Alcohol-addicted non-smokers showed the highest and most widespread differences from controls at the 10-day assessment versus the 3-day and 4-week assessments, whereas the alcohol-addicted smokers had a more consistent pattern of differences from controls across all assessment time points. In the alcohol-addicted smokers, higher GABAA receptor availability was correlated with more craving for alcohol and cigarettes . Overall, GABA was less studied than glutamate. MRS studies suggested lower GABA concentrations in abusers of alcohol, nicotine, and cocaine, which was also the typical direction of MRS effects for glutamate. Perhaps due to availability of more radiotracers, and/or because of their availability for a longer period of time, there were more PET/SPECT studies related to GABA than for glutamate, particularly for alcohol . These studies generally showed decreased GABAA receptor availability/distribution volume in the addicted individuals compared with controls. Nicotine, however, showed an opposite pattern of effects. History of smoking was not only associated with higher GABAA receptor availability on its own, but smoking also modulated the early abstinence course of individuals with alcohol dependence. Interestingly, the effects of smoking on alcohol dependence showed an opposite pattern of effects to that of glutamate. Examining the joint effects of smoking and alcohol abuse, while incorporating markers of both glutamate and GABA neurotransmission,vertical farming startup will be an interesting and important direction for future research. It is also important to note that, similarly to glutamate, GABA effects appeared to be sensitive to study participant characteristics, such as the length of abstinence and/or drugrelated medical diseases .
We did not locate any PET/SPECT studies labeling the GABAB receptor, which unlike the fast ligand-gated action of the GABAA receptor, is instead associated with long-term modulation through G protein regulated gene transcription and protein synthesis . More research, both MRS and PET, is also needed in opiates, methamphetamine, and cannabis.A large literature has examined RSFC deficits in drug addiction , and we did not reprise all of this important work here. Rather, our current goal was to provide evidence that some of the same regions implicated in glutamate and GABA MRS and PET studies in addiction are also functionally disrupted as revealed by RSFC. We focused on studies that examined RSFC differences between addicted individuals and healthy controls [using approaches that were seed-based and/or whole-brain or the graph theory-based metric degree ] in the ACC extending into the dorsomedial and/or ventromedial PFC, insula, and striatum . The rationales for focusing on these regions are as follows. The ACC and adjacent medial PFC form part of the default mode network , which is activated during the resting state . Moreover, the resting state is a condition replete with mind-wandering and self-generated thinking , and these self-referential functions have been linked with activation of cortical midline regions, including the pACC and medial PFC, in healthy individuals and addicted individuals . Thus, although larger regions, such as the ACC and medial PFC, have sometimes been selected as regions of interest in MRS studies for practical reasons , effects in these regions are nonetheless highly anticipated for both MRS studies and RSFC studies; recent combined fMRI-MRS studies in healthy participants further speak to this point . The insula has a critical role in mediating interoception and the detection of behaviorally relevant stimuli . In drug addiction, these functions subserved by the insula appear vital for the experience of drug craving.
The striatum forms a key part of the mesocorticolimbic dopamine projections that mediate the reinforcing effects of addictive drugs; chronic perturbation of this system ultimately leads to enduring changes in striatalPFC glutamatergic projections . Although MRS measurement of glutamate and GABA is more difficult in the striatum than in the insula , some studies included in this review indeed have reported striatal effects. Importantly, prior resting-state studies of healthy individuals have revealed functional connections between these three regions . Taken together, the literature indicates that drug-addicted individuals exhibit abnormal neurotransmission involving glutamate and GABA in corticolimbic brain regions of core relevance to their disease , and that these same regions also show disruptions in RSFC. Because glutamatergic and GABAergic neurotransmission in such regions also drive the resting state in health, we raise the hypothesis that corticolimbic RSFC can provide an intermediate phenotype to explain associations between addiction-relevant glutamatergic and/or GABA dysregulation and addiction symptomatology . Future work can center on the following areas. It is crucial to incorporate the modulating influences of clinical characteristics, especially withdrawal/abstinence and smoking . Withdrawal carries a high vulnerability to relapse, which may partially stem from associated perturbations in brain glutamate or GABA . Smoking history, as shown above, exerts important independent effects on brain glutamate and GABA metabolites. Current smoking also modulates the effects of other substances, such as alcohol , and the resulting effects on brain glutamate and GABA may differ depending on which neurotransmitter is examined. Future studies might also investigate whether neurochemical deficits in one corticolimbic brain region have reverberations across the brain. This may be especially true for deficits in glutamate, which has more global effects . RSFC methods, especially using whole-brain graph theory approaches, are ideally suited to test such hypotheses.
Finally, future studies can incorporate direct measures of brain metabolism, such as PET with [18F]fluorodeoxyglucose. Indeed, energy metabolism may represent an intermediary process between fast neurotransmission and the slow RSFC blood-oxygen-level dependent response, and this kind of precision would increase mechanistic understanding. Another important future direction for enhancing mechanistic understanding is to conduct studies with tighter experimental control, as can be achieved in animal models. Animal models offer the advantages of more controlled drug histories and more invasive assessments, which could clarify how addiction may causally change glutamate/GABA neurotransmission and metabolite levels in select brain regions, as well as their consequent associations with RSFC. In such animal studies, lower Glx levels in the dorsal striatum of rhesus monkeys due to chronic methamphetamine exposure showed a linear pattern of recovery with abstinence over one year [but see , where cocaine administration over the course of 9 months increased levels of glutamate and glutamine in squirrel monkeys]. In another study, rats received subcutaneous twice-daily injections of 2.5mg/kg methamphetamine for one week. This drug exposure resulted in decreased MRS-measured glutamate, glutamine, and GABA in hippocampus, nucleus accumbens, and PFC . Interestingly, a different study revealed decreased RSFC in cocaine-exposed rats between the nucleus accumbens and the dorsomedial PFC as a function of the degree of cocaine self-administration escalation .Alternatively, drug-administration schedules not intended to produce addiction have largely produced opposite results. For example, following short-term administrations of cocaine or alcohol , rats showed transient striatal or whole-brain increases in glutamate and/or GABA [but see ]. Such results are consistent with the idea that addiction-related decreases in glutamate or GABA could reflect neuroadaptations to chronic drug exposure. Such conclusions are difficult, if not impossible, to achieve in studies of already-addicted humans. Because human studies cannot achieve the level of precision attained in animal studies, mechanistic clarity needs to rely on more comprehensive and innovative experimental methods. A drug challenge model, if employed in combination with fMRI and with MRS or PET, can address causality by modulating underlying glutamate/GABA neurotransmission that can then be correlated with resting-state fMRI and then other clinical variables. We are aware of no previous studies in this field that have attempted this kind of ambitious design,vertical urban farming though some have incorporated various components. For example, one study showed that acute alcohol administration reduced occipital GABA levels . However, because this experiment was conducted in social drinkers , the potential relevance to addiction is unclear. Another study found that a heroin challenge in opiate-addicted individuals strengthened connectivity within an ICA-defined basal ganglia network . Similarly, opiate-addicted individuals receiving high methadone doses showed higher ACC glutamate levels . However, these studies did not incorporate both neurochemical measurements and RSFC. Finally, perhaps the most methodologically rich study to date evaluated the effects of 12-week varenicline administration on dACC Glx levels and fMRI BOLD response.
The varenicline regimen decreased dACC Glx levels, modulated DMN regions during task performance, and changed dACC-DMN connectivity as revealed by psychophysiological interaction analysis . Future iterations of this study type would need to include a control group and could benefit from using a pharmacological probe that modulates the neurotransmitter system of interest more directly . A future study that integrates these various components within a single design promises to be highly informative. It would be interesting to test whether addiction-related effects on brain glutamate and GABA are specific to addiction related to substances rather than behaviors. One could compare and contrast effects in individuals with substance use disorders with those in individuals who have behavioral addictions, such as gambling . We are aware of no MRS or PET studies that contrasted substance addiction and gambling addiction, but several studies on this front have been conducted using RSFC. For example, whereas increased intrinsic local connectivity of the PCC was observed for both behavioral and substance addictions, decreased connectivity of the ACC was specific to alcohol addiction . Moreover, cocaine addiction was uniquely associated with enhanced connectivity between the subgenual ACC with OFC or striatum . In contrast, connectivity in cocaine addiction overlapped with that in gambling addiction in the OFC and dorsomedial PFC, and in the amygdala and insula [note that this latter connection was also reported in opiate dependence ]. A relatively small but growing literature suggests that glutamatergic and/or GABAergic medications modulate neural activity in brain regions spotlighted in this review. In smokers, the GABAB receptor agonist baclofen, given both acutely and after 3 weeks of treatment, decreased cerebral blood flow during perfusion fMRI in several regions including the dACC . In an animal model , baclofen reversed neuropsychological deficits owing to acute cocaine injections in association with normalized metabolic activation in the PFC . Acamprosate, despite continuing debates regarding its clinical mechanism of action, appears to exert effects on brain glutamate . Consistent with this idea, 4-week treatment of acamprosate reduced MRS-measured pACC glutamate levels in recently abstinent alcoholaddicted individuals; such reductions appeared to be clinically warranted, as glutamate levels in cerebrospinal fluid were positively correlated with alcohol dependence severity . Moreover, in an animal model , acamprosate reduced Glx levels in the ventral striatum during alcohol withdrawal . In healthy controls, the GABA reuptake inhibitor tiagabine, which notably has been shown to decrease cocaine-positive urines in pilot clinical trials , increased the VT and/or BPND of [11C]flumazenil and [ 11C]Ro15 4513 in multiple PFC regions, including the ACC . We hypothesize that these medications – as well as potentially novel medications yet to be developed that act on these respective systems – could also modulate corticolimbic RSFC, providing a potential therapeutic target for intervention in drug addiction. In this regard, modulation of brain glutamate and GABA signaling may be particularly important during acute withdrawal, a time period when neurotransmission seems especially perturbed. Some researchers and advocates have raised concerns that alternative nicotine delivery systems act as a gateway into cigarette smoking and promote nicotine dependency for youth.However, other researchers argue that ANDS are important for harm minimization because they may replace higher risk combustible tobacco products, ultimately supporting goals related to the cigarette smoking endgame.Despite these debates, we still know little about how youth make sense of their transitions between ANDS and cigarettes and justify their unique initiation pathways of use. Existing research on pathways of nicotine and tobacco use has primarily focused on examining whether youth initiation of vaping encourages progression to smoking initiation. A few studies suggest that compared to never vapers, youth who use ANDS are likely to progress to smoking and that adolescent smokers who then initiate vaping are likely to adopt dual use practices of smoking and vaping. For example, cross sectional studies have found that among never smoking adolescents, ever use of ecigarettes was associated with increased susceptibility to initiate smoking, and that e-cigarette use was not associated with intentions to quit smoking.Recent longitudinal studies suggest that youth ecigarette use was associated with future cigarette initiation and current cigarette use, suggesting that e-cigarette use is a risk factor for cigarette smoking.