In addressing Substance Use Disorders (SUDs), a significant public health concern, it becomes important to explore the neuroscience of addiction and translate these insights into clinical practice. This approach is crucial, as SUDs are deeply entrenched in the fundamental biological drive to seek pleasure and avoid harm.
This article examines the neuroscientific perspective on how substances such as alcohol, cannabis, and others influence the brain’s reward system, triggering a cascade of neuroadaptations contributing to the development of addiction.
While we focus on substance addiction in this article, the principles apply to other disorders of addiction, such as pathological gambling and internet addiction disorder.
NEUROSCIENCE OF PLEASURE AND PAIN
Like all conscious entities, humans have evolved within their psychological framework to inherently gravitate towards positive stimuli and avoid negative ones, a tendency deeply structured to avert pain and pursue pleasure.
This pursuit of pleasure, instinctual and hereditary, aligns with Freud’s pleasure principle, a cornerstone of psychoanalytic theory.
The pleasure principle posits that the fundamental human drive to seek pleasure and avoid pain is an unconscious force that persistently influences behaviour. Freud asserted that this principle operates throughout an individual’s lifespan, subtly directing actions and moulding subjective experiences.
This drive for pleasure is considered a primary motivator in the development of human behaviour, exerting a significant influence on individuals’ choices and actions in pursuit of hedonic fulfilment.
This adaptive behaviour, while critical for survival, also predisposes individuals to the risk of addiction. Across species, the response to rewarding stimuli (like food and *****) and aversive stimuli (such as pain and threats) is remarkably conserved.
In terms of pain and reward dynamics, the pleasure principle aligns with the opponent-process theory (OPT) of emotion. This theory suggests that hedonic tone results from valuationally opposite reward and aversion processes that regulate emotional and motivational homeostasis. According to the OPT, repeated activation of one process can lead to its attenuation and the concurrent intensification of the opponent process.
This concept is central to the neurobiological model of addiction proposed by Koob and colleagues, which underscores the intricate interaction between the reward and stress systems within the brain, which we will cover later.
This article examines the neuroscientific perspective on how substances such as alcohol, cannabis, and others influence the brain’s reward system, triggering a cascade of neuroadaptations contributing to the development of addiction.
While we focus on substance addiction in this article, the principles apply to other disorders of addiction, such as pathological gambling and internet addiction disorder.
NEUROSCIENCE OF PLEASURE AND PAIN
Like all conscious entities, humans have evolved within their psychological framework to inherently gravitate towards positive stimuli and avoid negative ones, a tendency deeply structured to avert pain and pursue pleasure.
This pursuit of pleasure, instinctual and hereditary, aligns with Freud’s pleasure principle, a cornerstone of psychoanalytic theory.
The pleasure principle posits that the fundamental human drive to seek pleasure and avoid pain is an unconscious force that persistently influences behaviour. Freud asserted that this principle operates throughout an individual’s lifespan, subtly directing actions and moulding subjective experiences.
This drive for pleasure is considered a primary motivator in the development of human behaviour, exerting a significant influence on individuals’ choices and actions in pursuit of hedonic fulfilment.
This adaptive behaviour, while critical for survival, also predisposes individuals to the risk of addiction. Across species, the response to rewarding stimuli (like food and *****) and aversive stimuli (such as pain and threats) is remarkably conserved.
In terms of pain and reward dynamics, the pleasure principle aligns with the opponent-process theory (OPT) of emotion. This theory suggests that hedonic tone results from valuationally opposite reward and aversion processes that regulate emotional and motivational homeostasis. According to the OPT, repeated activation of one process can lead to its attenuation and the concurrent intensification of the opponent process.
This concept is central to the neurobiological model of addiction proposed by Koob and colleagues, which underscores the intricate interaction between the reward and stress systems within the brain, which we will cover later.
The model suggests addiction as a disorder of hedonic homeostasis, wherein the chronic pursuit of pleasure via substance use paradoxically results in heightened stress and diminished reward sensitivity. This dysregulation fuels compulsive drug-seeking behaviour and a challenging addiction cycle, mediated by the brain’s reward pathways, including dopamine neurotransmitter systems. These pathways, altered by substances of *****, drive the excessive pursuit of pleasure and the neglect of potential harm. Human innovation has led to the extraction and refinement of substances that are more compelling than natural rewards.
High-strength alcoholic beverages, cigarettes, and technologically advanced drug delivery systems, such as syringes and vaping devices, provide potent stimuli that can overpower the brain’s reward system.
Additionally, modern chemistry has introduced new, highly potent psychoactive substances, including synthetic opioids and cannabinoids, which can influence reward pathways more robustly than ever before, significantly increasing the risk of addiction.
Common substances leading to SUD include alcohol, tobacco, caffeine, cannabis, methamphetamine, heroin, and cocaine.
The availability of highly addictive drugs, combined with certain environmental factors (such as stress and peer influence) and individual vulnerabilities (including mental health conditions, chronic pain, genetic predisposition, age, and gender), significantly impact the likelihood of substance experimentation and the development of SUDs.
TERMS AND DEFINITIONS
Varying definitions of substance-related disorders have evolved, reflecting advancements in our understanding of addiction and its complexities. Substance addiction, commonly known as drug addiction, is a chronic relapsing disorder characterised by compulsive drug seeking, a loss of control in managing intake, and withdrawal symptoms upon cessation.
Classified as a chronic disease, drug addiction affects a significant portion of the population. It is associated with numerous secondary health issues, societal challenges, and a decline in work ethic, all carrying substantial societal costs.
The National Institute on Drug ***** (NIDA) describes addiction as…
High-strength alcoholic beverages, cigarettes, and technologically advanced drug delivery systems, such as syringes and vaping devices, provide potent stimuli that can overpower the brain’s reward system.
Additionally, modern chemistry has introduced new, highly potent psychoactive substances, including synthetic opioids and cannabinoids, which can influence reward pathways more robustly than ever before, significantly increasing the risk of addiction.
Common substances leading to SUD include alcohol, tobacco, caffeine, cannabis, methamphetamine, heroin, and cocaine.
The availability of highly addictive drugs, combined with certain environmental factors (such as stress and peer influence) and individual vulnerabilities (including mental health conditions, chronic pain, genetic predisposition, age, and gender), significantly impact the likelihood of substance experimentation and the development of SUDs.
TERMS AND DEFINITIONS
Varying definitions of substance-related disorders have evolved, reflecting advancements in our understanding of addiction and its complexities. Substance addiction, commonly known as drug addiction, is a chronic relapsing disorder characterised by compulsive drug seeking, a loss of control in managing intake, and withdrawal symptoms upon cessation.
Classified as a chronic disease, drug addiction affects a significant portion of the population. It is associated with numerous secondary health issues, societal challenges, and a decline in work ethic, all carrying substantial societal costs.
The National Institute on Drug ***** (NIDA) describes addiction as…
From a diagnostic perspective, the term addiction is now encompassed by the term substance use disorders. The ***** and dependence classifications of the DSM-IV were intended to be related yet distinct clinical syndromes.
***** was defined as a maladaptive pattern of use leading to clinically significant impairment or distress over a 12-month period. Dependence was defined as continued substance use despite behavioural impairment or distress in the same 12-month period. In 2013, DSM-5 combined what was previously conceptualised as two separate and hierarchical disorders (substance ***** and substance dependence) into one construct, defining substance use disorders on a range from mild to moderate to severe, with the severity of addiction depending on how many of the established criteria apply.
The DSM-5 outlines Substance Use Disorder (SUD) as a chronic relapsing neuropsychiatric disorder with three core characteristics:
***** was defined as a maladaptive pattern of use leading to clinically significant impairment or distress over a 12-month period. Dependence was defined as continued substance use despite behavioural impairment or distress in the same 12-month period. In 2013, DSM-5 combined what was previously conceptualised as two separate and hierarchical disorders (substance ***** and substance dependence) into one construct, defining substance use disorders on a range from mild to moderate to severe, with the severity of addiction depending on how many of the established criteria apply.
The DSM-5 outlines Substance Use Disorder (SUD) as a chronic relapsing neuropsychiatric disorder with three core characteristics:
- Compulsive seeking and taking of drugs
- Loss of control and craving in limiting intake
- Emergence of negative emotion states (e.g. dysphoria, anxiety, and irritability) and stress
A problematic pattern of substance use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12‐month period:
- The substance is often taken in larger amounts or over a longer period than was intended.
- There is a persistent desire or unsuccessful efforts to cut down or control the substance use.
- A great deal of time is spent in activities necessary to obtain the substance, use the substance, or recover from its effects.
- Craving, or a strong desire or urge to use the substance.
- Recurrent use of the substance resulting in a failure to fulfill major role obligations at work, school, or home.
- Continued use of the substance despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance.
- Important social, occupational, or recreational activities are given up or reduced because of use of the substance.
- Recurrent use of the substance in situations in which it is physically hazardous.
- Use of the substance is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance.
- Tolerance, as defined by either of the following:
— a need for markedly increased amounts of the substance to achieve intoxication or desired effect.
— markedly diminished effect with continued use of the same amount of the substance. - Withdrawal, as manifested by either of the following:
— the characteristic withdrawal syndrome for the substance.
— the substance (or a closely related one) is taken to relieve or avoid withdrawal symptoms.
To understand the mechanisms underlying addiction, it is essential to explore the concept of the reward cascade, as addiction, fundamentally a conditioned behaviour, hinges on the process of reward consolidation. Without the reinforcement provided by rewards, the learned behaviours that characterise addiction would not take hold. The neuroscientific understanding of addiction is intricate, with the Reward Cascade being a central component.
The Reward Cascade
Dopamine (DA) is central to the reward mechanisms triggered by drugs of *****, as every substance known for its addictive potential has been shown to increase levels of DA in the brain.
The mesolimbic dopamine pathway, extending from the ventral tegmental area (VTA) of the midbrain to the forebrain regions such as the Nucleus Accumbens (NAc), amygdala and medial prefrontal cortex (mPFC), is the crucial component of the brain reward and reinforcement system. These substances initially influence DA neurons within the ventral tegmental area (VTA). The subsequent impact of this interaction is the release of DA in the nucleus accumbens (NAc), a core region of the brain’s reward system.
The elevation of DA by these drugs is not uniform but varies depending on their molecular targets and the specific pharmacological effects they impart. Repeated use of addictive drugs leads to significant neuroadaptations across several neurotransmitter systems. Glutamatergic, GABAergic, opioidergic, endocannabinoid, cholinergic, serotonergic, and noradrenergic systems undergo changes that influence the brain’s affective and hedonic pathways and its aversive response circuits.
The mesolimbic dopamine pathway, extending from the ventral tegmental area (VTA) of the midbrain to the forebrain regions such as the Nucleus Accumbens (NAc), amygdala and medial prefrontal cortex (mPFC), is the crucial component of the brain reward and reinforcement system. These substances initially influence DA neurons within the ventral tegmental area (VTA). The subsequent impact of this interaction is the release of DA in the nucleus accumbens (NAc), a core region of the brain’s reward system.
The elevation of DA by these drugs is not uniform but varies depending on their molecular targets and the specific pharmacological effects they impart. Repeated use of addictive drugs leads to significant neuroadaptations across several neurotransmitter systems. Glutamatergic, GABAergic, opioidergic, endocannabinoid, cholinergic, serotonergic, and noradrenergic systems undergo changes that influence the brain’s affective and hedonic pathways and its aversive response circuits.
Endogenous opioid system and its effects
- Modulates the mesolimbic DA system, assigning hedonic values to rewards and aiding decision-making.
- Opiates increase DA indirectly by inhibiting GABAergic interneurons in the VTA.
- Mu opioid receptors (MOR) on NAc neurons are linked to the rewarding effects of opioids and analgesia.
- Delta opioid receptors (DOR) are implicated in analgesia, anxiolysis, and kappa opioid receptors (KOR) associated with dysphoric responses associated with addiction.
The endogenous cannabinoid system (ECS) interaction
- Modulates neurotransmitter systems such as GABA, glutamate, and DA in the mesolimbic pathway.
- CB1 receptor activation in cortical glutamatergic afferents inhibits DA release in the NAc, affecting reward behaviours.
- Cannabinoids act differently on GABA and Glu terminals due to variations in CB1 receptor-to-vesicle ratios.
- Both CB1 and MOR activation on GABA neurons can stimulate DA release by disinhibiting ACh, whereas activation on ACh interneurons could decrease DA levels in the accumbens.
- Cannabinoids like 2-archidonoylglycerol (2-AG) can disinhibit substantia nigra GABA-A neurons, leading to an increase in DA.
Glutamate and GABA
- The activity of DA neurons is regulated by local and long-range glutamatergic (excitatory) and GABAergic (inhibitory) inputs from multiple brain regions, including the prefrontal and orbitofrontal cortex and the rostromedial tegmental nucleus.
- Glutamatergic inputs to dopamine (DA) neurons in the ventral tegmental area (VTA) and medium spiny neurons (MSNs) in the nucleus accumbens (NAc) play a role in behavioural adaptations associated with reward sensitivity and habit formation, hallmarks of addiction.
- Excitatory glutamate stimulates NMDA receptors in the interneuron, resulting in GABA release.
- GABA, in turn, inhibits dopamine release from the mesolimbic pathway. Thus, the glutamatergic pathway acts as a break in the mesolimbic dopamine pathway.
- The glutamatergic system plays an essential role in learning through NMDA-dependent pathways, essentially reinforcing the learned associations between drug use and positive reinforcement.
- Concurrently, the GABAergic system inhibits action potential transmission, providing a modulatory balance that can be disrupted by addictive substances.
- This complex interplay is crucial to our broader understanding of addiction and will be explored in more detail later in this article.
- Neuromodulatory inputs such as norepinephrine, serotonin, acetylcholine, neuropeptides (oxytocin, neurotensin, orexin), and hormones (insulin, leptin) also influence DA neuron activity.
ROLE OF DOPAMINE IN LEARNING, BEHAVIOUR AND ADDICTION
Dopamine (DA) is one of the oldest neurotransmitters and is central to the phenomena of addiction, influencing behaviour and cognition. In the mammalian brain, dopamine accounts for 80% of catecholamine content, signifying its place as the dominant neurotransmitter.
Dopamine’s presence and function are incredibly conserved across the animal kingdom, indicative of its fundamental role in life processes. Dopamine’s evolutionary journey began around 600 million years ago, correlating with the emergence of motility in multicellular organisms. The architectural design of the basal ganglia in vertebrates is remarkable. It is characterised by dual output pathways that contrast with the singular direct pathway found in simpler species with less complex nervous systems.
The emergence of a secondary or indirect pathway in vertebrates signifies a significant evolutionary advance. This indirect pathway is integral to the nuanced and precise response selection for higher cognitive processes. This evolution of the basal ganglia’s indirect pathway is believed to be foundational to the sophisticated cognition observed in mammals, including humans, reflecting the intricacy of neural development through evolutionary history.
The axiom “To think is to move” underscores dopamine’s pivotal role in initiating and controlling movement.
Dopamine’s presence and function are incredibly conserved across the animal kingdom, indicative of its fundamental role in life processes. Dopamine’s evolutionary journey began around 600 million years ago, correlating with the emergence of motility in multicellular organisms. The architectural design of the basal ganglia in vertebrates is remarkable. It is characterised by dual output pathways that contrast with the singular direct pathway found in simpler species with less complex nervous systems.
The emergence of a secondary or indirect pathway in vertebrates signifies a significant evolutionary advance. This indirect pathway is integral to the nuanced and precise response selection for higher cognitive processes. This evolution of the basal ganglia’s indirect pathway is believed to be foundational to the sophisticated cognition observed in mammals, including humans, reflecting the intricacy of neural development through evolutionary history.
The axiom “To think is to move” underscores dopamine’s pivotal role in initiating and controlling movement.
Structural organization of DA-neurons
Last edited: