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Nigrostriatal denervation changes the effect of cannabinoids on subthalamic neuronal activity in rats.

Morera-Herreras T, Ruiz-Ortega JA, Linazasoro G, Ugedo L - Psychopharmacology (Berl.) (2010)

Bottom Line: Conversely, after dopaminergic depletion, WIN 55,212-2, Δ(9)-THC, or anandamide inhibited the STN firing rate without altering its discharge pattern, and stimulatory effects were not observed.Cannabinoids induce different effects on the STN depending on the integrity of the nigrostriatal pathway.These findings advance our understanding of the role of cannabinoids in diseases involving dopamine deficits.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Medicine, University of the Basque Country, 48940, Leioa, Vizcaya, Spain.

ABSTRACT

Rationale: It is known that dopaminergic cell loss leads to increased endogenous cannabinoid levels and CB1 receptor density.

Objective: The aim of this study was to evaluate the influence of dopaminergic cell loss, induced by injection of 6-hydroxydopamine, on the effects exerted by cannabinoid agonists on neuron activity in the subthalamic nucleus (STN) of anesthetized rats.

Results: We have previously shown that Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and anandamide induce both stimulation and inhibition of STN neuron activity and that endocannabinoids mediate tonic control of STN activity. Here, we show that in intact rats, the cannabinoid agonist WIN 55,212-2 stimulated all recorded STN neurons. Conversely, after dopaminergic depletion, WIN 55,212-2, Δ(9)-THC, or anandamide inhibited the STN firing rate without altering its discharge pattern, and stimulatory effects were not observed. Moreover, anandamide exerted a more intense inhibitory effect in lesioned rats in comparison to control rats.

Conclusions: Cannabinoids induce different effects on the STN depending on the integrity of the nigrostriatal pathway. These findings advance our understanding of the role of cannabinoids in diseases involving dopamine deficits.

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Representative tyrosine hydroxylase (TH) immunostaining in the striatum (a, b) and substantia nigra (c, d) following 6-OHDA infusion into the right nigrostriatal pathway. In control rats (a, c), TH immunostaining was intense and comparable between both sides. In rats microinfused unilaterally with 6-OHDA into the right nigrostriatal pathway (b, d), a substantial loss of TH immunostaining was observed in each area (right side) compared with the contralateral side (left side)
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Fig5: Representative tyrosine hydroxylase (TH) immunostaining in the striatum (a, b) and substantia nigra (c, d) following 6-OHDA infusion into the right nigrostriatal pathway. In control rats (a, c), TH immunostaining was intense and comparable between both sides. In rats microinfused unilaterally with 6-OHDA into the right nigrostriatal pathway (b, d), a substantial loss of TH immunostaining was observed in each area (right side) compared with the contralateral side (left side)

Mentions: The effectiveness of dopaminergic depletion by means of 6-OHDA lesion was verified by TH immunohistochemistry. All 6-OHDA lesioned animals included in the study showed >95% reduction (remaining dopaminergic fibers 2.9 ± 0.5%) in TH-fiber density in the striatum on the side ipsilateral to the lesion (Fig. 5). The precision of this method to quantify the degree of the lesion is confirmed by the linear relationship between the number of TH-immunoreactive neurons in the SNpc and optical density in the striatum (Bilbao et al. 2006). Thus, further cell counting in the SNpc was not necessary to verify lesion severity.Fig. 5


Nigrostriatal denervation changes the effect of cannabinoids on subthalamic neuronal activity in rats.

Morera-Herreras T, Ruiz-Ortega JA, Linazasoro G, Ugedo L - Psychopharmacology (Berl.) (2010)

Representative tyrosine hydroxylase (TH) immunostaining in the striatum (a, b) and substantia nigra (c, d) following 6-OHDA infusion into the right nigrostriatal pathway. In control rats (a, c), TH immunostaining was intense and comparable between both sides. In rats microinfused unilaterally with 6-OHDA into the right nigrostriatal pathway (b, d), a substantial loss of TH immunostaining was observed in each area (right side) compared with the contralateral side (left side)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3045509&req=5

Fig5: Representative tyrosine hydroxylase (TH) immunostaining in the striatum (a, b) and substantia nigra (c, d) following 6-OHDA infusion into the right nigrostriatal pathway. In control rats (a, c), TH immunostaining was intense and comparable between both sides. In rats microinfused unilaterally with 6-OHDA into the right nigrostriatal pathway (b, d), a substantial loss of TH immunostaining was observed in each area (right side) compared with the contralateral side (left side)
Mentions: The effectiveness of dopaminergic depletion by means of 6-OHDA lesion was verified by TH immunohistochemistry. All 6-OHDA lesioned animals included in the study showed >95% reduction (remaining dopaminergic fibers 2.9 ± 0.5%) in TH-fiber density in the striatum on the side ipsilateral to the lesion (Fig. 5). The precision of this method to quantify the degree of the lesion is confirmed by the linear relationship between the number of TH-immunoreactive neurons in the SNpc and optical density in the striatum (Bilbao et al. 2006). Thus, further cell counting in the SNpc was not necessary to verify lesion severity.Fig. 5

Bottom Line: Conversely, after dopaminergic depletion, WIN 55,212-2, Δ(9)-THC, or anandamide inhibited the STN firing rate without altering its discharge pattern, and stimulatory effects were not observed.Cannabinoids induce different effects on the STN depending on the integrity of the nigrostriatal pathway.These findings advance our understanding of the role of cannabinoids in diseases involving dopamine deficits.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Medicine, University of the Basque Country, 48940, Leioa, Vizcaya, Spain.

ABSTRACT

Rationale: It is known that dopaminergic cell loss leads to increased endogenous cannabinoid levels and CB1 receptor density.

Objective: The aim of this study was to evaluate the influence of dopaminergic cell loss, induced by injection of 6-hydroxydopamine, on the effects exerted by cannabinoid agonists on neuron activity in the subthalamic nucleus (STN) of anesthetized rats.

Results: We have previously shown that Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and anandamide induce both stimulation and inhibition of STN neuron activity and that endocannabinoids mediate tonic control of STN activity. Here, we show that in intact rats, the cannabinoid agonist WIN 55,212-2 stimulated all recorded STN neurons. Conversely, after dopaminergic depletion, WIN 55,212-2, Δ(9)-THC, or anandamide inhibited the STN firing rate without altering its discharge pattern, and stimulatory effects were not observed. Moreover, anandamide exerted a more intense inhibitory effect in lesioned rats in comparison to control rats.

Conclusions: Cannabinoids induce different effects on the STN depending on the integrity of the nigrostriatal pathway. These findings advance our understanding of the role of cannabinoids in diseases involving dopamine deficits.

Show MeSH