Because of astrocytes proximity and interaction with neurons and cerebral vessels, they present a possible target for therapeutic intervention. However, there is still a substantial gap in the literature regarding the role of astrocytes in regulative vasculature in CUD. At the time of writing, a PubMed search using the MeSH terms “Cocaine-Related Disorders,” “Astrocytes,” and “Cerebrovascular Circulation” yielded only one publication by Liu et al. In this investigation, the team utilized genetically encoded calcium indicators and chemogenetics to manipulate astrocytes and observed its impact on cocaine-induced changes. They found that while neurons had a greater increase in intracellular calcium following cocaine, astrocytic calcium stayed elevated longer and was correlated with the flow of oxygenated hemoglobin in cerebral arteries. Importantly, inhibition of astrocytes using DREADD (Gi) minimized cocaine-induced vasoconstriction (Liu et al., 2022).
Silent synapse-based re-development of NAc circuitry
- To understand the powerful nature of cocaine’s actions, it is helpful to realize that dopamine pathways in the brain are very old in evolutionary terms.
- It has been well established that chronic use of cocaine leads to global and regional CBF decreases in the brain.
- In contrast, the LFO changes in neuronal activity and CBF fluctuations deviated from a linear relationship in chronic cocaine-exposed animals, suggestive of hemodynamic uncoupling from neuronal activity under resting state conditions.
- These patients demonstrated CBF reductions of 30% within the anterior cingulate cortex (Wallace et al., 1996).
Over the past 10 years, there have been significant investments into the development of treatments for CUD (Supplementary Table S1). Advancements in the treatment of CUD have focused on either stimulating or inhibiting various types of dopamine (DA) receptors (i.e., D1R, D2R, and D3R) through agonists or antagonist but findings are inconclusive. Following a similar strategy to that of methadone as a replacement for opioid use, the utilization of amphetamine to treat CUD patients has been explored. The increase monoamines triggered by amphetamine might decrease cocaine seeking by increasing tonic DA levels and preventing burst firing (Grace, 1991; Grabowski et al., 2004; Brandt et al., 2021). Indeed, clinical trials have shown that dextro-amphetamine decreased cocaine intake in CUD patients (Shearer et al., 2003).
Whereas silent synapses can be generated either by a complete internalization of AMPARs or by insertion of NMDARs in new synaptic contacts, further analysis supports the latter possibility for cocaine-generated silent synapses (Fig. 2). First, cocaine-induced generation of synapses in NAc is accompanied by an increased number of dendritic spines, suggesting that new, synapse-like structures are formed82,83. Most of the new spines appear to be immature thin spines, as opposed to more mature mushroom-shaped spines (but see below)84. Second, cocaine-induced generation of silent synapses is abolished upon blockade of cocaine-induced activation of CREB52, and likely ∆FosB too85,86; both transcriptional factors have been critically implicated in synaptogenesis. Third, cocaine-induced generation of silent synapses is accompanied by the insertion of new NMDARs, and inhibiting newly inserted NMDARs disables cocaine-generated silent synapses51, suggesting that these silent synapses are formed in an NMDAR-driven manner rather than via the internalization of AMPARs at pre-existing synapses. Finally, cocaine-generated silent synapses are enriched in GluN2B NMDARs9,51,52, the type of NMDARs that are highly enriched in nascent synapses74,87,88.
- Participants were recruited over the course of 5 months by a psychiatrist (JN) visiting the treatment site to make a presentation about the study.
- These studies, together with related work in hippocampus77,80,93, paved the road toward the demonstration of cocaine-induced synaptic insertion of GluN2B NMDARs and generation of silent synapses in the NAc51,52.
- Following exposure to cocaine, whole brain levels of ɑ1 subunits are reduced114, a change that can be regarded as reversing the development of GABAA receptors.
- Addiction science is also well poised to use results from a number of the changes in the addictions landscape.1 Legalization of cannabis use by states provides opportunities to examine effects of reduced penalties for cannabis production and use; neighboring states that do not legalize provide control environments.
- The small sample size is a limitation of the current study (and one that is not easily corrected due to the subsequent decommissioning of the scanner) and although we have observed significant group functional differences, it will be important for future studies to replicate these effects with larger samples.
- Just as not all people with a propensity to develop addiction do so, not all addicts successfully complete treatment.
Also, blockade of GABAA receptors in NAc prevents the development of sensitized locomotor responses to repeated cocaine. According to this hypothesis, exposure to cocaine generates nascent immature excitatory synapses de novo in the NAc. 1) The potential cocaine-induced nascent synapses are either dormant (inactive) or do not exist before exposure to cocaine. 2) Exposure to cocaine activates signaling cascades, likely involving CREB, ∆FosB, BDNF, and numerous synaptogenesis molecules, both in the NAc to mediate postsynaptic adaptations and in innervating glutamatergic neurons to mediate presynaptic adaptations.
Effects of marijuana on the adolescent brain
An OR map included the voxels in clusters indicated as significant from any of the three constituent group maps. Mean activation levels of the clusters in the combined maps were calculated for each participant to allow a series of between-group ANOVAs to be conducted, using R (R Development Core Team, 2010), on these functionally defined ROIs. Due to significant differences (described below), total scores for the Buss Perry aggression scale and Barratt’s impulsiveness scale, and scaled participant socioeconomic status were included as covariates in all fMRI regions of interest ANOVAs for the neurobiology of cocaine addiction pmc STOPS, ERRORS and aggregate regions described below. Unless otherwise stated, pairwise post hoc differences between groups were assessed using Tukey’s Honest Significant Difference test (HSD). However, cocaine’s effects on neurovascular networks and their functional consequences have not been fully investigated. Attendees at the Sixth Annual Aspen Brain Forum “The Addicted Brain and New Treatment Frontiers” were privileged to hear NIH institute directors and political leaders join with clinical, translational, and basic researchers to discuss their varying perspectives on the neurobiology of addiction.
Heroin and prescription opioids
It is thereforeessential to conduct laboratory-based studies and translational studies to determine themolecular neurobiology and genetic factors contributing to addictions, including the role offunctional gene variants and epigenetic changes. The goal is to increase and optimize earlyinterventions for the therapy of chronic addictive diseases that are extraordinarily costly interms of human life, productivity, and expense to society (116). The preoccupation/anticipation stage has long been hypothesised to be a key element of relapse in humans, and defines addiction as a chronic relapsing disorder. Several other transcription factors, including c-Fos23 and NFκB24, as well as numerous forms of epigenetic regulation21, induced by exposure to cocaine are also potentially important, but are not discussed in this article. Rather, activation of CREB- and ΔFosB-signaling is used here as a prototype of how diverse types of transcriptional mechanisms contribute to the reemergence of developmental forms of plasticity in the NAc after exposure to cocaine or other drugs of abuse.
The role of dopamine in addiction
In the developed brain, expression of neurotrophins can be re-induced during reparative processes after brain injury26. Following exposure to cocaine or other drugs of abuse, one of the neurotrophins, brain-derived neurotrophic factor (BDNF), is upregulated in the NAc shell, ventral tegmental area (VTA), and related reward regions27-29 and directly implicated in cocaine self-administration, conditioned place preference, and locomotor sensitization30. While rodent studies have help determine how different subregions, of the PFC contribute to the development of CUD, translating these findings from rodents to humans has been challenging as the rodent networks need to be identified and mapped to the human brain (Box 1). Therefore, to determine how chronic cocaine use, abstinence, and relapse alters normal human brain function, clinical functional imaging studies have investigated resting functional connectivity. Hu et al., used fMRI to measure resting functional connectivity in 56 patients with CUD and reported that patients with higher impulsivity scores (BIS-11) or who used cocaine recently had increased connectivity between the striatum and dorsal lateral PFC (Hu et al., 2015).
Despite its complex nature, drug addiction is at its core an acquired behavioral state formed in vulnerable individuals after they repeatedly experience cascades of emotional and motivational extremes during bouts of drug exposure and withdrawal. A major focus of the field has, therefore, been on identifying and characterizing drug-induced neuroadaptations in the relevant brain regions important for addiction1,2. An interesting observation over the years is the implication of many widely reported mechanisms of neuroplasticity, known to mediate diverse aspects of normal learning and memory, in the development of drug addiction3. The medial prefrontal cortex in the rodent brain can be further subdivided into the Prelimbic (Prl) and infralimbic (IL) cortex.
1 Cocaine curtailed CBF velocity in microvessels and led to microischemia with repeated exposure
While this approach cannot reveal whether neurobiological differences in abstinent users preceded or arose from that abstinence, it can nonetheless characterize the functioning of those who have demonstrated the ability to abstain for either short or long periods. We hypothesized that any changes that may occur with prolonged abstinence or any pre-existing differences that might facilitate successful abstinence would be reflected in functional brain measurements of cognitive control. Most NMDARs in the developed brain are believed to be tetramers, containing two GluN1 and two GluN2 subunits. Following non-contingent exposure to cocaine, the cell surface levels of GluN1 and GluN2B subunits in NAc neurons is increased, accompanied by an increase in the ratio of GluN2B to GluN2A NMDAR-mediated synaptic currents51.
Arguably, these traits are related to executive dysfunction (Lyvers, 2000) wherein chronic cocaine users show deficits in the brain structures implicated in cognitive control of behavior, in particular, in regions thought to be the seat of higher executive brain functions (Miller and Cohen, 2001). Indeed, chronic cocaine users consistently demonstrate impairments on neuropsychological tests of executive function (Ardila et al., 1991; Di Sclafani et al., 2002; Yücel et al., 2007). Following exposure to cocaine, whole brain levels of ɑ1 subunits are reduced114, a change that can be regarded as reversing the development of GABAA receptors. By contrast, we showed recently that chronic cocaine induces in the NAc expression levels of ɑ1 subunits, with no change in ɑ2 subunits, and that this is accompanied by an increased frequency of spontaneous IPSCs of NAc neurons115.
Silent synapses
In general, younger synapses exhibit a higher ability to undergo experience-dependent plastic changes likely because different and presumably more efficient plasticity mechanisms are employed, some involving NMDARs59-61. In addition, internal or external experience may influence the stoichiometric ratio of GluN2B/2A of NMDARs to dictate the direction of synaptic plasticity (i.e., potentiation or depression). This has been extensively demonstrated in the visual cortex, in which excitatory synapses become more prone to undergo LTP in animals with little visual stimulation (animals reared in dark)62,63. This form of metaplasticity is proposed to be mediated by an increase in the GluN2B/2A ratio induced by dark-rearing, and preventing the shift of GluN2B/2A by knocking out GluN2A subunits erases the shift of the long-term potentiation (LTP) threshold in dark-reared animals63-66. Thus, a logical extension of these results is that an increase in the relative weight of GluN2B subunits in synaptic NMDARs facilitates the induction of LTP at excitatory synapses.
By decreasing neuronal background firing, stimulants, such as cocaine, may improve detection of salient stimuli leading to enhanced attention. However, with chronic cocaine exposure, the suppression of spontaneous neuronal activity in the ventromedial PFC or anterior cingulate cortex could also contribute to compulsive cocaine intake in addiction by promoting inflexible behaviors (Volkow et al., 2011). An enhanced signal-to-noise ratio to a conditioned stimulus (cocaine or its cues) could produce an accentuated response to it while reducing the influence of weaker competitive stimuli. This would further strengthen conditioning while reducing the salience of nonrelated drug stimuli accounting in part for the behavioral inflexibility observed in individuals suffering from addiction (Wise and Kiyatkin, 2011; Volkow et al., 2013).
Optogenetics takes advantage of light‐sensitive ion channels to perturb neural circuits by either depolarizing or hyperpolarizing neurons. The most common ion channel used is the H134 channelrhodopsin, which opens when illuminated with blue light and depolarizes neurons when optically stimulated. While the animal is traditionally tethered to a fiber optic cable inserted into the expressing brain region, this restraint can limit the types of behavior and analyses that can be conducted.181 Similar limitations can come from traditional drug self‐administration apparatus. Functional MRI studies reveal that teens who become heavy drinkers display lower levels of brain activity during visual working memory tasks even before they start drinking, without any deficit in performance.139 This suggests that they are not as cognitively involved in the nonrewarding task as those who do not become drinkers.
We elaborate here a heuristic framework based on the behavioural and imaging phenotypes of addiction as three stages linked by three functional domains that are mediated by three major neurobiological circuits (basal ganglia, extended amygdala, and prefrontal cortex) and numerous microcircuits of neuroplasticity. We outline 18 neurochemically defined mini circuits that can independently or interactively load the outputs of the major common neurobiological circuits to produce incentive salience and compulsive-like habits, negative emotional states of low reward and excessive stress, and compromised executive function. Identification of these molecular and neurochemical loads on the circuitry provides key information about vulnerability, resilience, treatment, and recovery from addiction, as well as information on how different drugs of abuse enter the overall addiction cycle.
Of potential translationalimportance, a recent article has suggested that high preexisting levels of PdynmRNA in the NAc (observed in a mouse strain) may protect against the acquisition ofmorphine-induced CPP (52). This suggests that highKOP-r/dynorphin tone may be protective at particular stages of addiction trajectory. The neuroanatomical localization of the immediate effects of cocaine overlap with those of theMOP-r agonists, with the nucleus accumbens (NAc) having been the most intensively studiedregion, as this region is thought to play an important role in the initial rewarding effects ofcocaine.
