This brain region is thought to integrate different possible outcomes given a situation an individual has never experienced before (Levy and Glimcher, 2012). Following the event, the OFC might process the outcome and determine where errors were made in its prediction calculation in a process named “Credit error” (Lak et al., 2014). In addition, impaired OFC processing may lead to incorrect value attribution and the decision to pursue cocaine triggering relapse. Patrick J. Kennedy (One Mind, former United States representative from Rhode Island) oversaw the passage of the Mental Health Parity and Addiction Equity Act of 2008 (MHPAEA), which requires health insurance companies to cover mental health and substance use disorders in the same manner as physical disorders and diseases. Issues with the current state of mental health and addiction care include a need for more physicians willing to treat addiction, the lack of coordinated and integrated care with a patient’s primary provider, and the need to incorporate proven, evidence‐based methods into treatment.

Silent synapses

Chronic drug exposure-induced neurochemical changes in systems that are implicated in acute drug reward are called within-system neuroadaptations. Evidence from rodent studies suggests that drug-induced reinstatement is mediated by the circuit that links the prelimbic prefrontal cortex to the ventral striatum94 (for correspondence with humans, see figure 2; tables 1, 2, circuits 12 and possibly 13). In rats, neurotransmitter systems that are involved in drug-induced reinstatement involve a glutamatergic projection from the prelimbic prefrontal cortex to the nucleus accumbens that is modulated by dopamine activity through D1 and D2 receptors in the frontal cortex. Astrocytes display unique signaling dynamics in which calcium oscillations can propagate between astrocytes that are thought to represent gliotransmission (Xu et al., 2010; Srinivasan et al., 2015; Hanani and Verkhratsky, 2021). The regulation of glutamate, a bidirectional neuronal and glial transmitter, has been specifically implicated in addictive behaviors. The development of drug seeking and reinstatement have been linked to disruptions in astrocytic glutamate within the NAc.

The three approved agents for opioid dependence—methadone, buprenorphine, and naltrexone—each has different characteristics in practice. Methadone is the most tightly controlled and least accessible of the three, dispensed by the 1300 certified methadone clinics in the United States. In randomized controlled trials, methadone treatment has been shown to stabilize people in recovery and to reduce harms including HIV and HCV transmission.198 After terminating methadone treatment, 82% of patients return to heroin use within a year.199 Because of this, methadone is best used as a long‐term treatment. Because of its tightly controlled access, patients with more chaotic lifestyles who need close, daily supervision and who are prepared for long‐term treatment, including those with psychiatric illness or a high tolerance for opioids, may be suitable candidates for methadone treatment. Lovinger showed that the connection between the OFC and dorsomedial striatum (DMS) is critical for goal‐directed behavior.

• The regulation of glutamate, a bidirectional neuronal and glial transmitter, has been specifically implicated in addictive behaviors.
• They occur in the limbic system, the primary site for cocaine effects, and are sufficiently fundamental and long-lasting to contribute significantly to the transition from drug abuse to addiction.
• Patrick J. Kennedy (One Mind, former United States representative from Rhode Island) oversaw the passage of the Mental Health Parity and Addiction Equity Act of 2008 (MHPAEA), which requires health insurance companies to cover mental health and substance use disorders in the same manner as physical disorders and diseases.
• They further regulate the amount of dopamine available to stimulate the receptors by pulling some previously released dopamine molecules back into themselves.

Effects of marijuana on the adolescent brain

This is supportiveof long-lasting adaptations in this crucial dopaminergic end point in the context of repeatedexposure to and prolonged withdrawal from a prescription opioid. Addiction is characterized by an uncontrollable, compulsive drive to obtain and consume an abused drug, despite the profound negative health and social consequences likely to ensue (Everitt et al., 2001; Garavan and Stout, 2005; Goldstein and Volkow, 2002). Substance dependent individuals preferentially select actions that yield short-term gains, though they may lead to long-term losses (Bechara and Damasio, 2002). They are more likely to engage in risky behavior (Lane and Cherek, 2000) and show less consideration of the consequences of their actions (Petry et al., 1998).

Computational modeling of dopamine cells

Recent results suggest that some of these newly inserted CP-AMPARs are recruited by cocaine-generated silent synapses during cocaine withdrawal, resulting in maturation of these synapses and remodeling of affected NAc circuits102. Unlike CREB, whose activation is transient, ΔFosB, because of its unusual stability, accumulates gradually in response to repeated exposure to cocaine or other abused drugs12,21. ΔFosB has been proposed to contribute importantly to certain long-lasting cellular and behavioral alterations following drug exposure.

Abstinence may place extra demands on cognitive control and, specifically, the monitoring processes subserved by the ACC suggesting that the increased activity in this region, as indicated by the linear trend in the activity of the aggregate ACC region, may be a defining characteristic of successful abstinence. MPFC, the medial prefrontal cortex which comprises the infralimbic and prelimbic PFC; OFC, the orbitofrontal cortex; Hipp, the hippocampus; BLA, the basolateral amygdala; and Thal, the thalamus. Other major inputs to the NAc include the VTA (ventral tegmental area) and Hypo (hypothalamus), which send dopaminergic and peptidergic inputs to the NAc, although some of these projections may also be glutamatergic. In conclusion, it is clear that cocaine use poses a significant risk to cerebrovascular health, not just because of its direct effects but also due to the cascade of physiological responses it triggers. Comprehensive studies, innovative imaging techniques, and a deeper understanding of the physiological changes induced by cocaine are paramount in designing effective treatments and interventions.

Further Clues About ΔFosB’s Significance

Addictive diseases, including addiction to heroin, prescription opioids, or cocaine, posemassive personal and public health costs. Addictions are chronic relapsing diseases of thebrain caused by drug-induced direct effects and persisting neuroadaptations at the epigenetic,mRNA, neuropeptide, neurotransmitter, or protein levels. These neuroadaptations, which can bespecific to drug type, and their resultant behaviors are modified by various internal andexternal environmental factors, including stress responsivity, addict mindset, and socialsetting. Here, we review the molecular neurobiology andgenetics of opiate addiction, including heroin and prescription opioids, the neurobiology of cocaine addiction pmc and cocaineaddiction.

• In the PFC, dopamine (DA) has been shown to suppress spontaneous neuronal firing of pyramidal neurons, an effect that was enhanced by cocaine (Kroener et al., 2009).
• In 1931, Edwin Holt suggested in his well-known essay, entitled “Animal drive and the learning process,” that some embryonic or developmental mechanisms might be used during learning4.
• Inhibitory control has also been identified as a risk factor for addiction that precedes drug use (Dalley et al., 2007; Tarter et al., 2003; Verdejo-García et al., 2008).
• Participants with any history of neurological disorders, psychiatric illness, head trauma, contra-indications for MRI, or HIV seropositivity were excluded.
• 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).

1 Cocaine curtailed CBF velocity in microvessels and led to microischemia with repeated exposure

Activation in thedopaminergic mesocortico/mesolimbic and nigrostriatal systems, either directly in the case ofcocaine or indirectly for heroin/prescription opioids or alcohol, appears to be a commonneurobiological consequence of exposure to drugs of abuse (5–7). Differences between the short- and long-abstinence groups in the patterns of functional recruitment suggest different cognitive control demands at different stages in abstinence. Short-term abstinence showed increased inhibition-related dorsolateral and inferior frontal activity indicative of the need for increased inhibitory control while long-term abstinence showed increased error-related ACC activity indicative of heightened behavioral monitoring.

Neurobiological mechanisms of the withdrawal/negative affect stage

These results suggest that excitatory synapses in the NAc become re-enriched in GluN2B-containing NMDARs following repeated exposure to cocaine. Additional evidence suggests that cocaine-induced re-enrichment of synaptic GluN2B is mediated by activation of CREB52. The genes encoding GluN1 and GluN2B, but not GluN2A, contain a CREB-binding site, which can be activated upon CREB activation53. In NAc slice cultures, activation of CREB increases protein levels of GluN1 and GluN2B subunits, but not GluN2A subunits52,54.

The authors would like to thank NIDA’s Drug Supply Program for providing cocaine used in the preclinical images. The ongoing cannabis legalization efforts offer an opportunity for policymakers to learn from lessons in alcohol and tobacco regulation. However, Kleiman argues that, owing to the influence of corporate interests, which focus on the small percentage of heavy (and profitable) users, effective measures to moderate cannabis use have not been implemented.

Still other approaches attempt to take advantage of the fact that cocaine’s acute effects on the brain involve increased activation of dopamine receptors. NAc nerve cells make five types of dopamine receptors; drugs that affect the functioning of one or more of them could, in theory, produce a palliative effect on cocaine addiction. Efforts are under way in each of these areas, including clinical trials, but so far no clear breakthrough has been reported. Anti-reward circuits are engaged as neuroadaptations during the development of addiction, producing aversive or stress-like states. These aversive states are manifest when the drug is removed during acute withdrawal but also during protracted abstinence.2 Thus, the within-system and between-system construct could be equally valid for the preoccupation/anticipation stage. The combination of decreases in reward function and increases in stress function in the motivational circuits of the ventral striatum, extended amygdala, and habenula is a powerful trigger of negative reinforcement that contributes to compulsive drug-seeking behaviour and addiction.

Implications for medication development

While a medication that counters the powerful biological forces of addiction is essential, it will not be a “magic bullet.” People in recovery from addiction will always need support and rehabilitation to rebuild their lives. Presumably, effective psychosocial treatments for addiction work by causing changes in the brain, perhaps even some of the same changes that will be produced by effective medications. While very little information is currently available on the neurobiological mechanisms underlying psychosocial treatments, this is a topic of great interest. One cell differs from another—a liver cell looks and acts differently from a brain cell, for example—because, in each, certain genes are turned on, while others are turned off. We identified seminal articles published in peer-reviewed journals and reports that were pertinent to the neurobiology of addiction using in-house expertise, consultations with other experts in the field, and searches of key databases, including PubMed.