Outcomes of such practices and variations between trauma registries leads to a lack of confidence regarding data accuracy and resulting analyses. Motor impairment and/or execution of complex behavioral sequences often accompany psychotic symptoms, as in the case of obsessive-compulsive disorders. Such an occurrence likely reflects the anatomical overlapping of brain areas serving both motor and cognitive functions.Cannabimimetic drugs represent an interesting tool to investigate psychomotor behaviors, because of their documented ability to influence both motor and cognitive performances . Indeed, cannabinoid administration is accompanied by profound effects on motor behaviors, as well as by attenuation of d-amphetamine-induced hyperactivity and stereotypy. In addition, cannabinoid substances produce a large spectrum of psychotropic effects in humans, ranging from euphoria, short-term memory impairment, altered perception of space and time, and dream states. Similarities between certain cognitive impairments occurring in psychoses and the pharmacological effects of D 9 -tetrahydrocannabinol, the active principle in marijuana and hashish, have also been documented. The discovery of the brain cannabinoid receptor, CB1, and the mapping of its neuroanatomical distribution, have greatly improved our understanding of the effects of cannabimimetic drugs on psychomotor functions. CB1 receptors are most concentrated in areas of the central nervous system that are critical for the regulation and processing of motor functions, cognition,stacking pots and motivation. In keeping with this distribution, disruption of the CB1 receptor gene has been shown to severely impair movement control and to result in a functional reorganization of the basal ganglia.
The pharmacological properties of cannabis-derived drugs have prompted clinical evaluations of marijuana use in motor disturbances, such as spasticity, tremor, and dystonias . At the same time, the discovery of naturally occurring ligands of cannabinoid receptors, and the identification of their pathways of biosynthesis and inactivation, have opened a new research field aimed at investigating the physiological role of these molecules in health and disease, as well as their possible use as a new target for therapeutic interventions. The purpose of this mini-review is to draw together these studies, pointing out to the potential involvement of the endogenous cannabinoid system in psychomotor disorders.The cloning of the CB1 cannabinoid receptor and the mapping of its distribution in the brain has impelled the search for the corresponding naturally occurring ligands within the brain. Two endogenous cannabimimetic substances have been identified so far, arachidonylethanolamide and 2-arachidonylglycerol. Unlike neurotransmitters that are released from synaptic terminals via vesicle secretion, both anandamide and 2-AG are thought to be produced upon demand through stimulus-dependent cleavage of two distinct phospholipid precursors present in neuronal membranes . Anandamide, but not 2-AG, is released extracellularly by neural activity evoked by localized pulses of high K1, and it is thought to act near its sites of production as a local neuromodulator. Whether 2-AG is produced in vivo under physiological circumstances and/or it exits neurons in other regions of the CNS, has not been determined yet. The biological actions of anandamide are terminated by two subsequent reactions consisting of high-affinity transport into cell, followed by hydrolysis catalyzed by an amidohydrolase enzyme. 2-AG is thought to be inactivated by cleavage into glyceroland arachidonic acid. The enzyme activity involved in this reaction has not been clearly identified, though anandamide amidohydrolase and monoacylglycerol lipase have been suggested to play a role. Other saturated and monounsaturated fatty acylethanolamides are produced by activated neurons together with anandamide.
Although these lipids share a common biosynthetic mechanism with anandamide, they do not bind to cannabinoid receptors and they are not released extracellularly in vivo. The possible physiological roles of these compounds are still largely unexplored. One exception is represented by palmitylethanolamide which was shown to exert peripheral anti-inflammatory and antinociceptive effects, mediated through a putative CB2-like cannabinoid receptor .The basal ganglia are a forebrain region playing a key role in sensorimotor and motivational aspects of behavior. The high density of CB1 receptors in this area indicates that cannabinoid substances may modulate essential aspects of basal ganglia physiology. The existence of an endogenous cannabinergic tone in the basal ganglia has been suggested by the finding that the CB1 receptor antagonist SR141716 was able to produce increased locomotion in mice and stereotypies in rats. These findings have been recently confirmed by in vivo microdialysis studies, showing that membrane depolarization stimulates the outflow of anandamide from striatal neurons. Functional interactions between endogenous cannabinoids and distinct neurotransmitter systems modulating basal ganglia functions have been also postulated. Neuroanatomical studies have shown that CB1 receptors are mainly located in the terminals of GABA-ergic medium-spiny neurons projecting from the striatum to the globus pallidum and substantia nigra. Although direct evidence for an interaction between endogenous cannabinoids and GABA-ergic system is still lacking, it is known that exogenously administered cannabinoids can modulate GABA transmission, as suggested by their ability to inhibit GABA release from striatal and hippocampal nerve terminals and potentiate GABA-induced catalepsy. Coexpression of m -opioid and CB1 receptors in striatal cells indicates that opioids and endocannabinoids can also interact within the striatum. In keeping with this, chronic cannabinoid exposure regulates proenkephalin mRNA levels in the rat striatum. Finally, a role for the cannabinoid system as a modulator of dopaminergic activity in basal ganglia is emerging.
Activation of cannabinoid receptors was shown to cause significant reductions of the electrically evoked dopamine release from rat striatal slices, and to potentiate neuroleptic-induced catalepsy. Moreover, injection of cannabinoid receptor agonists into the basal ganglia counteracts the motor responses of locally administered D2-receptor agonists. Conversely, cannabinoid-mediated motor behaviors can be affected by dopamine manipulations. For example, chronic administration of dopamine D1 and D2 receptor agonists results in differential modulation of the locomotor effects of the cannabinoid agonist HU-210, suggesting a possible cross-talk between dopaminergic and cannabinergic systems within the striatum. In this regard, the observation that anandamiderelease can be induced by pharmacological activation of the D2 class of dopamine receptors in freely moving animals suggests that endogenous cannabinoids may represent a primary component of the network of neurochemicals modulating striatal function. Further support to this hypothesis is provided by behavioral studies showing that the hyperactivity associated with post-synaptic D2 receptor activation is markedly potentiated by the CB1 antagonist SR141716A. Taken together, these data suggest that pharmacological blockade of cannabinoid receptors enhances quinpirole-induced motor activation by removing the inhibitory control exerted by the endogenously released anandamide. Furthermore, the lack of effect of SR141716A when given alone at the same dose used to potentiate quinpirole-induced motor activation, indicate that anandamide can reach a sufficient concentration to induce its behavioral effects only after stimulation of D2 receptors. Thus, the released anandamide may offset dopamine D2-induced facilitation of psychomotor activity . Functional interactions between endogenous cannabinoids and dopaminergic system may have important therapeutic implications in pathologies that involve disregulated dopamine neurotransmission, such as Parkinson’s disease, Tourette syndrome,grow lights and schizophrenia. On a speculative basis, the blockade of anandamide inactivation and the consequent increase of endogenous levels of this lipid, may be beneficial in reducing hyperactivity and hyperkinesia associated with Huntington’s disease, a pathology where a massive loss of CB1 receptor binding has been reported in the basal ganglia of postmortem patients. However, the potential therapeutic use of cannabinoids for the treatment of psychomotor disorders is not only matter of speculation. It has been shown that blockade of CB1 receptors may potentiate or prolong the effects of dopamine-based therapies currently used in Parkinson’s disease and use of D 9 -THC for the treatment of Tourette syndrome has been reported. Increasing evidence suggests that schizophrenia may be associated with abnormalities in the function of the endogenous cannabinoid system. Clinical evidence indicates that cannabis consumption is significantly higher in schizophrenic patients than normal individuals and chronic use of high doses of cannabinergic substances may precipitate schizophrenic symptoms in vulnerable patients. Additional support for a role of cannabinoid signaling in schizophrenia comes from the observation that anandamide is markedly elevated in the cerebrospinal fluid of schizophrenic individuals. The non-cannabinoid acylethanolamide PEA is also increased in these patients. Although PEA is produced in the CNS through a biosynthetic mechanism similar to anandamide’s, this lipid is not released in vivo as a consequence of D2-receptor stimulation. Therefore, further investigations are needed to clarify the physiological role of PEA in the CNS as well as its possible link to schizophrenia. Drugs that block D2-like dopamine receptors have been extensively used to mitigate symptoms of psychoses and motor disorders.
Given the linkage between D2-receptor activation and anandamide release, it is likely that the high CSF levels of this lipid may reflect homeostatic adaptations of the endogenous cannabinoid system to disturbances in dopamine neurotransmission occurring in schizophrenia. Additional support for this possibility comes from the observation that chronic treatment with D2-family antagonists results in upregulated expression of CB1 receptor mRNA in striatum. On the other hand, alterations in cannabinoid signaling may directly contribute to the manifestation of subgroups of symptoms in schizophrenic syndromes. Further investigations in larger populations of patients and studies aimed at determining the neuronal origin of the AEs in CSF may help elucidate the possible participation of these lipids in the pathogenesis of schizophrenia.Successful viral suppression from combination antiretroviral therapy has led to an increase in life expectancy among persons living with HIV . While severe HIVassociated neurocognitive disorder is less prevalent in the cART era, mild to moderate HAND persists despite virologic suppression. HAND affects up to 50% of HIV-positive persons, with older HIV-positive adults at greater risk for neurocognitive impairment than their younger counterparts.Among neurocognitive domains affected by HAND, complex motor skills are consistently compromised across time. Complex motor skills refer to a combination of cognitive and perceptual-motor abilities, including perception, planning, continuous tracking, and sequential movements.Although the prevalence of complex motor impairment has receded in comparison to the pre-cART era, deficits in complex motor functioning are still observed in approximately 30% of those with HAND. Complex motor impairment is related to everyday functioning impairment, including driving ability, highlighting the clinical relevance in understanding mechanistic pathways underlying HIV-associated motor dysfunction. A recent longitudinal study found that complex motor function is particularly vulnerable to the effects of age and stage of HIV infection, and implicated the basal ganglia as a neural correlate of interest.The effects of acute HIV infection on the basal ganglia are well documented, with greater atrophy associated with psychomotor slowing.Inflammatory processes are one putative factor that may contribute to central nervous system injury, including deficits in complex motor skills. Biomarkers of inflammation, such as cytokines and monocytes, are elevated in the context of HIV infection. HIV, viral products, and activated immune cells are able to cross the blood brain barrier and contribute to inflammation in the CNS. Neuroimaging studies have shown that peripheral inflammatory biomarkers are able to alter neural activity in the basal ganglia, including dopaminergic activity, which is reflected by psychomotor slowing in HIV-negative adults. Among HIV-positivepersons, global neurocognitive impairment is associated with elevation of various peripheral biomarkers of inflammation and coagulation . Taken together, deficits in complex motor performance are commonly observed among HIV-positive persons, and elevation in peripheral biomarkers of inflammation may be a contributing factor. Thus, we hypothesize that HIV will have negative direct and indirect effects via inflammation on complex motor performance.Participants were 90 HIV-positive and 94 HIV-negative persons, with balanced recruiting in each age decade , from the five-year Multi-Dimensional Successful Aging among HIV-Infected Adults study conducted at the University of California, San Diego .Only baseline data were included in this analysis. The study received approval from the UCSD Institutional Review Board. Participants provided written, informed consent. Exclusion criteria for the parent study were diagnosis of a psychotic disorder and presence of a neurological condition known to impact cognitive functioning . Additional exclusion criteria for current analyses included being off ART, having detectable HIV viral load , and meeting criteria for a current substance use disorder. HIV infection was screened via a finger stick test and confirmed with an Abbott Real Time HIV-1 test or by submitting specimens to a Clinical Laboratory Improvement Amendments -certified laboratory for HIV-1 viral load quantitation. Although neurologic findings commonly associated with HIV infection have been suggested to largely remit with initiation of cART, our cross-sectional study observed worse complex motor skills across the adult age continuum of HIV-positive, relative to HIV-negative, adults. Inflammation burden was higher among HIV-positive adults, compared to the HIV negative comparison group.