By follow-up in June 2021, on average, there were no significant differences from pre-pandemic patterns of alcohol and nicotine use. Findings are consistent with previous short-term studies showing a pandemic related increase in the number of days drinking. In our data, this change reflected a different distribution of drinking across the population: compared to pre-pandemic, fewer young adults were drinking, but those who did drank more frequently. While two previous studies found decreases in binge drinking , we did not find a statistically significant change in the number of days of binge drinking at any timepoint in the current study. However, the non-significant reduction we observed in binge drinking in June and December 2020 was directionally consistent with these previous studies. In addition, the time frame of measurement may explain the discrepancy: those two previous studies focused on changes earlier during the pandemic, in March and April 2020, whereas another study focusing on changes in June and July 2020 also found no significant change in binge drinking. As in one previous study , we did not find an average effect of the pandemic on nicotine use. However, this appeared to obscure opposing changes among those who suffered vs. did not experience impacts on their financial security. Relative to pre-pandemic, in June 2020, those with past-month nicotine use had increased the number of days using if they experienced financial impact and had stable or decreased number of days using if they denied experiencing financial impact. Loss of job or reduction in work hours could increase smoking during periods of boredom at home or to cope with the attendant stress. This pattern is consistent with the larger literature documenting how the pandemic may exacerbate health dis parities based on pre-existing socioeconomic advantage.
However,cannabis grow kit moderation of multiple out comes was tested, so the current findings should be regarded as preliminary and await replication. This study had limitations. First, findings may not generalize beyond emerging adults ages 18–22 years old. Second, for nicotine use, we did not measure the quantity used each day, which could have changed. Third, we did not consider other substances such as cannabis. Fourth, the mode of assessment differed from the pre pandemic to during-pandemic assessments, potentially introducing differences.Fifth, secular changes in the rates of alcohol or nicotine use among young adults between 2016 and 2021 could be confounding the effect of the pandemic, potentially introducing bias.Sixth, pre-pandemic responses on a free-response scale had to be mapped onto the discrete response options , potentially limiting precision. Seventh, we assessed the degree to which the pandemic impacted in dividuals’ financial security but not the form of this impact. Eighth, pre-pandemic observations were not anchored to the months of June and December, so seasonal effects could explain part of the observed differences. We reported here the most extended follow-up to date of pandemic related changes in drinking and nicotine use in emerging adults. The study had several further strengths. We used seven years of pre pandemic assessments and a rigorous age-based design to identify the pandemic’s impact over and above typical developmental changes. We incorporated three assessments spanning the first 15 months of the pandemic to study whether early changes in drinking and nicotine use persisted. Participants spanned five sites across the U.S and multiple racial and ethnic backgrounds. Finally, we focused on a critical developmental period associated with elevated risk for problematic use. In summary, in a heterogeneous group of young adults, pandemic related changes in drinking patterns were no longer detectable in June 2021. Pandemic-related increases in nicotine use occurred only for participants who reported greater impact of the pandemic on their financial security—these subgroup effects were no longer statistically significant in June 2021, though a large effect size for past-month nicotine use remained. Thus, those whose financial security has been adversely impacted by the pandemic may reflect a vulnerable group worth targeting for supports to manage drinking and nicotine use.
Continued follow-up beyond summer 2021 is necessary to verify that the pandemic’s effects on drinking and nicotine use have indeed faded and understand the pandemic’s long-run impacts of substance use trajectories into adulthood. Parkinson’s Disease treatment has been based on dopamine replacement therapy for 35 years. Yet, side effects resulting from long-term use of DA agonists, namely dyskinesias and on–off responses, are prompting investigations of alternative neurotransmitter manipulations to modulate basal ganglia function and normalize motor activity. Dyskinesias often result from lesion or disturbance affecting the transcortical loop or indirect pathway, with disruption of balance between excitation and inhibition in the globus pallidus pars externa-subthalamic nucleus-globus pallidus pars interna circuit. Thus, dyskinesias reflect altered patterns of neuronal firing in this circuit, which result in the improper selection of specific motor programs and, eventually, in the development of hyperkinetic movements. Endocannabinoids, the endogenous ligands of cannabinoid receptors, are synthesized upon demand by neurons in response to depolarization , and, once released, diffuse backwards across synapses to suppress pre-synaptic GABA or glutamate release. Because of these properties, the endocanna binoid system may offer new pharmacological targets for the treatment of neurologic conditions characterized by abnormal firing patterns. One application of cannabinoid based therapeutics would be for dyskinetic syndromes, hyperkinetic disorders characterized by changes in pattern, synchronization, mean discharge rates, and somatosensory responsiveness of neurons in the direct and indirect extrapyramidal motor circuits. Further applications of cannabinoid-based therapeu tics may extend to treatment of seizure disorders, changes in behavioral or cognitive state resulting from hypersynchro nous excessive neuronal discharges in other, for example, limbic, cortical or thalamic circuits. To test the hypothesis that endocannabinoids act as endogenous antidyskinetic agents with modulatory effects on abnormal basal ganglia circuits, we examined endocan nabinoid production in specific areas of the basal ganglia of rats infected with Borna disease virus and how cannabinoid agonists and antagonists affect their motor behaviors. Borna disease virus is a negative strand RNA virus epidemiologically linked to patients with neuropsychi atric disorders and Parkinson’s-plus syndromes.
After infection, BD rats develop an extrapyramidal disorder with sponta neous dyskinesias, hyperactivity,cannabis drying racks stereotypic behaviors, partial DA deafferentation, DA agonist hypersensitivity, and Huntington’s-type striatal neuropathology. Our investigations revealed elevations in the endocannabinoid anandamide in the subthalamic nucleus of BD rats, associated with increased metabolic activity in this key basal ganglia relay nucleus. As pharmacological antagonism of CB1 receptors caused BD rats to seize, we also evaluated the relationship between changes in anandamide levels and seizure phenomena. Our results suggest that anandamide acts as both an endogenous antidyskinetic and anticonvulsive compound, in part via interactions with the opioid system.Our results are consistent with a functional role for anandamide signaling as a natural mechanism to buffer abnormal firing patterns in various neural circuits. Using BD rats, a rodent model of viral-induced neurodegenerative syndrome and spontaneous dyskinesias, we showed significant anandamide elevations in the STN, a critical basal ganglia relay nucleus in which abnormal firing has been linked to dyskinesias, dystonia and hemiballismus. The characteristics of STN neurons, such as fast firing kinetics, short membrane refractory periods and ability to modify their firing pattern after small changes in impinging synaptic input , render the STN well-suited to regulation by activity-dependent modulators such as endocannabinoids. In keeping with this hypothesis, CB1 receptor protein and functional CB1 receptors have been found in the STN of rats. However, neither WIN 55,212-2 nor AM404 had robust antidyskinetic effects in BD rats, which we attribute to loss of CB1 receptors along with GABA neurons in other nuclei of the basal ganglia circuit, as indicated by striking loss of GAD immunoreactivity in BD rats. STN hyperactivity is a recognized feature of PD , but may also signifying abnormal patterns of firing, as in dystonia. Thus, in BD rats, which display mixed Parkinsonian and Huntington’s lesions, the anandamide and Col activity elevation observed in the STN may represent an important compensatory or modulatory reaction to abnormal input to STN, with the net effect of reducing pathologic or dyskinetic movements.
The convulsant effect of CB1 receptor antagonist SR141716A was an unexpected result. Since abrupt reduction of endocannabinoid tone produced hippocampal seizures in BD rats, we suggest that anandamide, in addition to its compensatory function in the basal ganglia, may have a role in maintaining homeostatic or balanced activity in limbic networks.To further evaluate the role of anandamide in convulsive phenomena, we used a seizure paradigm already developed in BD rats. In these rats, degenerative changes extend to hippocampus and amygdala and self-limited limbic seizures can be consistently produced within 5 to 10 min of administration of the general opiate antagonist naloxone. We found that administration of naloxone did not change anandamide levels in the hippo campus and amygdala of BD rats that seized, while naloxone did cause significant anandamide elevation in the same brain areas of normal rats that did not seize. The failure of BD rats to increase limbic region levels of anandamide in response to the opiate antagonist naloxone is consistent with the idea that decreased availability of anandamide on demand contributed to seizures induced by a chemoconvulsant. Dynamic neurotransmitter buffering in rapid response to excitatory stimuli may be a general principal of endogenous anticonvulsants, applying to classic inhibitory neurotrans mitters such as GABA and to neuromodulators such as opioids or endocannabinoids. For example, when opioid tone was reduced by naloxone, the result was increased EEG activity of both normal and BD rats. When BD rats developed increased or hypersynchronous EEG activity but could not increase anandamide levels, it was the ananda mide transport blocker AM404 that limited or reversed naloxone excitability and rescued the animal from seizures. Anticonvulsant efficacy was most likely via elevation of anandamide or other endocannabinoid tone, an interpreta tion consistent with anecdotal reports by patients of improvement in seizure frequency or severity with mar ijuana use. However, at this time, we cannot exclude a vanilloid-mediated effect of AM404, since this drug binds to the TRPV1 receptor. Our study widens the role of potential cannabinoid– opioid interactions beyond substance abuse, tolerance dependence phenomena, analgesia, hypothermia, and inflammation and suggests a reciprocal relation between these two systems with respect to convulsive phenomena. So far, cannabinoids and opioids have been implicated separately in seizures. While CNS opioid dysregulation has been considered a substrate for the interictal personality disorder , CNS endocannabinoid signaling changes because of their association with schizophrenia and psychotic symptoms might also contribute to interictal cognitive or personality syndromes. Endocannabinoid upre gulation during opiate withdrawal could explain the absence of seizures during opiate withdrawal. The opioid system includes several families of related neuropeptides and A, y, n opioid receptors. In other work , kappa opioid receptors have been identified as a major contributor to anticonvulsant efficacy. When K and CB1 receptors are compared, they are found to have convergent biochemical mechanisms. Both are members of Gi/o protein coupled receptor family and signal through cAMP-Protein Kinase A, inwardly rectifying K+ channels and N, P/Q, R type Ca++ channels. KOR and CB1 receptors exhibit overlapping neuroanatomic dis tribution in hippocampus. CB1 receptors are found on CCK expressing interneurons , while KOR receptors are found on mossy fiber terminals, principal neurons, perforant path and supramammillary afferents, and GABA/SOM/NPY containing interneurons.At each step, excitatory tone is modulated by a diverse group of inhibitory and excitatory neurons. KOR or CB1 stimulation of selective interneurons could desynchronize GABA inputs to a post synaptic network. Desynchronization of signals from GABA containing interneurons to their networks of pyramidal cells is one mechanism of enhanced inhibition of principal neurons. KOR stimulation at other sites, producing pre- or postsynaptic inhibitory effects on large pyramidal neurons, would also modulate excitability of principal neurons, with net effect the modulation of hippocampal outflow pathways. Further studies in our model will investigate the effect of AM404 on endocannabinoid production in the limbic system. Greater understanding of the conditions for inter action between endocannabinoids and opioid system will enhance our knowledge of neural circuits that serve fundamental or broad homeostatic functions and also will be the goal of future studies. In conclusion, knowledge of endocannabinoid distribu tion and function throughout basal ganglia circuits could lead to the identification of non-dopamine pharmacologic targets for dyskinetic disorders and a greater understanding of the role of output pathways in the genesis of motor behaviors and involuntary movements.