Long lasting effects of chronic WIN55,212-2 treatment on mesostriatal dopaminergic and cannabinoid systems in the rat brain

Perdikaris, Panagiotis; Tsarouchi, Martha; Fanarioti, Eleni; Natsaridis, Evangelos; Mitsacos, Ada; Giompres, Panagiotis

doi:10.1016/j.neuropharm.2017.11.005

Cited by 17 publications

(12 citation statements)

References 97 publications

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“…Accordingly, an administration of Δ9‐THC for 21 days has down‐regulated tyrosine hydroxylase mRNA expression in the substantia nigra and in the ventral tegmental area midbrain nuclei, but not in the cortex or striatum (Ginovart et al ., ). Further studies have replicated this result (Fanarioti et al ., ; Perdikaris et al ., ), and they have added that alterations to tyrosine hydroxylase expression was observed up to 7 days following cessation (Perdikaris et al ., ). Altogether, these studies show that following chronic treatment with CB 1 agonists there are some alterations in the activity of the dopaminergic‐neurons.…”

Section: Cannabinoids and The Dopaminergic Systemmentioning

confidence: 97%

“…Further studies have consistently repeated these results and have demonstrated that an acute administration of either Δ9‐THC, WIN55,212‐2, HU‐210 and CP55,940 results in a receptor‐specific activation of the ventral tegmental area and substantia nigra dopamine neurons in vivo and in vitro (Gessa et al ., ; Wu & French, ; Cheer et al ., ; Morera‐Herreras et al ., ; Ginovart et al ., ; Fanarioti et al ., ; Perdikaris et al ., ). These results have demonstrated that CB 1 agonists may act as dopamine agonist‐like in the meso‐cortical dopamine circuitry, known to be involved in the brain's reward mechanism (Chen et al ., ; Tanda et al ., ).…”

Section: Cannabinoids and The Dopaminergic Systemmentioning

confidence: 99%

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Modulatory effects of cannabinoids on brain neurotransmission

Cohen

Weizman

Weinstein

2019

Eur J of Neuroscience

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Recreational and chronic cannabis use has been associated with a range of acute and chronic effects including; anti‐nociceptive actions, anxiety, depression, psychotic symptoms and neurocognitive impairments. The mechanisms underlying cannabinoid‐based drugs effects are not fully known but given the neuro‐modulatory functions of the endocannabinoid system, it seems likely that agonistic activity at the cannabinoid type‐1 receptors (CB1) might modulate the functions of other neurotransmitter systems. The present review has summarized the currently available pre‐clinical and clinical data on the interactions of CB1 and cannabinoid type‐2 receptors (CB2) with the central neurotransmitters; dopamine, serotonin, noradrenaline, GABA, glutamate and opioids. Acute and chronic exposures to cannabinoids exert pharmacological alterations in the mammalian brain that have profound implications for our understanding of the neuropharmacology of cannabinoid‐based drugs and their effects on mental health and the brain. A recent emergence uses of cannabis for medical purpose together with legalization and decriminalization of cannabis and increasing use of highly potent synthetic cannabinoids raise a growing concern over the effects of cannabinoids and their interaction with other neurotransmitters on physical and mental health.

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Section: Cannabinoids and The Dopaminergic Systemmentioning

confidence: 97%

Section: Cannabinoids and The Dopaminergic Systemmentioning

confidence: 99%

Modulatory effects of cannabinoids on brain neurotransmission

Cohen

Weizman

Weinstein

2019

Eur J of Neuroscience

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“…Functionally, WIN55,212-2 under high concentrations significantly blocked GIRK1/2 activated by CB1 or CB2, and thus inhibited the CB-GIRK1/2 signaling. Previous studies have shown that after chronic administration of WIN55,212-2 to adult male rats, CB1 binding and mRNA levels were reduced in the substantia nigra and the striatum [ 42 ]. Moreover, chronic treatment with WIN55,212-2 impaired the recognition memory and brain network functional connectivity of adult male mice [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

WIN55,212-2, a Dual Modulator of Cannabinoid Receptors and G Protein-Coupled Inward Rectifier Potassium Channels

Peigneur

Tytgat

2021

Biomedicines

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The coupling of cannabinoid receptors, CB1 and CB2, to G protein-coupled inward rectifier potassium channels, GIRK1 and GIRK2, modulates neuronal excitability in the human brain. The present study established and validated the functional expression in a Xenopus laevis oocyte expression system of CB1 and CB2 receptors, interacting with heteromeric GIRK1/2 channels and a regulator of G protein signaling, RGS4. This ex vivo system enables the discovery of a wide range of ligands interacting orthosterically or allosterically with CB1 and/or CB2 receptors. WIN55,212-2, a non-selective agonist of CB1 and CB2, was used to explore the CB1- or CB2- GIRK1/2-RGS4 signaling cascade. We show that WIN55,212-2 activates CB1 and CB2 at low concentrations whereas at higher concentrations it exerts a direct block of GIRK1/2. This illustrates a dual modulatory function, a feature not described before, which helps to explain the adverse effects induced by WIN55,212-2 in vivo. When comparing the effects with other typical cannabinoids such as Δ9-THC, CBD, CP55,940, and rimonabant, only WIN55,212-2 can significantly block GIRK1/2. Interestingly, the inward rectifier potassium channel, IRK1, a non-G protein-coupled potassium channel important for setting the resting membrane voltage and highly similar to GIRK1 and GIRK2, is not sensitive to WIN55,212-2, Δ9-THC, CBD, CP55,940, or rimonabant. From this, it is concluded that WIN55,212-2 selectively blocks GIRK1/2.

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“…Systemic acute administration of a CB1R agonist decreased gene expression of DAT and tyrosine hydroxylase, the ratelimiting enzyme in dopamine biosynthesis, in the VTA. 94 CB2Rs can also modulate VTA dopamine neuronal activity, such that CB2R agonism inhibited VTA dopaminergic neuronal firing both in vivo and ex vivo. 95 By contrast to CB1 receptors that are primarily located presynaptically at GABAergic or glutamatergic terminals in the VTA, 96,97 CB2Rs are expressed on dopamine neuronal cell bodies and mediate direct postsynaptic inhibition.…”

Section: The Endo C Annab Inoid Sys Tem In the Me Solimb Ic Circu Itmentioning

confidence: 99%

Insulin and endocannabinoids in the mesolimbic system

Sallam

Borgland

2021

J Neuroendocrinology

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Our food intake is governed by homeostatic and non-homeostatic processes concentrated in hypothalamic and mesocorticolimbic circuits in coordination with peripheral tissues and hormonal signals. 1 Homeostatic feeding occurs in response to energy deficits, aiming to maintain a metabolic homeostasis. Instead, non-homeostatic feeding refers to energy intake beyond restoring energy deficits and is often associated with the pleasurable qualities of energy-dense food, termed hedonic feeding, although it can also include eating for stress, social, habit or other reasons. 2 In modern societies, access to energy-dense, palatable food and the abundance of food-related cues aggravate food-seeking independent of satiety. 3 Therefore, the metabolic cost of non-homeostatic/hedonic feeding overweighs that of homeostatic feeding and can lead to obesity. The mesocorticolimbic system is the primary circuit that generates motivational states to promote the seeking and ingestion of food and its activity is influenced by central and peripheral hormonal signals, including insulin. The motivational state of hunger is necessary for an animal to restore energy deficits. Similarly, thirst and salt appetite motivate the animal to restore fluid balance. These motivated states energise the animal to engage in goal-directed behaviour and seek food to replenish energy. Goal-directed behaviour can also be engaged during sated states when the incentive value of the food or cues predicting food is high, such as in the case of palatable, energy-dense food. The mesocorticolimbic dopamine system, comprising the ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC), is the main circuit responsible for coordinating responses to salient, appetitive or aversive stimuli in terms of initiation and organisation of motivated behaviours. 4 VTA dopamine projections to the NAc have a major role in translating motivational drive into goal-directed behaviours. The activity of dopamine neurones in VTA is modulated by inhibitory GABAergic and excitatory glutamatergic synapses. Pharmacological and optogenetic inhibition of GABAergic transmission within the VTA disinhibits dopaminergic projections and increases dopamine release in the NAc 5 and reward-seeking behaviour. 6 Palatable foods, amongst other appetitive stimuli and their predictive cues, activate VTA dopaminergic projections to release dopamine in NAc and PFC. 7,8 The NAc is comprised of principal GABAergic medium spiny neurones (MSNs), cholinergic tonically

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Long lasting effects of chronic WIN55,212-2 treatment on mesostriatal dopaminergic and cannabinoid systems in the rat brain

Cited by 17 publications

References 97 publications

Modulatory effects of cannabinoids on brain neurotransmission

Modulatory effects of cannabinoids on brain neurotransmission

WIN55,212-2, a Dual Modulator of Cannabinoid Receptors and G Protein-Coupled Inward Rectifier Potassium Channels

Insulin and endocannabinoids in the mesolimbic system

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