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Ron Crystal (Weill Cornell Medical College) described work in developing vaccines against addictive drugs that would prevent them from entering and thus affecting the brain. Though the immune system does not readily produce good antibodies directed against addictive drugs, this hurdle is being addressed via two approaches. Diana Fishbein (Pennsylvania State University) described some of the efforts to use neuroscience research in drug prevention programs.

Both chemogenetic and pharmacological manipulation of glutamate transporters ameliorated these behaviors (Kenny et al., 2005; Miguens et al., 2008; Li et al., 2018). Specifically, activation of excitatory DREADD (Gq) selectively expressed in astrocytes in NAC prevented cue-induced reinstatement following extinction (Scofield et al., 2015). It is hypothesized that astrocytes enable increased intrasynaptic glutamate to feed back onto presynaptic inhibitory glutamate receptors preventing overexcitation by limiting the release of this excitatory transmitter (Knackstedt et al., 2009). In the absence of astrocytic stimulation, such as with chronic cocaine exposure, the excess of synaptic glutamate from the loss of presynaptic mediated inhibition of release may contribute to cocaine’s neurotoxicity through glutamate mediated excitotoxicity (Olney et al., 1991). These findings are consistent with theories implicating cocaine-induced damage to the mesencephalic dopamine (DA) system (Franken et al., 2005; Spanagel and Weiss, 1999).

The natural function of this response is to help keep us focused on activities that promote the basic biological goals of survival and reproduction. When a thirsty person drinks or someone has an orgasm, for example, dopaminergic cells flood the NAc with dopamine molecules. The receiving cells’ response makes us feel good and want to repeat the activity and reexperience that pleasure. Naltrexone (a potent MOP-r antagonist which also has considerable affinity at KOP-r) isapproved for the treatment of alcoholism and has had some effectiveness in reducing cocaine usein alcoholic patients (35).

Nora D Volkow

Taken together, these findings revealed that cocaine attenuated blood flow and depressed spontaneous neuronal activity at rest. Following stimulation, it did not change the neuronal response but reduced CBF responses, indicating that neurovascular coupling during stimulation was temporarily disrupted by cocaine. Neurovascular uncoupling could contribute to cocaine’s neurotoxicity, particularly for stimulation conditions when CBF might be insufficient to sustain the energetic demands of neuronal tissue (Chen et al., 2016).

• Prior studies have examined the effects of social isolation exposure to addictive drugs administered immediately following the isolation.108, 109, 110 However, discrete periods of stress can lead to long‐lasting changes in behavior that can persist even after the stress has been removed.
• A medication aimed at preventing or reversing such changes might be an effective approach for treating cocaine addiction.
• Efforts are under way in each of these areas, including clinical trials, but so far no clear breakthrough has been reported.
• Neurovascular uncoupling could contribute to cocaine’s neurotoxicity, particularly for stimulation conditions when CBF might be insufficient to sustain the energetic demands of neuronal tissue (Chen et al., 2016).

Cocaine decreases cerebral blood flow

To further characterize chronic cocaine’s effects, we measured the CBF responses along with oxygenated-hemoglobin (HbO2) and deoxygenated-hemoglobin (HbR) dynamics to forepaw electrical stimulation in naive and chronic cocaine treated animals. Our experiments showed that stimulation-evoked tissue HbO2 response decreased after cocaine in both control (naïve) and chronic groups compared to their baselines (prior to acute cocaine administration) and did not recover until 28 min post cocaine. The HbO2 decrease in the chronic cocaine group was slower (minimum value ∼16 min after cocaine) than in the control group (minimum value at 4–8 min). A CBF decrease was also observed after acute cocaine that partially recovered in the control group at 28 min and fully recovered in the chronic group at around 20 min.

The role of dopamine in addiction

Further, the presence of specific variants of multiple genes may enhance or decreasethe vulnerability to developing specific addictions. These gene variants may functionsynergistically with genetic polymorphisms involved in common comorbid conditions, such asanxiety or depression, and stress responsivity. Excitatory synapses in the NAc, formed from projections from several limbic and paralimbic brain regions (Fig. 1), are targets of drugs of abuse to induce addition-related behaviors.45 At a fully functional excitatory synapse, there are two major types of ionotropic glutamate receptors, NMDARs and AMPA receptors (AMPARs). Whereas AMPARs serve as the main mediator of excitatory synaptic transmission, NMDARs mainly function by regulating synaptic transmission through their coupled intracellular signaling mechanisms. In many brain regions, a signature feature of newborn excitatory synapses is the enrichment in GluN2B-containing NMDARs46. During synaptogenesis, GluN2B NMDARs may function to drive the formation of postsynaptic structures; overexpression of these receptors substantially increases the number of dendritic spines47.

INDIVIDUAL RISK FOR COCAINE ADDICTION

The most important goal for the next decade is to translate the knowledge we have already gained, along with any future advances we make, into better treatments for addiction. For example, variations in the genes encoding ΔFosB or any of hundreds of other genes affected by cocaine could conceivably contribute to the genetic risk for addiction. It is easy to imagine, by way of illustration, that an individual with a gene that expresses ΔFosB at high levels might be more prone to addiction; such a person would be analogous to the experimental mice that are engineered to produce more ΔFosB and are, consequently, more addiction prone. (Main panel) Cocaine causes the neurotransmitter dopamine to build up at the interface between VTA cells and NAc cells, triggering pleasurable feelings and NAc cellular activities that sensitize the brain to future exposures to the drug. Among the activities are increased production of genetic transcription factors, including ΔFosB; altered gene activity; altered production of potentially many proteins; and sprouting of new dendrites and dendritic spines. One particular part of the limbic system, the nucleus accumbens (NAc), seems to be the most important site of the cocaine high.

The accumulations of ΔFosB are much smaller in these regions than those that cocaine causes in the NAc, and their behavioral consequences are still unknown. It is tempting to speculate, though, that the presence of ΔFosB in the frontal cortex may contribute to the loss of frontal cortex control over cocaine urges that is seen in addiction. Although we do not yet have direct evidence of this possibility, it represents an additional mechanism by which ΔFosB may contribute to a state of addiction.

• DBS is currently used in the treatment of a number of neurological conditions, especially Parkinson’s disease, but also epilepsy and OCD.
• Most currently approved therapeutic agents in drug or alcohol addiction pharmacotherapy (i.e.,methadone, buprenorphine, and naltrexone) are opioid receptor ligands (Figure 1).
• Glutamate receptors and receptors for the brain’s natural opioid-like substances (e.g., κ opioid receptors) are two examples.
• Thesecompounds bind MOP-r (e.g., on interneurons in the substantia nigra and ventral tegmental area)and relieve GABAergic inhibition of dopaminergic neurons (46).

The 5 Hz and 50 Hz stimuli were used to mimic DA neuronal tonic and phasic firing in the VTA, respectively (Schultz, 2007). The high temporal and spatial resolutions of optical imaging techniques have greatly advanced our understanding of neural circuits (Knopfel, 2012). This includes giving researchers the ability to capture single neuronal Ca2+ transients from individual stimuli with “tonic-like” stimulation and neuronal activation evoked by “phasic-like” VTA stimulation. Second, we aim to identify neurochemically defined mini circuits that can independently or interactively mediate functional neuroplasticity within the three major circuits to produce incentive salience and compulsive-like habits, negative emotional states of low reward and excessive stress, and compromised executive function. Building on previous identification of the three overall domains, this Review provides a framework for integration of the ever-expanding neuroplastic complexity of motivational systems that are involved in addiction and for identification of new targets for diagnosis, treatment, and prevention of addiction. With respect to cocaine-generated silent synapses, Thomas, Malenka and colleagues initially showed that in mice with repeated injections of cocaine and a withdrawal period, re-exposure to cocaine decreases the AMPAR/NMDAR ratio at NAc excitatory synapses128.

After they become drinkers, however, their brain activity increases during these tasks, likely indicating that their brains are working harder to do the same task than their nondrinking counterparts. Eric Nestler (Icahn School of Medicine, Mount Sinai) is identifying genes that display changed transcriptional regulation in settings combining social isolation with drug exposure and genes involved in neuronal structure following chronic drug exposure. To measure histone modifications and other chromatin changes, he used RNA sequencing (RNA‐seq) to identify changes in RNA levels and chromatin immunoprecipitation (CHiP) followed by deep sequencing (ChiP‐seq). With repeated exposure to cocaine, these short- and intermediate-term effects cumulatively give rise to further effects that last for months or years and may be irreversible. Carriers of the 118G allele show an elevated sensitivity to pain and reduced analgesicresponse to opioids. Results of several studies suggest that the effect of the 118G allelemay vary among different opioids, different routes of drug administration, or different painetiologies, as recently reviewed (107).

Effects of marijuana on the adolescent brain

These cocaine-generated silent synapses appear to be present at most NAc excitatory inputs52, and are enriched in GluN2B NMDARs51. These findings suggest that exposure to cocaine not only rejuvenates excitatory synapses, but also creates highly efficient plasticity substrates to form new and potentially more durable adaptive changes. The concept of silent synapse was first raised by the finding of “ineffective synapses”, at which activation of presynaptic fibers fails to trigger postsynaptic responses124. Some of these ineffective synapses were later found to possess typical morphology of synapses, but with either a non-functional postsynaptic membrane or non-functional presynaptic release125,126, thus rendering them “silent”. Focusing on hippocampal CA1 neurons, two studies were published in 1995, demonstrating a form of AMPAR-silent excitatory synapses77,93.

Research to understand the neurobiology of cocaine addiction is essential because the available treatments do not work for everyone, and the surest path toward definitive treatments and even cures, as well as prevention, is through greater appreciation of the underlying neurobiological mechanisms (Goldstein, 2001; O’Brien, 2003). The identification of underlying biological mechanisms has been crucial for all major advances in treatment of other medical disorders, and there is no reason to think addiction will be any different. Cocaine affects the expression of numerous genes within the NAc, including some that influence the important neurotransmitter chemical glutamate and the brain’s natural opioid-like compounds produced by the body (Kalivas and McFarland, 2003; Nestler, 2001). In the author’s University of Texas laboratory, investigators have been studying cocaine’s effect on one particular genetic component, a protein called ΔFosB. Dopamine originates in a set of brain cells, called dopaminergic (dopamine-making) cells, that manufacture dopamine molecules and launch them into their surroundings. Some of the free-floating dopamine molecules latch onto receptor proteins on neighboring (receiving) cells.

Susan Weiss (National Institute on Drug Abuse) summarized thoughts that much of the current research into effects of policy is the neurobiology of cocaine addiction pmc inconclusive as it fails to take into account heterogeneity between states with regard to how new policy laws are implemented. In addition, the measures being collected, namely prevalence of drug use, do not always correspond to measures of harm, such as hospitalizations. State legislatures legalizing marijuana are not using evidence‐based policy research from tobacco and alcohol control. The legalization process, such as regulations on advertising, pricing, taxes, and potency, can have significant effects on mitigating the harm of legalized marijuana.