Cannabinoid CB1 and Cholecystokinin CCK2 Receptors Modulate, in an Opposing Way, Electrically Evoked [3H]GABA Efflux from Rat Cerebral Cortex Cell Cultures: Possible Relevance for Cortical GABA Transmission and Anxiety

Antonelli, Tiziana; Tomasini, Maria Cristina; Mazza, Roberta; Fuxé, Kjell; Gaetani, Silvana; Cuomo, V.; Tanganelli, Sergio; Ferraro, Luca

doi:10.1124/jpet.109.150649

Cited by 7 publications

(10 citation statements)

References 40 publications

(42 reference statements)

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“…Anatomical and electrophysiological studies carried out in rodents have shown that CB 1 receptors are primarily located on the presynaptical terminals of GABAergic interneurons expressing the anxiogenic neuropeptide CCK. This expression pattern has been observed in many brain regions, including the mPFC (Marsicano and Lutz, 1999) and amygdala (Ramikie and Patel, 2011), in which CB 1 stimulation decreases GABA (Antonelli et al, 2009) and CCK (Beinfeld and Connolly, 2001) release. CCK has an important role in the neurobiology of anxiety, and administration of CCK2 receptor antagonists to rats can enhance social interaction (Supplementary Figure S1).…”

Section: Pcp-induced Social Withdrawal Results From Deficient Cb 1 Rementioning

confidence: 73%

Phencyclidine-Induced Social Withdrawal Results from Deficient Stimulation of Cannabinoid CB1 Receptors: Implications for Schizophrenia

Seillier

Bahillo

Giuffrida

2013

Neuropsychopharmacol

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The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB 1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB 1 -dependent manner, whereas pharmacological blockade of CB 1 receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB 1 receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB 1 -mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP-and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB 1 receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission.

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Section: Pcp-induced Social Withdrawal Results From Deficient Cb 1 Rementioning

confidence: 73%

Phencyclidine-Induced Social Withdrawal Results from Deficient Stimulation of Cannabinoid CB1 Receptors: Implications for Schizophrenia

Seillier

Bahillo

Giuffrida

2013

Neuropsychopharmacol

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“…CCK 2 agonists are anxiogenic, and CCK 2 antagonists reduce potentiated states of anxiety but do not appear to affect baseline anxiety responses (Rotzinger and Vaccarino, 2003). Recently, microdialysis experiments have revealed an increase in GABA efflux underlying the anxiogenic-like effect produced by the CCK 2 agonist CCK-8S (Antonelli et al, 2009). Paradoxically, the use of benzodiazepines is an established treatment for anxiety disorders.…”

Section: Anxietymentioning

confidence: 99%

“…Muscimol, a potent GABA A receptor agonist, was able to increase the percentage of open arm time and entries in the elevated plus-maze, when injected into the CA1 area of rat hippocampus (Rezayat et al, 2005). A possible explanation for this paradox could be that CCK and GABA operate on different steps in a sequence of neuronal events that initiates and maintains the anxiolytic reaction (Antonelli et al, 2009). Strikingly, in the same study, sub-threshold concentrations of the CB1 receptor agonist WIN55,212-2 and CCK-8S, induced an enhancement of GABA efflux when injected in combination, suggesting the intriguing possibility of a CB1 receptor-CCK 2 interaction at the membrane level (Fuxe et al, 2008).…”

Section: Anxietymentioning

confidence: 99%

The endocannabinoid system in anxiety, fear memory and habituation

et al. 2011

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Evidence for the involvement of the endocannabinoid system (ECS) in anxiety and fear has been accumulated, providing leads for novel therapeutic approaches. In anxiety, a bidirectional influence of the ECS has been reported, whereby anxiolytic and anxiogenic responses have been obtained after both increases and decreases of the endocannabinoid tone. The recently developed genetic tools have revealed different but complementary roles for the cannabinoid type 1 (CB1) receptor on GABAergic and glutamatergic neuronal populations. This dual functionality, together with the plasticity of CB1 receptor expression, particularly on GABAergic neurons, as induced by stressful and rewarding experiences, gives the ECS a unique regulatory capacity for maintaining emotional homeostasis. However, the promiscuity of the endogenous ligands of the CB1 receptor complicates the interpretation of experimental data concerning ECS and anxiety. In fear memory paradigms, the ECS is mostly involved in the two opposing processes of reconsolidation and extinction of the fear memory. Whereas ECS activation deteriorates reconsolidation, proper extinction depends on intact CB1 receptor signalling. Thus, both for anxiety and fear memory processing, endocannabinoid signalling may ensure an appropriate reaction to stressful events. Therefore, the ECS can be considered as a regulatory buffer system for emotional responses.

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“…CB 1 receptors are co-localized with GABA receptors in regions throughout the brain, including the hippocampus, cortex, basolateral and cortical amygdaloid nuclei, striatum, cerebellum and the majority of hypothalamic nuclei (Freund, 2003; Hohmann and Herkenham, 2000; Mailleux and Vanderhaeghen, 1992; Westlake et al, 1994). Additionally, CB 1 receptor activity modulates synaptic GABA levels (Antonelli et al, 2009; Engler et al, 2006; Ohno-Shosaku et al, 2001; Wilson and Nicoll, 2001). For example, GABAergic transmission is enhanced by reducing GABA reuptake via stimulation of presynaptic cannabinoid receptors in certain GABA neurons (Banerjee et al, 1975; Maneuf et al, 1996; Romero et al, 1998) and also possibly by direct interactions with the GABA transporter (Coull et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Separate and combined effects of the GABA reuptake inhibitor tiagabine and Δ9-THC in humans discriminating Δ9-THC

Lile

Kelly

Hays

2012

Drug and Alcohol Dependence

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Background The involvement of non-cannabinoid neurotransmitter systems in the abuse-related behavioral effects of cannabis has not been well characterized in humans. GABAergic drugs have overlapping effects with cannabis and Δ9-tetrahydrocannabinol (Δ9-THC) on certain behavioral measures, but those measures lack the specificity to draw conclusions regarding the involvement of GABA in cannabinoid effects. The aim of this study was to assess the separate and combined effects of the GABA reuptake inhibitor tiagabine and Δ9-THC using more pharmacologically specific drug-discrimination procedures. Methods Eight cannabis users learned to discriminate 30 mg oral Δ9-THC from placebo and then received tiagabine (6 and 12 mg), Δ9-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. Results Δ9-THC produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug), elevated heart rate and impaired rate and accuracy on psychomotor performance tasks. The higher tiagabine dose substituted for the Δ9-THC discriminative stimulus and engendered subjective and performance-impairing effects that overlapped with those of Δ9-THC when administered alone. In combination, tiagabine shifted the discriminative-stimulus effects of Δ9-THC leftward/upward and enhanced Δ9-THC effects on other outcomes. Conclusions These results indicate that GABA is involved in the clinical effects of Δ9-THC, and by extension, cannabis. Future studies should test selective GABAergic compounds to determine which receptor subtype(s) are responsible for the effects observed when combined with cannabinoids.

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Cannabinoid CB₁ and Cholecystokinin CCK₂ Receptors Modulate, in an Opposing Way, Electrically Evoked [³H]GABA Efflux from Rat Cerebral Cortex Cell Cultures: Possible Relevance for Cortical GABA Transmission and Anxiety

Abstract: The effects of treatments with cannabinoid (CB) 1 and cholecystokinin (CCK) 2 receptor agonists and antagonists, as well as compounds that enhance endocannabinoid signaling by inhibiting degradation, e.g., the fatty acid amide hydrolase inhibitor 3Ј-carbamoyl-biphenyl-

Cited by 7 publications

References 40 publications

Phencyclidine-Induced Social Withdrawal Results from Deficient Stimulation of Cannabinoid CB1 Receptors: Implications for Schizophrenia

Phencyclidine-Induced Social Withdrawal Results from Deficient Stimulation of Cannabinoid CB1 Receptors: Implications for Schizophrenia

The endocannabinoid system in anxiety, fear memory and habituation

Separate and combined effects of the GABA reuptake inhibitor tiagabine and Δ9-THC in humans discriminating Δ9-THC

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