Abstract
Different classes of neurons in the CNS utilize endogenous cannabinoids as retrograde messengers to shape afferent activity in a short- and long-lasting fashion. Transient suppression of excitation and inhibition as well as long-term depression or potentiation in many brain regions require endocannabinoids to be released by the postsynaptic neurons and activate presynaptic CB1 receptors. Memory consolidation and/or extinction and habit forming have been suggested as the potential behavioral consequences of endocannabinoid-mediated synaptic modulation. However, endocannabinoids have a dual role: beyond a physiological modulation of synaptic functions, they have been demonstrated to participate in the mechanisms of neuronal protection under circumstances involving excessive excitatory drive, glutamate excitotoxicity, hypoxia-ischemia, which are key features of several neurodegenerative disorders. In this framework, the recent discovery that the endocannabinoid 2-arachidonoyl-glycerol is released by midbrain dopaminergic neurons, under both physiological synaptic activity to modulate afferent inputs and pathological conditions such as ischemia, is particularly interesting for the possible implication of these molecules in brain functions and dysfunctions. Since dopamine dysfunctions underlie diverse neuropsychiatric disorders including schizophrenia, psychoses, and drug addiction, the importance of better understanding the correlation between an unbalanced endocannabinoid signal and the dopamine system is even greater. Additionally, we will review the evidence of the involvement of the endocannabinoid system in the pathogenesis of Parkinson’s disease, where neuroprotective actions of cannabinoid-acting compounds may prove beneficial.The modulation of the endocannabinoid system by pharmacological agents is a valuable target in protection of dopamine neurons against functional abnormalities as well as against their neurodegeneration.
Highlights
In the last 15 years, the discovery and molecular dissection of the endocannabinoid system has opened a new avenue in neuropsychopharmacological research
We will focus on the interaction between endocannabinoids and midbrain dopamine (DA) neurons, as recent studies highlight that it spans from the fine regulation of synaptic inputs to neuroprotection/neurorescue mechanisms, which may bear relevance in several neuropsychiatric disorders involving primarily dysfunctions of the DA neurons
The reader will find an extensive list of recent reviews that explore the physiological relevance of the eCB system elsewhere [99, 153, 165], whereas we focus on the cellular and system physiological events mediated by eCBs that are relevant to our understanding of their interplay with the DA system
Summary
In the last 15 years, the discovery and molecular dissection of the endocannabinoid (eCB) system has opened a new avenue in neuropsychopharmacological research. The interest in this system was further fuelled by the characterization of the dual nature of its actions within the central nervous system: modulation of synaptic functions and neuroprotection. We will focus on the interaction between endocannabinoids (eCBs) and midbrain dopamine (DA) neurons, as recent studies highlight that it spans from the fine regulation of synaptic inputs to neuroprotection/neurorescue mechanisms, which may bear relevance in several neuropsychiatric disorders involving primarily dysfunctions of the DA neurons
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