Someone recently bought our

students are currently browsing our notes.

X

Drug Addiction (Long) Notes

Medicine Notes > Neuroscience Notes

This is an extract of our Drug Addiction (Long) document, which we sell as part of our Neuroscience Notes collection written by the top tier of University Of Oxford students.

The following is a more accessble plain text extract of the PDF sample above, taken from our Neuroscience Notes. Due to the challenges of extracting text from PDFs, it will have odd formatting:

Drug addiction - disrupted self-control

*

*

*

Current evidence shows that drugs of abuse exert their initial reinforcing effects by inducing dopamine surges in limbic regions, affecting other NT systems and leading to characteristic plastic adaptations Significant changes can be detected in circuits implicated in reward, motivation and/or drive, salience attribution, inhibitory control and memory consolidation Therefore, addiction treatments should attempt to reduce the rewarding properties of drugs while enhancing those of alternative reinforcers, inhibit conditioned memories and strengthen cognitive control

What is addiction?

*

Addiction still ill-defined but we can agree on several established principles o Sustained exposure to drugs of abuse might be a prerequisite for addiction but its emergence is ultimately a function of interactions between drug effects, biological and environmental factors, which are crucially influenced by the developmental stage of the individual ?
most experimentation with drugs and the development of addiction occur during adolescence/early adulthood o Addiction usually takes hold when vulnerable individuals repeatedly seeks to replicate an originally pleasurable experience
? During the gradual transition from recreational use to addiction, a fundamental motivation shift takes place - a drug is no longer taken to derive pleasure from it but to satiate intense craving and to relieve the distress of not having the drug o Serious consequences that the acute and repeated administration of drugs can bring upon the brain at a molecular, cellular and circuit organizational levels

The neurobiology of drug addiction Dopamine: a major node in the addiction network

* Initial reinforcing effects of most drugs of abuse rely upon the induction of large and rapid increases in the level of DA in the nucleus accumbens

* In contrast to the increases in DA neurotransmission that are observed during acute drug intake, imaging studies have shown that in drug-addicted individuals, supraphysiological levels of DA in the nucleus accumbens are followed by marked decreases in dopamine function o PET studies have shown long-lasting reductions in the level of striatal D2 receptors in drug abusers - as drug-associated experiences gain in significance, the threshold required for natural reinforcers to activate DA might increase

* Drug addicts suffer from an overall reduction in the sensitivity of their reward circuits to natural reinforcers

*

*

*

Not just natural rewards but also the ENTIRE reward system is compromised in addicted individuals Accumbal DA increases might not by synonymous with pleasure per se; rather, the firing rate of Da neurons at that site has been proposed to encode the saliency of a given event or stimulus as a function of prevalent expectations, and in a way that facilitate the consolidation of memory traces connected to such stimulus (SEE LECTURE NOTES) Increasingly thought that the computational outcome of synaptic transmission within DA networks might drive motivation to modify the behaviour in response to a stimulus o If this view is correct, then drugs of abuse might induce addiction not just because they are experienced as pleasurable but also because they are being processed as salient events that motivate procurement of more drug, while they help solidify memories linked to the experience o ? explains why nicotine (which triggers DA release without being particularly euphorigenic) can nevertheless be highly addictive, and why in some instances addicts claim that they take the drug compulsively even when they say it is no longer pleasurable

Other neurotransmitter systems:

* There is a large body of evidence regarding the direct and indirect mechanisms that drugs can use to activate the DA system supraphysiologically

* Cocaine, amphetamine, methamphetamine and ecstasy - increase DA level by inhibiting/perturbing DA reuptake mechanisms and facilitating DA release

* Other drugs such as nicotine, alcohol, opiates, marijuana - work indirectly by stimulating neurons (GABAergic or gluatamatergic) that modulate DA-cell firing through their effects on nicotine, GABA or CB1 receptors respectively

* Although an increase in DA during intoxication seems necessary for its ability to produce addiction, it is clearly NOT sufficient - such increases are observed in both addicted and non-addicted individuals - other NT and neuropeptide systems have equally important roles in modulation of the reward system, the establishment of addiction-related adaptations and the manifestation of behavioural consequences. For example: o An intact noradrenergic system seems to be crucial for psychostimulant-dependent mesoacccumbal DA release o Orexin (neuropeptide) has been shown to support addiction-related plastic changes (Borgland 2006) o Chronic cocaine induces long-lasting changes in accumbal glutamate transmission o Ecstasy can produce long-term alterations in serotonin function in rats and monkeys (Wallace 2001, Ricaurte 1988 respectively) Plastic changes and short-circuits in the brain

*

Psychoactive drugs are known to induce profound adaptations in NT systems, reminiscent of those associated with LTP o There is mounting evidence that exposure to stimulants, nicotine or opiates produces persistent adaptive changes in the structure of

*

*

*

*

*

*

*

*

*

dendrites and dendritic spines on cells in key areas of the brain with roles in motivation, reward, judgment and the inhibitory control of behaviour For example, chronic adaptations in DA receptor signaling might trigger compensatory glutamate-receptor responses with the potential to affect synaptic plasticity The fact that DA, glutamate, GABA and other NTs are all highly versatile effectors of synaptic plasticity draws a direct path connecting the effects of drug abuse with the adaptive alterations not only in the reward center but also in many other circuits, through the strengthening, formation and elimination of synapses Imaging studies have shown that the reduced DA activity observed in drugaddicted subjects is associated with disrupted metabolism in frontal brain regions, and most accentuated in the orbitofrontal cortex (OFC - associated with motivation) (Tremblay 1999) and in anterior cingulate gyrus (ACG - involved in inhibitory control) o Activity of OFC varies as a function of drug withdrawal - goes from hyper- to hypo-metabolism as an addict goes through ha 4 week long detoxification Imaging studies during craving provocation associate the increases in OFC and ACG activity with the subjective experience of drug craving in addicts It is interesting that OFC has been implicated in OCD and also that OFC lesions lead to behavioural compulsion ACG (ventral area in particular) has also been linked with craving responses and mood elevations experienced by cocaine abusers when exposed to a stimulant drug by Volkow (2005) Involvement of Pavlovian conditioning mechanisms in drug-addiction processes has been demonstrated repeatedly in animal models in which a single exposure to drug-related cues can re-instate addiction behaviours - these studies have implicated limbic structures (hippocampus, amygdala) as major contributers to the acquisition, consolidation and expression of the drugstimulus learning that drives relapse "Executive" component to addiction - impaired cognitive functions might have an important role in prolonging abuse or predisposing users towards relapse - cocaine uses have a compromised ability to reign in urges - linked to reduced activity in AGC and PFC (Hester 2004) Also growing evidence that other brain regions are implicated in the manifestation of addictive behaviours - suggests that the recruitment of far more complex networks o Cerebellar activation has been associated with cue-induced alcohol craving (Olbrich 2006) and with cocaine persisting and acute effects (Anderson 2006) - interesting since previous findings suggest that the dysexecutive component of cocaine addiction might be due in part to a compensatory imbalance in the cerebellum o Discrete lesions of the STN in rats have been reported to reduce the motivation to self-administer cocaine but to increase it for food reward
- suggests that this area might be a promising target for new, more discriminative treatments for cocaine addiction (Baunez 2005)

*

*

*

*

*

*

Baler (2006) suggests an integrated model to explain some of the behavioural signatures of addiction as the corruption of information-processing events within this network of brain circuits According to the model, the major neural substrates underlying addiction make up a network of at a minimum 4 interdependent and overlapping circuits: o Reward (in nucleus accumbens (NAc), VP and hypothalamus) o Motivation/drive (OFC) o Memory and learning (amyala, hippocampus) o Cognitive control (PFC, dorsal ACG) In addition, brain regions and NTs that are involved in the sensitivity to stress, such as the amygdala through corticotrophin releasing factor and regions involved with mood e.g. ventral cingulate are also likely to modulate the reactivity of the above circuits These 4 circuits are modulated by DA via indirect and direct pathways Connect with each other mostly through glutamatergic and GABA-ergic projections ? plasticity in these NT systems might ultimately sustain an important fraction of the long-term molecular changes that mediate addictive behaviours Baler endorses the hypothesis according to which addiction entails the attribution of distorted weights onto key variables within the network ?
saliency value of a drug is thus enhanced, that of natural reinforcers is decreased and the strength of inhibitory control is weakened ? sets of the stage for an unrestrained cycle resulting in compulsive drug-taking without regard for consequences

Integrating science to treat addiction

*

*

Given the long-lasting nature of many of the drug-induced adaptations, addiction might be best construed as a chronic disease - addicted patients require long-term treatment and relapse can be expected to occur sometimes during treatment Interventions should be multi-modal and incorporate approaches to: o Decrease the reward value of the drug of choice o Weaken conditioned memories to the drug and drug-related stimuli o Increase the saliency value of non-drug reinforces o Strengthen frontal inhibitory and executive control - prevent relapse

Replacement therapies:

* Medications acting on same molecular targets but with different potencies and pharmacokinetics

* Useful for the treatment of heroin (e.g. methadone, LAAM and buprenorophine) and nicotine (patches, chewing gum, breathalysers) addictions

* Unfortunately the potential of current D2 selective agonists as maintenance mediations for cocaine addiction seems low since they all tend to have a high degree of abuse liability

o Preliminary studies with D1 agonists however suggest they are more promising DA transporter blockers:

* Generated considerable interest as potential treatments for cocaine addiction but the results of clinical trials with compounds such as methylphenidate or bupropion have been for the most part disappointing

* Bupropion might be useful for nicotine addiction Non-DA drugs:

* Because many of the adaptations that lead to addiction occur in cortical circuits that involve glutamate and GABA neurotransmission, these NTs are attractive targets for pharmacological intervention

* Medications that target either or both of these NTs could interfere with drug self-administration in pre-clinical models

* Topiramate - shown some promise for the treatment of alcohol, opiate and cocaine addictions

* The muscle relaxant baclofen - reduced acquisition of cocaine selfadministration and attenuated reinforcing effects of the psychostimulant damphetamine in rats - could block craving in alcoholics Cannabinoid agonists:

* CB-receptor system is involved in reward, learning, memory

* Rimonabant - first CB-receptor antagonist developed by the pharmaceutical industry - pre-clinical studies suggest that it might be effective for addiction treatments Adenosine-receptor antagonists and corticotropin-releasing factor antagonists also promising, as well as memory blockers and enhancers (which might inhibit the establishment of the conditioned responses to cocaine) Future directions Advances in brain imaging, neurochemistry and molecular neurobiology are adding crucial depth to the understanding of the complex pathophysiology involved and revealing, along the way, new targets for pharmaceutical, behavioural and combined treatments The medical implications of such developments might be profound. Wide genomic associations for addiction will enhance the ability to identify vulnerable populations and enable individually tailored treatments of those affected by addiction. Intriguingly, one of the most persistent obstacles to the successful translation of this growing knowledge is the stigma surrounding drug abuse and addiction - it is a considerable barrier to the paradigm shift needed to address this disease as a mental health issue.

Neural systems of reinforcement for drug addiction

*

*

*

Everitt & Robbins hypothesise that the change from voluntary drug use to more habitual and compulsive drug use represents a transition at the neural level from prefrontal cortical to striatal control over drug seeking and drug taking behaviour as well as a progression from ventral to more dorsal domains of the striatum, involving its dopaminergic innervation These neural transitions may themselves depend on the neuroplasticity in both cortical and striatal structures that is induced by chronic self-administration of drugs Nucleus accumbens is well known to mediate the reinforcing effects of drugs but more recent research emphasizes the role of the striatum as a whole (including the nucleus accumbens) in the process leading first to drug abuse and then addiction o This view has been stimulated by progress in understanding the dopamine-dependent, serial communication between the various domains of the striatum via a cascading loop interconnectivity and by an improved understanding of associative learning mechanisms that conceive of behavioural output as an interaction between Pavlovian and instrumental learning processes

Reinforcement, conditioning and the nucleus accumbens

*

*

*

*

Drugs act as "instrumental reinforcers" - they increase the likelihood of responses that produce them, resulting in drug self-administration of "drug taking" Environmental stimuli that are closely associated in time and space with the effects of self-administered drugs gain incentive salience through the process of Pavlovian conditioning Everitt et al postulate that any combinations of the effects of drugs (distortions in sensory processing, and in the case of stimulant drugs such as cocaine, an exaggeration of the perceptual impact of environmental stimuli, especially those that already predict important environmental events, which are known as conditioned stimuli) may constitute the "rewarding" effect of a drug - it is the sense of EXPECTANCY or the sense of "control" over such interoceptive and exteroceptive states, including the overall level of arousal accompanying them, acquired through action-outcome learning that constitutes instrumental drug reinforcement Motivational effects of conditioned stimuli can be ascribed to a hypothetical process of Pavlovian arousal, which serves to energise or activate responding o Considerable evidence now shows that the midbrain dopamine neurons show fast phasic burst firing in response to such CSs but may also be active, at least in their tonic mode, under other circumstances in

*

*

*

*

response to factors such as unpredictability, novelty, stress and food deprivation Thus, in terms of drug abuse, in addition to obvious direct influences such as cocaine on extracellular dopamine, it might be feasible in certain circumstances to detect the effects of CSs themselves on striatal dopamine function o Unexpected presentations of drug-paired CSs elicit dopamine release in the CORE but not SHELL region of the nucleus accumbens (Ito et al 2000) o Selective lesions of the core or infusions of NMDA or dopamine receptor antagonists into the core during training greatly retard the acquisition of Pavlovian approach responses, whereas infusions of NMDA or D1 receptor antagonists into this region after a training trial disrupt the consolidation of this response into memory In certain circumstances CSs can also function as conditioned reinforcers o Conditioned reinforcement occurs when stimuli that were initially neutral (light etc) become reinforcing in their own right via association with primary reinforcers (food, cocaine etc) o Drugs such as amphetamine, nicotine etc greatly increase responding with conditioned reinforcement - for example, infusion of amphetamine into the nucleus accumbens increases the acquisition of responding for a food-related conditioned reinforce
? Here, the nucleus accumbens core mediates the effects of the conditioned reinforce via its afferent inputs from limbic cortical structures
? Mesolimbic dopamine projection esp. to shell mediates the response rate-increasing or psychomotor stimulant effects of the drug, hypothetically by simulating the behaviourally activating effects of Pavlovian arousal and affecting the incentive salience of the conditioned reinforce o This dopamine dependent potentiation of conditioned reinforcement is a key component of the reinforcing effects of stimulant drugs such as cocaine, amphetamine and nicotine and probably others too The effects of conditioned reinforcers support the learning of new drug seeking responses Drug self-administration behaviour, including drug seeking under secondorder schedules of reinforcement, initially involves action-outcome learning before extended training additionally leads to the formation of stimulusresponse (habit) associations that help maintaining responding.

Interacting roles of striatal subregions in reinforcement

*

*

Experiments discussed in this review show that the nucleus accumbens core (distinct from shell) is important in the maintenance of instrumental behaviour involving delays in the provision of cocaine, in particular in the capacity of CSs to bridge that delay Where does the drug exert its primary reinforcing effects?

Buy the full version of these notes or essay plans and more in our Neuroscience Notes.