Neuropharmacology of Drug Abuse

Question 1

Identify Neuroanatomical Regions Involved in Addiction and Discuss Their Function

Answer 1

1. Ventral Tegmental Area (VTA)

VTA is a group of neurons located in the midbrain that plays a crucial role in reward circuit of the brain. It is primarily involved in the release of dopamine

• Function in Addiction: Activated by psychoactive drugs which leads to the release of dopamine in other brain regions, notably the nucleus accumbens. This dopamine release is associated with the euphoria commonly experienced during drug use

(Volkow, Koob & McLellan, 2016) provides a comprehensive review of the neurobiological advances in understanding addiction as a brain disease, focusing on the role of the brain’s reward system, including the VTA and nucleus accumbens.

2. Nucleus Accumbens (NA)

NA situated in the basal forebrain is a key component of the reward circuit. It is involved in reward, pleasure, reinforcement learning and motivation.

• Function in Addiction: Drugs of abuse cause an increased release of dopamine in the nucleus accumbens, reinforcing drug taking and promoting repeated use. Changes in this area can lead to the compulsive drug seeking, typical of addiction.

(Koob & Volkow., 2010) Neurocircuitry of Addiction. A detailed review of the neurocircuitry involved in addiction, detailing the roles of the prefrontal cortex, nucleus accumbens, and amygdala in the pathology of addiction.

3. Prefrontal Cortex

Involved in complex behaviours including decision making, impulse control and self-regulation. It moderates social behaviour and then the expression of personality

• Function in Addiction: Shows reduced activity in addiction, resulting in poor decision-making, increased impulsivity and diminished ability to resist urges - perpetuating addictive behaviours

(Everitt & Robbins, 2005). highlights the role of the prefrontal cortex and basal ganglia in the transition from voluntary drug use to compulsive drug taking

4. Extended Amygdala

Role in processing emotion, including amygdala and bed nucleus of the stria terminalis (BNST). Stress and fear contributing to aspects of drug withdrawal and craving

• Function in Addiction: Negative reinforcement. Affects the emotional memory of drug experiences and is crucial in the negative emotional state such as anxiety and irritability that accompanies withdrawal. Drive relapse during periods of stress or exposure to cues

(Kalivas & Volkow, 2005) An exploration of how changes in the brain circuitry affect motivation and choice, implicating regions such as the insula and extended amygdala.

5. Hippocampus

Involved in forming new memories and connecting emotions and senses, such as smell and sound

• Function in Addiction: Negative reinforcement. In drug addiction, the hippocampus can associate specific environments and emotional states with drug use, which can trigger cravings and relapse when the individual is exposed to similar situations

(Goldstein & Volkow, 2002)

6. Insula

Contribute to the emotional urges that drive drug-seeking behaviour and is thought to integrate environmental, emotional and bodily cues with drug use memory

• Function in Addiction: Activation of the insula is linked to cravings and the urge to use drugs when presented with cues. Damage to the insula can reduce cravings and may lead to a disruption in addictive behaviours

Question 2

Discuss the Effect of Acute Administration of Drugs of Abuse on the Brain

Answer 2

1. Dopaminergic System Activation

Most drugs of abuse directly or indirectly target the brain’s reward system by increasing dopamine levels, particularly in the nucleus accumbens and other parts of the mesolimbic pathway.

This increase in dopamine contributes to the feelings of euphoria and pleasure that are commonly associated with drug use

• Mechanism: Drugs like cocaine and amphetamines inhibit the reuptake of dopamine or enhance its release, leading to elevated dopamine levels in synaptic clefts. Overstimulating the reward circuitry

(Volkow et al., 2009) discusses the pivotal role of dopamine in drug reward and addiction, supported by neuroimaging studies.

2. Alteration of Glutamate Transmission

Glutamate is the primary excitatory neurotransmitter in the brain and is critical for synaptic plasticity, learning and memory. Acute drug use can disrupt glutamate homeostasis

• Impact: Substances such as alcohol may inhibit glutamate receptor activity (Such as NMDA receptors), which can lead to cognitive impairment and sedative effects. Conversely, stimulants may increase glutamate release, enhancing neuronal excitability and activity

(Kalivas, 2009) presents a detailed review of how dysregulation of glutamate transmission at synapses in key brain regions contributes to addiction

3. Modulation of GABAergic Transmission

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. Many drugs of abuse affect GABAergic transmission, leading to anxiolytic and sedative effects

• Mechanism: Drugs like benzodiazepines and alcohol enhance the effect of GABA by increasing GABA receptor activity, which generally depresses nervous system activity, leading to relaxation, decreased anxiety and lowered inhibitions.

(Kumar et al., 2009) explores the influence of GABAergic systems on alcohol use and dependency, illustrating the broader impact on inhibitory neurotransmission.

4. Opioid Receptor Activation

Opioids like heroin and morphine exert their effects primarily by binding to opioid receptors in the brain, mimicking the action of endogenous opioids (endorphins). Involved in pain relief, reward and addictive behaviours

• Effects: Activation of mu-opioid receptors leads to acute pain relief, euphoria, and a profound sense of well-being. However this can also depress respiration and affect the regulatory functions of the brainstem

(Williams et al., 2013) provides comprehensive insights into the regulation of mu-opioid receptors and their role in the pharmacological effects of opioids.

5. Serotonergic System Changes

Psychoactive drugs like hallucinogens and MDMA primarily affect the serotonergic system, which influences mood, emotion and perception

• Consequences: Drugs like LSD and MDMA increase serotonin levels, which can cause altered sensory perception and emotional upliftment. However, acute spikes in serotonin can also lead to confusion, agitation and paranoia.

(Liechti, 2015) reviews the pharmacology of designer drugs, including their effects on the serotonergic system.

_6. Impact on the Stress Axis (HPA Axis)

• Responses: Stimulants like cocaine activate the HPA axis, leading to increased production of cortisol, heightening alertness and mood temporarily. Conversely, opioids tend to inhibit HPA axis, reducing stress response

(Koob & Kreek, 2007) discusses how acute and chronic stress influences the reward pathways and the hypothalamic-pituitary-adrenal axis in the context of addiction.

Question 4

Discuss the Effect of Chronic Administration of Drugs of Abuse on the Brain (Dependence)

Answer 4

1. Neurochemical Changes

Chronic drug uses causes sustained increases in neurotransmitter levels, particularly dopamine, which in turn leads to neurochemical imbalances

• Downregulation of Receptors: Decrease in receptor density (downregulation). Chronic stimulation of dopamine receptors can lead to fewer D2 receptors in the brain, diminishing the pleasurable effects of drugs and every activities, thereby increasing drug intake to achieve the same high
• Alterations in Neurotransmitter Production: Prolonged opioid use alters endorphin levels, which can exacerbate feelings of pain when the drug is absent

(Nestler, 2001) delves into the molecular and cellular changes induced by chronic drug use, emphasizing the alterations in neurotransmitter systems and receptor downregulation.

2. Neuroplasticity and Structural Changes

Chronic drug use can lead to long-term changes in brain structure and function, affecting areas involved in judgement, decision making, learning, memory and behaviour:

• Neural Circuitry Changes: Drugs alter the connectivity and function of neural circuits, especially those linking the reward regions to the prefrontal cortex. This can impair cognitive functions and emotional regulation, increasing compulsivity and the risk of addiction
• Brain Volume Reduction: Imaging studies have shown that chronic drug use can lead to reductions in brain volume, particularly in areas like the cortex and hippocampus, which are critical for cognitive functions and memory

(Robinson & Kolb, 2004) highlights the impact of drugs of abuse on structural plasticity in the brain, including changes in dendritic structure and brain volume associated with addiction.

3. Behavioural and Cognitive Impairments

The alterations in brain structure and function correlate with significant behavioural and cognitive impairments:

• Impaired Executive Functions: Due to changes in the prefrontal cortex, individuals may suffer from poor impulse control, impaired judgement and decision-making abilities, perpetuating the cycle of addiction
• Memory Issues: Changes in hippocampus can affect an individual’s ability to form new memories or recall past experiences without drug-related cues, complicating recovery efforts

(Goldstein and Volkow, 2011) reviews neuroimaging studies that document the impact of drug addiction on the prefrontal cortex, linking these changes to behavioural and cognitive impairments seen in addicted individuals.

4. Changes in Stress Responsiveness

Chronic drug use impacts the HPA axis, altering stress response:

• Increased Stress Sensitivity: As the reward pathways become less sensitive, systems that mediate stress responses become more sensitive, leading to increased anxiety and stress levels when not using the drug - driving further drug use

(Koob, 2008) explores the role of brain stress systems, including the HPA axis, in the development and persistence of drug addiction, highlighting increased stress sensitivity as a result of chronic drug exposure

5. Tolerance and Withdrawal

as the body adapts to the drug, tolerance develops, requiring larger doses to achieve the same effect

• Withdrawal Symptoms: When drug use is reduced or stopped, users may experience severe physical and psychological symptoms due to the body’s reliance on the drug to function normally. Withdrawal symptoms can include pain, seizures, depression, anxiety and cravings which often lead to relapse.

(Koob and Le Moal, 2008) provides a comprehensive overview of the neurobiological mechanisms of addiction, focusing on the development of tolerance and the physiological basis of withdrawal symtpoms

Question 5

Identify Neurobiological Changes That Take Place During the Transition from Non-Addicted to Addicted Brain

Answer 5

transformation is marked by modifications in neural circuits that are critical for reward, motivation, learning, and memory

1. Neuroadaptation in Dopamine Systems

Alterations of dopamine signalling. Initially, drugs of abuse cause a substantial increase in dopamine, leading to intense feelings of pleasure. Over time, the brain adapts to these high levels of dopamine by reducing dopamine receptor availability and dopamine production - dopamine downregulation

• Implications: Reduction can dull the brain’s response to natural rewards and increase the threshold for pleasure, driving individuals to continue using drugs to achieve baseline levels of dopamine function and to avoid feelings of discomfort and depression associated with low dopamine levels.

(Volkow, Koob & McLellan, 2016) review of the brain disease model of addiction, emphasizing the role of dopamine in addiction and how chronic exposure to drugs leads to neuroadaptations that decrease the brain’s sensitivity to natural rewards.

2. Alterations in Glutamate Transmission

Glutamate is crucial for synaptic plasticity, essential for learning and memory. Chronic drug use disrupts glutamate homeostasis, leading to changes in the synaptic architecture.

• Consequences: Impair the brain’s ability to learn new information and make adaptive decisions, facilitating compulsive drug-seeking behaviours despite adverse consequences

(Kalivas, 2009) discusses how disruptions in glutamate transmission due to drug use lead to synaptic changes that affect both addiction development and the potential for recovery.

3. Changes in Brain Structure and Function

Chronic exposure to drugs leads to structural changes in several regions, substance dependence is associated with volumetric reductions in prefrontal cortex and hippocampus and changes in white matter integrity.

• Effects: Correlates with cognitive impairment including problems with decision-making, judgement, impulse control and emotional regulation - compulsivity seen in addiction

(Ersche et al., 2013) examines the structural brain changes in individuals with drug dependence, highlighting reductions in brain volume and alterations in white matter integrity.

4. Stress Response Alterations

Addiction affects the HPA axis, Chronic drug use can sensitise the brain to stress, making stress response more hyperactive during drug withdrawal and less responsive to normal stressors

• Results: This heightened stress sensitivity can exacerbate drug cravings and withdrawal symptoms, making abstinence more challenging and relapse more likely

(Koob & Kreek, 2007) explore how chronic drug use affects the HPA axis and enhances stress responses, contributing significantly to addiction pathology.

5. Involvement of Anti-Reward Systems

As addiction progresses, the brain’s anti-reward systems become more active

• Transition: Initially, drugs suppress these anti-reward pathways, but with chronic use, these pathways become more sensitive, leading to an increased experience of negative emotions during drug withdrawal periods, driving the cycle of dependence and addiction

(Koob & Ke Niak, 2008) overview of the antireward system and how it becomes activated during addiction, leading to increased negative emotional states during withdrawal.