This review article attempts to elucidate the SV concept. SV can be defined as increased sensitivity to natural or experimental alterations of the serotonergic (5-HTergic) system. Several factors that may disrupt the 5-HTergic system and hence contribute to SV are discussed, including genetic factors, female gender, personality characteristics, several types of stress and drug use. It is explained that SV can be demonstrated by means of manipulations of the 5-HTergic system, such as 5-HT challenges or acute tryptophan depletion (ATD). Results of 5-HT challenge studies and ATD studies are discussed in terms of their implications for the concept of SV. A model is proposed in which a combination of various factors that may compromise 5-HT functioning in one person can result in depression or other 5-HT-related pathology. By manipulating 5-HT levels, in particular with ATD, vulnerable subjects may be identified before pathology initiates, providing the opportunity to take preventive action. Although it is not likely that this model applies to all cases of depression, or is able to identify all vulnerable subjects, the strength of the model is that it may enable identification of vulnerable subjects before the 5-HT related pathology occurs. Molecular Psychiatry ( Keywords: serotonin; mood disorders; stress; genetics; sex; tryptophan Involvement of serotonin in depressionMood disorders are one of the most prevalent forms of mental illness. 1 According to the DSM-IV, the lifetime risk for major depressive disorder is between 10 and 25% for women and between 5 and 12% for men. 2 Depression has been studied intensively during the last few decades, but the psychological and neurobiological determinants of depression have not yet been precisely defined. Although several factors are known to contribute to the etiology of depression, it is not clear how these factors cause depression, and why some subjects become depressed while others remain unaffected. In terms of biological factors in the etiology of depression, there are several hypotheses. These include neurotransmitter dysfunctions (serotonin, 5-HT; dopamine, DA; norepinephrine, NE); dysregulations in hypothalamic-pituitary-adrenal (HPA) axis activity; and immune system imbalance. The aim of this article is not to discuss all of these hypotheses in detail, but to evaluate the role that serotonin may play within these hypothesized mechanisms.It is widely accepted that diminished serotonergic (5-HTergic) function is involved in the onset and course of depression. 3,4 The 5-HTergic system is a large and complex system. Although nearly all cell bodies of 5-HTergic neurons are located in the raphe nuclei in the brain stem, the axons of these neurons innervate almost the entire brain. The actions of 5-HT are mediated by 16 types and subtypes of receptors. 5 As the 5-HTergic system is assumed to be a modulatory system, the exact func...

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“…It is noteworthy that information about the putative adaptations of brain CB 1 receptors at the cAMP signaling level in response to long-term antidepressants treatment is lacking, despite the proposed importance of this transduction pathway for the long-term adaptations underlying antidepressants efficacy (Malberg and Blendy, 2005). Taking into account that 5-HT receptors are the primary targets of SSRIs and the fact that experimental data support the existence of cross-talk mechanisms between brain EC and 5-HT systems (Marco et al, 2004;Gobbi et al, 2005;Hill et al, 2006b;Mato et al, 2007;Aso et al, 2009), it is noteworthy that the possible implication of 5-HT receptors in the adaptations of the EC system induced by long-term AD treatment has not been addressed.…”

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confidence: 99%

Long-Term Fluoxetine Treatment Modulates Cannabinoid Type 1 Receptor-Mediated Inhibition of Adenylyl Cyclase in the Rat Prefrontal Cortex through 5-Hydroxytryptamine_1AReceptor-Dependent Mechanisms

Mato

Vidal²,

Castro³

et al. 2009

Mol Pharmacol

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Increasing data indicate that brain endocannabinoid system plays a role in the effects of antidepressant medications. Here we examined the effect of in vivo exposure to the selective serotonin uptake inhibitor fluoxetine on cannabinoid type 1 (CB 1 ) receptor density and functionality in the rat prefrontal cortex (PFC) and cerebellum. Long-term treatment with fluoxetine (10 mg/kg/day) enhanced CB 1 receptor inhibition of adenylyl cyclase (AC) in the PFC and reduced it in the cerebellum without altering receptor density and agonist stimulation of guanosine 5Ј-O-(3-[ oxetine-induced modulation of CB 1 receptor coupling to G␣ subunits and AC in the PFC but not in the cerebellum. These results indicate that increased CB 1 receptor signaling at the G␣ i -AC transduction level is a long-term adaptation induced by fluoxetine in the PFC and point to a role for 5-HT 1A receptors in this effect. Basal AC activity, protein kinase A (PKA) catalytic subunit expression, and phospho-cAMP response element-binding protein (pCREB)/CREB ratio were also up-regulated in the PFC of fluoxetine-treated animals, whereas no differences were detected in the cerebellum. It is interesting that long-term ⌬ 9 -tetrahydrocannabinol treatment did not elicit antidepressant-like effects or modulated behavioral responses of fluoxetine in an animal model of depression (olfactory bulbectomy). These data suggest that altered signal transduction through CB 1 receptors in the PFC may participate in the regulation of the AC-PKA-CREB cascade induced by fluoxetine in this brain area.

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Altered responsiveness of serotonin receptor subtypes following long-term cannabinoid treatment

Cited by 88 publications

References 64 publications

Cannabinoids Elicit Antidepressant-Like Behavior and Activate Serotonergic Neurons through the Medial Prefrontal Cortex

Cannabinoids Elicit Antidepressant-Like Behavior and Activate Serotonergic Neurons through the Medial Prefrontal Cortex

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

Long-Term Fluoxetine Treatment Modulates Cannabinoid Type 1 Receptor-Mediated Inhibition of Adenylyl Cyclase in the Rat Prefrontal Cortex through 5-Hydroxytryptamine_1AReceptor-Dependent Mechanisms

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Altered responsiveness of serotonin receptor subtypes following long-term cannabinoid treatment

Cited by 88 publications

References 64 publications

Cannabinoids Elicit Antidepressant-Like Behavior and Activate Serotonergic Neurons through the Medial Prefrontal Cortex

Cannabinoids Elicit Antidepressant-Like Behavior and Activate Serotonergic Neurons through the Medial Prefrontal Cortex

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

Long-Term Fluoxetine Treatment Modulates Cannabinoid Type 1 Receptor-Mediated Inhibition of Adenylyl Cyclase in the Rat Prefrontal Cortex through 5-Hydroxytryptamine1AReceptor-Dependent Mechanisms

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Long-Term Fluoxetine Treatment Modulates Cannabinoid Type 1 Receptor-Mediated Inhibition of Adenylyl Cyclase in the Rat Prefrontal Cortex through 5-Hydroxytryptamine_1AReceptor-Dependent Mechanisms