How cannabinoid therpay may help Parkinson's disease . inflammation and assuaging symptoms of PD, as well as mitigating disease progression to a degree. Parkinson's disease and cannabinoid system: prevalence and disease . interest because of their potential to mitigate motor symptoms . The first study with CBD on PD patients aimed to verify Scale and the Parkinson Psychosis Questionnaire.
Mitigating Parkinson’s for Cannabidiol
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Borys HK, Karler R. Cannabidiol and delta 9-tetrahydrocannabinol metabolism. In vitro comparison of mouse and rat liver crude microsome preparations.
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The others go by these names: Each state has its own procedure for allowing its residents to purchase medical marijuana. These lists, while they vary from state to state, often include conditions like cancer, anxiety, and inflammatory bowel disease. Find a registered physician who will confirm in writing that you have a qualifying condition that would be improved by the drug. Receive an ID card that allows you to purchase medical marijuana at a dispensary.
States, and sometimes counties within states, charge fees for card applications. Some, like California, will waive or reduce the fee for eligible patients.
What Is a Dispensary? Dispensaries are the medical marijuana equivalent of pharmacies. They sell marijuana and other cannabis-derived products to people who have been certified by their home state to purchase it. Depending on what state you live in, you can also purchase marijuana for recreational use at dispensaries. Sign up for our Healthy Living Newsletter! Thanks for signing up for our newsletter!
You should see it in your inbox very soon. Please enter a valid email address Subscribe We respect your privacy. National Academies of Sciences, Engineering, and Medicine. Novel Therapies for Arthritis? Journal of Pain and Symptom Management. Efficacy, Tolerability, and Safety of Cannabinoids in Gastroenterology: Shannon S, Opila-Lehman J.
Moving Toward the Clinic. Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence. Singh Y, Bali C. Case Reports in Oncology. Love and Grace Yoga Studio. Clearing the Smoke on Cannabis. A few of these pathways include neuroinflammation, mitochondrial dysfunction, oxidative stress, kinase pathways, calcium dysregulation, protein aggregation, and prion-like processes.
These pathways have helped to identify molecular targets [ 5 ], and based on experimental data, there has been a moderate increase in the tentative treatment choices for both early and later stages of PD and non-motor symptoms [ 6 ]. Thus, to avoid the motor complications arising with use of levodopa, on-going research pursues to develop new non-dopaminergic symptomatic agents capable to attenuate motor deficits and to restore dopamine transmission without producing dyskinesia [ 7 ].
Cannabinoids are one such interesting class of agents that not only have demonstrated neuroprotective ability but have also been evaluated for their potential to alleviate motor symptoms observed in PD. In this review we discuss the possibility of various cannabinoids and their respective target pathways that may hold potential to be used as an therapeutic for PD.
Cannabinoids have been demonstrated to be effective in preclinical studies involving excitotoxicity, oxidative stress, neuroinflammation, and motor complications associated with PD [ 8 ]. Two major cannabinoid receptors, CB1 and CB2, have been cloned and several endogenous cannabinoids were identified along with their synthetic and degradative pathways.
ECBs were discovered initially in the brain, but were also found in the periphery in humans and animals. ECBs are not only produced by cultured neurons [ 9 ], but also by microglia and astrocytes [ 10 ].
Years of research has identified few major ECBs such as arachidonoyl ethanolamide anandamide, AEA , 2-arachidonoyl glycerol 2-AG , O-arachidonoyl ethanolamine virodhamine , and 2-arachidonoyl glyceryl ether noladin ether [ 11 ]. AEA is mainly been localized in the brain and periphery [ 12 ]. AEA is well distributed in the brain and shows high distribution in the hippocampus, thalamus, striatum, and brainstem and to a lesser extent in the cerebral cortex and cerebellum [ 14 ].
Lower concentrations of AEA are found in human serum, plasma, and cerebrospinal fluid [ 15 ]. Similarly, 2-AG is observed in both the brain and periphery, although its concentration is almost times higher in brain compared to that of AEA [ 16 , 14 ]. Higher 2-AG levels are found in rat hippocampus, brainstem, striatum, and medulla [ 16 ]. Two prominent areas involved in the control of movement, such as the globus pallidus and the substantia nigra, not only contain the highest densities of CB1 receptors [ 20 ] but also the highest levels of ECBs, specifically anandamide [ 21 ].
The physical composition of the nerve cells that yield ECBs in the basal ganglia is currently unknown, although the basal ganglia contain the precursor of anandamide and N-arachidonoyl phosphatidylethanolamine [ 22 ], which strengthens the theory of in situ synthesis for this ECB.
Synthesis of anandamide seems to be related to dopamine. This hypothesis was backed by Giuffrida et al. Distinct synthesizing and metabolizing enzymes have been identified, which actively regulate the levels of endogenous cannabinoids under normal and diseased conditions, and hence may be considered promising therapeutic targets.
Both AEA and 2-AG are synthesized by cleavage of plasma membrane phospholipids, and calcium acts as a biosensor to depolarize the membrane to induce synthesis in an activity-dependent fashion [ 24 ].
AEA is synthesized by sequential actions of two intracellular enzymes, such as N-acyl phosphatidylethanolamine-specific phospholipase D NAPE-PLD that catalyzes the release of anandamide by a phospholipase D from its precursor N-arachidonoyl phosphatidylethanolamine and N-acyltransferase that catalyzes the transfer of arachidonic acid to a molecule of phosphatidylethanolamine to generate the precursor [ 24 ].
Second pathway works via action of phospholipase-A1 to convert phosphatidyl lipid to 2-arachidonoyl lyso phosphatidyl lipid and then to 2-AG by the action of lyso-phospholipase-C. The third pathway includes hydrolysis of lipid phosphate by an lipid phosphate phosphatase [ 27 ]. Degradation of ECBs occurs rapidly in vivo [ 28 - 30 ]. FAAH is the predominant ECB metabolizing enzyme located intracellularly on post-synaptic neuron membranes [ 31 - 33 ].
Monoacylglycerol lipase MAGL is a pre-synaptically localized enzyme that primarily inactivates 2-AG through hydrolysis to arachidonic acid and glycerol [ 36 , 37 ].
Although, COX-2 can only be considered as an alternative metabolic pathway addressed to the synthesis of novel bioactive lipids rather than a central degrading pathway.
All these new metabolising enzymes produce different molecules like, prostaglandin glycerol esters, lysophosphatidic acid and hydroperoxy derivatives of 2-AG. These by-products often have antagonizing role as compared to 2-AG. Therefore, impeding these metabolic enzymes may also act as a therapeutic target [ 27 ].
ECBs are lipophilic molecules and hence are capable of passing through the plasma membrane if their intracellular concentration is less than their extracellular concentration. However, crossing the plasma membrane as a mechanism for inactivation is too slow a process. Although AMT has not been isolated or cloned, its existence remains debated. However, reports have established cellular uptake of virodhamine [ 40 ] by AMT.
Cannabinoids have been contemplated as clinically neuroprotective molecules, as they can reduce oxidative injury, excitotoxicity, and calcium influx [ 41 ]. They also decrease inflammation by modulating glial processes that are associated with neuronal survival.
Cannabinoids may provide neuroprotection in PD by means of these processes. Two important neuroprotective mechanisms are elicited by cannabinoids in experimental models of PD. First, they decrease increased oxidative stress in PD, a mechanism that seems to be independent of any involvement of cannabinoid receptors.
Second, they increase density of CB2 cannabinoid receptors, mainly in reactive microglia, which regulate micro-functions of glial cells and homeostasis of surrounding neurons [ 42 ]. The basal ganglia is a part of a complex neuronal network that coordinates activity from different cortical regions that directly or indirectly participate in the control of movement [ 43 ].
Structural elements of basal ganglia include the corpus striatum and other subcortical regions such as subthalamic nucleus STN , the substantia nigra and the pedunculopontine tegmental nucleus [ 43 ].
Historic and new data have empowered the notion of a marked role for the endocannabinoid ECB signaling system in the control of movement. This discovery is backed by three important lines of evidence. Second, there is evidence for a powerful inhibitory action of plant-derived, synthetic and endogenous cannabinoids on motor activity by fine tuning the activity of various classical neurotransmitters.
Third, prominent changes take place in transmission of ECBs in the basal ganglia of humans and in animal models of PD. These lines of evidence strengthen the idea that cannabinoids act on key pathways of ECB transmission including receptors, transporters, fatty acid amide hydrolase FAAH , which might be of therapeutic interest because of their potential to mitigate motor symptoms [ 44 ].
Considering the appropriateness of this preclinical evidence and the lack of efficient therapeutic strategies for PD, we will reassess the components of the ECB system with respect to their involvement in neuroprotection and alleviating the motor dysfunction associated with PD.
We will also provide support for the hypothesis that modulators of the ECB system may have therapeutic potential for treating PD. The molecular identification of the CB1 and CB2 receptors, the ion channel TRPV1, with their respective endogenous ligand systems has opened a whole arena of pharmacological effects elicited by each one of these specific receptor targets.
CB1 and CB2 receptors belong to the superfamily of G protein-coupled receptors, which are coupled to inhibitory G proteins [ 30 , 45 , 46 ]. As such, both receptors inhibit adenylyl cyclase and activate mitogen activated protein kinase MAPK [ 47 ].
Additional signaling mechanisms encompass focal phosphatidylinositolkinase, adhesion kinase, sphingomyelinase, and nitric oxide synthase NOS [ 51 - 55 ]. The cDNA for CB1 receptor was first isolated from a rat cerebral cortex library using an oligonucleotide probe resulting from a member of G-protein-coupled receptors [ 45 ].
CB1 receptors are most highly expressed on axons and nerve terminals, but substantial functional evidence also confirms their expression on somata [ 47 , 56 ]. Autoradiography investigations have convincingly reported that the basal ganglia encompass the highest levels of both mRNA expression and binding sites for the CB1 receptor [ 57 , 58 ]. Including striatum [ 59 ], other three regions that receive striatal efferent outputs, such as the globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata SNpr , contain high levels of CB1 receptor binding sites [ 20 , 60 , 61 ].
However, CB1 receptor mRNA transcripts are also present in the caudate-putamen, which is deficient of striatal outflow nuclei [ 62 ]. This observation agrees with the concept that CB1 receptors are presynaptically located in striatal projection neurons, a belief that has been backed by a series of anatomical experiments in which specific subpopulations of neurons in the basal ganglia were lesioned [ 63 , 64 ].
CB1 receptors are positioned in striatonigral direct striatal efferent pathway and striatopallidal indirect striatal efferent pathway projection neurons [ 59 , 65 ], which use gamma-aminobutyric acid GABA as a neurotransmitter.
Glutamic acid decarboxylase, prodynorphin, substance P, as well as D1 or D2 dopaminergic receptors are other markers co-expressed in these pathways [ 59 , 66 ].
In contrast, intrinsic striatal neurons, which contain acetylcholine or somatostatin, do not express CB1 receptors [ 66 ]. Axon terminals and post-synaptic dendrites in the prefrontal cortex that express CB1 receptor are documented to have sub-cellular presence of D2 receptors [ 67 ].
Real-time PCR assays and quantitative autoradiography binding study demonstrated higher levels of cannabinoid receptor binding in the lateral globus pallidus and weaker CB1 receptor gene expression in the prefrontal cortex [ 68 ]. CB1 are localized both pre and post-synaptically. CB1 receptors are localized in GABAergic terminals of interneurons or collaterals from medium spiny neurons MSNs , and also in glutamatergic but not in dopaminergic terminals Post-synaptically, CB1 receptors are localized in the somatodendritic area of MSN [ 70 ].
More extensive but less vigorous pre and post-synaptic CB1 receptor occurrence by electrophysiological and electron microscopic studies was also displayed in many brain regions including those enriched in dopaminergic neurons [ 71 ]. Thus displaying that the CB1 receptor is a significant retrograde signaling molecule in excitatory as well as in inhibitory-type axon terminals.
Immunohistochemical, immunoblot [ 72 ] and autoradiographical studies have suggested the presence of CB1 receptor in substantia nigra, striatum and globus pallidus [ 73 ]. CB1 receptor immunolabeling is also abundant in SNpr [ 74 ]. Immunolabeling study by Matyas et. These anatomical studies and data strengthen the assumption that CB1 receptors play an important role in mediating the motor effects of various cannabinoid receptor agonists [ 78 - 80 ].
CB1 receptor expression is only partially known in glial cells. Microglia, astrocytes, and oligodendrocytes have been reported to express CB1 receptors [ 81 , 82 ]. CB1 immunoreactivity has been reported in perisynaptic and perivascular astrocytes [ 83 ] of rat striatum [ 84 ].
However, these data have not been reproduced by other researchers [ 85 , 86 ]. In addition, another study reported CB1 expression in primary astrocyte cultures and in astrocytoma cell lines [ 87 , 88 ]. Although CB1 expression on glial cells is debated, it is at a considerably lower density than that observed on neurons [ 47 ].
Primary microglial cell cultures express CB1 receptors. However, CB1 receptor expression is affected due to culture-influenced morphological changes that occur in microglia [ 81 ]. Thus, it is unclear whether the presence of CB1 receptors on microglia is a consequence of their activation, as there are no in vivo data regarding CB1 receptor expression in microglia. Carrier and colleagues reported that a non-transformed rat microglia cell line expresses CB1 receptors [ 89 ].
The functional relevance of CB1 receptors in microglial function remains dubious, although their role may be linked to nitric oxide NO production [ 54 ], which is a pivotal event in microglia-mediated neuroinflammation [ 90 ].
A second cannabinoid receptor was discovered in a human promyelocytic cDNA library within a few years following discovery of the CB1 receptor. Based on its homology to the CB1 receptor and similar ligand binding profile, this receptor was named the CB2 receptor [ 46 ].
There has been uncertainty with CB2 receptor expression on neurons. Some evidence described CB2 receptor expression in rat dorsal root ganglion DRG cultures [ 91 , 92 ] and F cells that exhibits several features of authentic DRG neurons [ 93 ].
Related reports also indirectly displayed CB2 receptors on primary sensory neurons [ 94 ]. Furthermore, the localization of CB2 receptors in granules and purkinje cerebellar neurons of mouse brain was demonstrated [ 95 , 96 ].
CB2 receptors are primarily expressed on immune cells. Prolific expression of CB2 receptors is found in B-lymphocytes, natural killer cells, monocytes, neutrophils, T8 lymphocytes, and T4 lymphocytes [ 97 ]. Several other researchers have demonstrated the presence of CB2 receptors in in vitro cultures [ 98 ]. Notably, CB2 receptor expression is affected due to culture-influenced morphological changes that occur in microglia [ 89 ]. However, data obtained by Benitoa and Nunez et al. Recent evidences through anatomical localization, behavioural studies for central effects of CB2 receptor agonists and mRNA expression profile in neurons are pointing towards the neuronal expression of CB2 receptors [ ] in GABAergic neurons of layer II and V of medial entorhinal area of rats [ ] as well as in CA1 hippocampus and substantia nigra [ ].
Within the basal ganglia, CB2 receptors are also found to be expressed in neurons from both segments of the globus pallidus of Macaca fascicularis [ ] and SNpr region of neonatal rats [ ].
Immunohistochemical evidence suggests that activated microglia are able to express the CB2 cannabinoid receptor during chronic degenerative processes [ ]. Past reports have also shown CB2 expression in neural progenitor cells [ ]. These results indicate that CB2 might be involved in the neuroinflammatory process that develops in some forms of neurodegeneration such as PD [ 42 ]. Thus, various studies have established that CB2 receptors are significantly induced in different parts of brain, including the basal ganglia, in response to different types of insults including injury or inflammation [ , ].
Therefore, CB2 may become a promising target for modulating neuroinflammatory responses, as the agonists for this receptor are devoid of psychoactive effects [ 81 , ]. The gist of these data is that immunocytochemical experiments claiming CB2 expression are several, but are often inconsistent.
Also, before accepting any claim of CB2 expression in a specific tissue, the inclusion of coexisting and cautious controls is obligatory. Although these settings have been followed for many immune cells and neurons, but still many other tissues are yet to be established [ ]. Some reports have also stated the importance of vanilloid TRPV1 receptors in the basal ganglia and their ability to interact with ECBs [ - ].
TRPV1 receptors have been studied for their role as molecular integrators of nociceptive stimuli present abundantly on sensory neurons. Apart from sensory neurons, TRPV1 receptors are also found in the basal ganglia circuitry co-localized with tyrosine hydroxylase, indicating that they are located in dopaminergic neurons of the nigrostriatal pathway [ , ]. Various neurochemical and pharmacological studies have reported the involvement of these receptors in the control of motor function [ ] as well as in the manifestation of motor effects by certain cannabinoid receptor agonists [ ].
The orphan G-protein-coupled receptor 55 GPR55 has been discovered as another possible cannabinoid receptor [ ]. Regardless of high GPR55 expression in the striatum [ ], contrasting pharmacological data may not consider GPR55 as a novel cannabinoid receptor [ , , ]. The outcomes of various investigations on the status of the ECB system in PD patients indicates a similar trend as that observed in animal models of PD. The cannabinoid signaling system in PD becomes over activated in the basal ganglia [ - ].
Impacts of cannabinoids on motor activity depend on the effect of the cannabinoid on the dopaminergic system. A recent study has revealed a reduction in the availability of CB1 receptors in the SN of PD patients as compared with healthy controls [ ].
Mice deficient of CB1 receptors display less severe dyskinesias, when lesioned with 6-hydroxy dopamine 6-OHDA and treated with levodopa, compared with normal animals [ ] thus, providing an indication for the participation of CB1-related mechanisms in motor regulation [ ]. Electrophysiological studies have revealed that cannabinoid agonists increase the firing rate of SNpc neurons [ - ]. Mice lacking the CB1 receptor display a reduction in tyrosine hydroxylase-labeled varicosities, the majority of which are dopaminergic, in the accumbens shell as well as a loss of dopamine-dependent reward function [ ].
In vivo microdialysis investigations have shown improved dopamine release in the striatum after administration of endogenous or exogenous cannabinoid agonists [ , ]. Patients with PD have increased efficacy of CB1 receptor activation along with an escalated binding of the CB1 receptor [ ]. In addition, the cerebrospinal fluid of untreated patients with PD has augmented levels of AEA [ ].
Notably, one of the key symptoms of PD, bradykinesia, was most frequently ameliorated by cannabinoids, which is followed by muscle rigidity and tremor [ ]. In a short pilot study involving patients with PD, nabilone, a cannabinoid receptor agonist significantly decreased LID [ ]. However, a larger, double-blind, randomized, placebo-controlled crossover trial demonstrated that orally administered cannabis extract was ineffective for alleviating parkinsonism or dyskinesia in patients with PD [ ].
With respect to the neuroanatomical distribution, functional and behavioral studies, it suggests that the ECB system can act as an indirect modulator of dopaminergic neurotransmission in the basal ganglia which involves CB1 receptor mediated inhibition of GABA transmission. Another double-blind, randomized, placebo controlled study investigated the probable effects of antagonizing CB1 receptors in patients with PD, wherein progress in motor function or a decrease in LID was observed [ ].
In another experimental randomized, double-blind, placebo-controlled trail, the CB1 receptor antagonist SR was ineffective for improving parkinsonian motor disability [ ]. These discouraging outcomes indicate the necessity for more research in this area. Therefore, based on the above observations, we propose that a few CB1 receptor-related effects could be favored as compensatory mechanisms, whereas others effects might embody a part of the pathogenetic process, an issue that is further complicated with chronic L-DOPA use.
Heterogeneous loss of dopaminergic neurons in the SNpc and their projecting fibers in the striatum are the core pathological features of PD.
The striatal nucleus is the main input area to the basal ganglia, as it gathers and holds glutamatergic cortical inputs from all operative sub-sections of the neocortex and a remarkable input straight from the thalamic nuclei. The striatal network, which consists of GABAergic projecting MSNs contributing to the sole striatal output, and cholinergic interneurons carry out the neuronal signal processing functions from the cortex [ 59 ].
Two sets of neuronal circuits exist for striatal MSNs that connect to the output nuclei of the basal ganglia. One is a direct circuit direct pathway or via a sequence of connections that include the STN and the external segment of the globus pallidus GPe indirect pathway [ ]. The output nuclei [SNpr and the internal segment of the globus pallidus GPi ] connect to the thalamus, which further has efferent extensions that form the cortico-basal ganglia-thalamo-cortical loop [ ].
The physiological effect of dopamine originating from the SNpc on MSNs is intricate and not fully revealed.
In fact, the intensity of membrane depolarization on the dopamine receptor dictates the type of effect produced.
D1 dopamine receptors are positively coupled to adenylyl cyclase; hence, their activation increases the cytosolic cAMP level and subsequently elicits numerous downstream effects including an increase in NMDA receptor-mediated currents. In contrast, D2 dopamine receptors are negatively coupled to adenylyl cyclase and their activation decreases neuronal excitability and neuronal feedback to glutamatergic inputs [ ].
Based on the classical hypothesis, MSNs in the direct pathway principally contain D1 dopamine receptors, whereas MSNs in the indirect pathway contain D2 dopamine receptors. Flow of dopamine through these two pathways produces opposite motor effects and thereby modulates activity of output nuclei that is thought to be essential for normal motor function. In fact, when a specific set of striatal neurons are triggered, repression of a subpopulation of pallidal neurons occurs which further clears the tonic inhibition from a specific target motor center, thereby initiating a motor reflex [ 59 , ].
The continuous demise of pigmented dopaminergic neurons that occurs in PD decreases striatal levels of dopamine and creates an imbalance between the direct and the indirect basal ganglia pathways.
This imbalance leads to over activity of GPi, which results in over-inhibition of the motor thalamus [ ]. Recently, numerous levels of cross-talk between direct and indirect pathways have been discovered.
As a result, a first level of interaction is represented by the molecular cross-talk between heteromeric D1and D2 receptors [ , ]. These mechanisms are prerequisite for striatal physiology and LID [ , ]. A series of electrophysiological, biochemical, and anatomical experiments established that the constituents of the ECB system are markedly expressed at different levels in the basal ganglia neural circuitry and thus critically organize motor function and plasticity [ - ].
Recent report is also supporting a role for the malfunctioning of corticostriatal glutamatergic signaling in the occurrence of LID [ ].
Compared to the canonical neurotransmitters mentioned above, ECBs function as retrograde synaptic messengers. Retrograde signaling is the primary mode by which ECBs facilitate short and long-term forms of plasticity both at excitatory and inhibitory synapses and interacts with dopaminergic system [ , ].
The release and reverse journey of ECBs from postsynaptic neurons activates CB1 receptors located on presynaptic axons and thus decreases the release of neurotransmitter [ ].
In fact, stimulation of presynaptic CB1 receptors on corticostriatal terminals decreases glutamate release [ , ]. Similarly, stimulation of CB1 receptors in the output segment of basal ganglia antagonizes both glutamate release from STN afferents and GABA release from striatal afferents [ , , ]. Progressive loss of dopaminergic innervation in PD causes overactivity of the indirect inhibitory pathway, resulting in excess glutamatergic drive to the GPi and SNpr and diminished activity of the inhibitory GABAergic direct pathway, further disinhibiting the activity of the GPi and SNpr.
Dopaminergic signaling is bi-directionally linked to ECB signaling within the basal ganglia. In fact, D1 and D2 dopamine receptors are co-localised with striatal CB1 receptors on GABAergic neurons of striatonigral and striatopallidal pathways [ 58 , , , , ]. United activation of D1 and CB1 receptors causes a decrease in adenylyl cyclase and a net decrease in the inhibitory activity of direct striatal projection neurons ultimately leading to an inhibited motor response due to increased neuron activity in the SNpr.
In contrast, co-stimulation of D2 and CB1 receptors increases adenylyl cyclase [ 59 , 60 , ] which increases activity in the indirect striatal pathway that activates STN neurons leading to decreased motor activity [ , ].
This phenomenon of co-existence of macromolecular complexes composed of functional receptor units with biochemical properties that are different from those of its individual components is called receptor heteromers. In another study it was proposed that just by co-expressing CB1 and D2 receptors is adequate to induce stimulation of adenylyl cyclase in response to CB1 receptor activation [ ]. The reasons for dissimilarities between these studies remains to be resolved, but all of these studies demonstrate that activation of CB1-D2 receptor heteromer can have completely opposite effects than activation of the individual receptors.
Recent electron microscopy analysis with double labeling in the ventral striatum has established the presence of overlapping subcellular distributions of CB1 and D2 receptor immunoreactivities both at the pre and postsynaptic levels [ ], providing significant support for the presence of CB1-D2 receptor heteromers in the striatum.
Although some reports have suggested heterodimerization of CB1 and D2 receptors, [ , ] the functionality of these heteromers in striatal glutamatergic terminals has not been confirmed [ 70 , ].
Apart from, CB1-D2 receptor heteromers, recently with the aid of biochemical and biophysical studies CB1-CB2 receptor heteromers is reported in nucleus accumbens and globus pallidus [ ]. Typical characteristic feature observed with CB1-CB2 receptor heteromers is that, CB1 receptor antagonists blocks the effect of CB2 receptor agonists and, conversely, CB2 receptor antagonists blocks the effect of CB1 receptor agonists thus demonstrating a bidirectional phenomenon of cross-antagonism [ ].
These heteromers may describe preceding conflicting results and may serve as therapeutic targets. Recent evidence suggests that dopamine modulates the activity of SNpc neurons not only by conventional dopamine receptors, but also by CB1 receptors, possibly via N-arachidonoyl-dopamine [ ]. In addition to localization of CB1, the presence and functional role of TRPV1 on dopaminergic nigral neurons and their role in modulating synaptic transmission within the SNpc have also been determined [ ].
TRPV1 immunostaining was observed in fibers and post-synaptically in striatal neurons [ ], however the specific anatomical uniqueness of these TRPV1 expressing components has not been examined. It has been recently presented that CB1 and TRPV1 receptors decrease and increase the glutamate release from gliosomes [ ] signifying a possible association of TRPV1 receptors in the regulation of cortical activity and plasticity.
Additionally recent studies that establish the existence of different forms of TRPV1-mediated synaptic plasticity in the striatum [ ], the presence of dissimilar forms of TRPV1-mediated cortical plasticity is highly probable, although this remains to be confirmed.
Based on these reports, it is speculated that ECBs may critically regulate physiological functioning of the basal ganglia neuronal circuit. Additionally, the existence of elements of the ECB system in different neural circuits and their direct interaction with GABAergic, glutamatergic, and dopaminergic signaling systems makes these components an ideal non-dopaminergic target for PD.
Synapses, particularly those in the striatum, sustain long-lasting morphological and functional modifications after continuously activating neuronal pathways [ ].
Synaptic plasticity seems to play an important role in the dynamics and development of a neuronal circuit in the corticostriatal region, particularly motor learning. Continuous stimulation of striatal synapses of MSNs in the corticostriatal pathway elicits both long-term depression LTD and long-term potentiation LTP of synaptic transmission efficacy. This phenomenon is observed to be impaired in both the striatum and the motor cortex of patients with PD as well as in experimental models of PD [ , ].
In contrast, ECBs are actively involved in the formation of LTD synapses that connect striatal and cortical neurons and therefore plays a vital role modulating the dynamics of the striatal neural circuit. Hence, it is speculated that release of AEA from postsynaptic neurons under such circumstances might act as retrograde messenger stimulating presynaptic CB1 receptors and initiating long-lasting depression of excitatory glutamatergic transmission [ - ].
However, it has been hypothesized that MSNs of the direct and indirect striatal pathways might manifest diverse synaptic properties [ ]. ECB-dependent synaptic plasticity of MSNs could depict a synaptic mechanism for the formation of persistent drug-related behaviors [ 59 ]. Synapses between MSNs in the indirect-pathway are abolished in experimental models of PD [ , ]. Administering URB and quinpirole significantly decreases catalepsy and increases locomotor activity in experimental models of PD [ ].
This result indicates a direct interrelationship between recovery of ECB-mediated synaptic plasticity at corticostriatal synapses and improvement in PD motor symptoms. Also, within the striatum, sub-class of GABAergic interneurons that are observed to produce NO [ 59 ] and cholinergic interneurons are found to express CB1 receptors [ ]. In line with these reports various electrophysiological experiments have also demonstrated that inhibitors of NOS avert induction of LTD [ , ].
Therefore, damage to ECB-dependent striatal LTD at corticostriatal synapses may contribute to the abnormal activation of this specific neuronal circuit culminating in over stimulation of GPi and subsequent over-inhibition of the motor cortex leading to the initiation of parkinsonian syndrome.
Cannabinoids were previously reported to only produce behavioral patterns such as catalepsy and hypolocomotion in experimental animals. Due to these peculiar behavioral effects of cannabinoids, their therapeutic use for alleviating bradykinesia, rigidity, and other hypokinetic symptoms typical of PD is limited [ , , ].
These effects lead to an array of studies that investigated various facets of cannabinoids on motor symptoms in PD. The evidence obtained in different animal models and in clinical trials produced a basis for the involvement of cannabinoids in motor behaviors. As cannabinoids lack specificity of binding to the desired target, the data obtained varied in specific motor effects of cannabinoids but it also opened new doors for their clinical utility.
Therefore, the presence of ECBs in different regions of the basal ganglia circuitry along with the polymorphous nature of cannabinoid-mediated mechanisms makes it a complex physiological phenomenon eliciting behavioral effects. Since CB1 receptors are highly expressed in both D1 and D2 receptor containing MSN, and they antagonize D1 and D2 receptor mediated behaviors, mounting evidences have suggested the involvement of endocanabinoid system in dyskinesia [ 58 ].
This is the central motive to hypothesize CB1 receptor as a therapeutic target to regulate the imbalance of glutamatergic or GABAergic neurons in PD and dyskinesia [ ]. There is also a report that ECBs and cannabinoid agonists decrease dopamine reuptake by inhibiting dopamine transporters [ ] and hence may have applications for fine tuning the striatal neuronal network involved in dyskinesia [ ]. Rotational behavior induced by SKF was mitigated by both cannabinoid agonists, but the same response was not observed when they were tested with the D2 agonist quinpirole.
In contrast, WIN, decreased the effects of the D2 agonist, but not those of a D1 agonist in reserpinized rats [ ]. Although there was a discrepancy in the effects elicited by the cannabinoid agonist on different dopamine agonists, these data demonstrate that cannabinoid agonists antagonize the effect of dopaminergic drugs.
Consistent with the pharmacological model, the cannabinoid receptor antagonist rimonabant SR A was found to boost the locomotive effects of quinpirole in normal and reserpinized rats and also increased the locomotor activity in mice pre-exposed to 9-THC [ 21 , 23 , ]. However, paradoxical results were obtained by the SR A in primate models [ ]. Rimonabant was found to be unsuccessful [ ] to antagonize motor deficits in 1-methylphenyl-1,2,3,6-tetrahydropyridine MPTP -intoxicated primates [ ], although these experiments used different primate species.
Also, in a confined clinical trial, rimonabant had no antiparkinsonian effects in combination with levodopa [ ]. Blocking CB1 receptors may be effective only in particular circumstances, such as when low doses of CB1 receptor antagonists are used, when patients do not respond to dopamine therapy, or when they are in progressive phases of the disease [ - ].
Although the data obtained were from drugs with different specificities and in different animal models, these results indicate an indecisive effect of CB1 antagonists on parkinsonian symptoms. This result indicates a central advantage, as it may provide a novel anti-parkinsonian agent useful for circumstances in which classic dopaminergic replacement therapy is futile. The synergism of antiparkinsonian effects caused by cannabinoid antagonists with dopaminergic drugs to stimulate movement suggests that cannabinoid agonists may antagonize the actions of dopaminergic drugs, including LID.
Long-term levodopa therapy for PD generally results in variations in motor responses called dyskinesias or abnormal involuntary movements AIM [ , ].
Few evidences supporting this hypothesis are cannabinoid agonist, WIN, that produced antidyskinetic effects in rodents [ ], and nabilone that reduced dyskinesia in primate models and patients [ , ]. Therefore, it can be proposed that cannabinoid agonists may decrease dyskinesia by antagonizing the effects of dopaminergic drugs.
Nonetheless, some evidence does not match the above hypothesis, as the selective cannabinoid antagonist rimonabant decreases LID in MPTP-treated marmosets [ ]. In contrast, another study reported the ineffectiveness of the CB1 antagonist CE in parkinsonian rhesus monkeys [ ]; thus, indicating a tentative role of animal species and behavioral outcome.
However, clinical trials failed to reproduce the same effect using a cannabis extract; thus, questioning the true use and activity profile of cannabinoids [ , ]. In contrast, another study demonstrated amelioration of parkinsonian symptoms and dyskinesia after discontinuing use of cannabis for months with no clear explanation [ ].
In conclusion, it can be stated CB1 antagonists seem to have antiparkinsonian effects antidyskinetic effect , whereas activities of CB1 agonists appear to be highly ambiguous [ ]. A very recent study by Mathur et. Furthermore decreased levels of cGMP signaling in the brain were also observed in hemiparkinsonian rats with LID [ ]. Specific inhibition of phosphodiesterase-5 by zaprinast and UK was found to restore ECB-LTD in these dyskinetic rats and mitigate the incidence of dyskinetic behaviors [ ].
This data agrees with the study done my Picconi et. Cannabinoid-mediated mechanisms in the striatum play a crucial role regulating dopamine-induced motor behaviors. Activating CB1 receptors increases neuronal activity in SNpc [ ]. This finding is opposed by a report wherein ECBs such as AEA and other related congeners acting through postsynaptic TRPV1 receptors may diminish nigrostriatal dopaminergic cell activity [ ]. Nevertheless, other authors have stated a surge in dopamine release after stimulating TRPV1 receptors in the SNpc [ , ]; however, this improvement may be facilitated by TRPV1 receptors located in glutamatergic terminals in the SNpc rather than by receptors located in dopaminergic terminals.
Based on interacting dopaminergic mechanisms and their corresponding regulatory status, modulating glutamate transmission might result in different motor effects. Furthermore, coupling postsynaptic CB1 receptors with G-proteins has contrasting regulatory effects on D1 and D2-mediated responses, such as negative and positive regulation, respectively [ ]. It is unclear whether the striatal reduction is due to a lesion or by an increase in ECBs as a compensatory mechanism [ ] with respect to changes occurring after dopaminergic loss in the cannabinoid system [ ].
Correspondingly, CB1 receptor binding also changes with the demise of dopaminergic neurons [ , ]. Some modulation by cannabinoids may occur due to the changes produced by dopamine deprivation during the early and preclinical stages of the disease, and this modulation becomes incompetent and motor symptoms develop as the disease advances [ ].
Regardless of the controlling position of the striatal cannabinoid system in PD, pre and postsynaptic machinery mutually result in precise effects on isolated projection neurons contributing to the drug induced-behavioral changes. Thus, numerous factors intercede in the striatal activities of cannabinoid agonists and antagonists to regulate their effects on motor responses to dopaminergic drugs.
The effects of CB1 agonists to attenuate LID may be facilitated by striatal machinery where the cannabinoid system is controlling a weakened dopamine system that pushes errors of activity mistake-proofing and discharges involuntary movements.
Both the cannabinoid actions have been established by electrophysiological studies on the discharge of GABA and glutamate, although their communication may lead to specific synaptic transmission effects, and these effects remain unspecified. In addition, it is unknown whether one of these mechanisms dominates after dopaminergic loss to elicit a clear behavioral response, as they are functionally contrasting. Hallmark features of cannabinoids to increase GABA and reduce glutamate transmission strongly impede neuronal activity in GPe and result in catalepsy [ ].
Promising cannabinoid-based therapies for Parkinson’s disease: motor symptoms to neuroprotection
Researchers are testing marijuana, which is also called cannabis, as a through an agonist, like marijuana, can improve tremors and may alleviate dyskinesia. Medical cannabis is a safe and effective way for older people to alleviate symptoms of Parkinson's, cancer and other diseases, particularly pain. Pc Cannabidiol for the treatment of psychosis in Parkinson's disease ), and has been shown to mitigate some of the negative effects of THC.