Addiction Psychopharmacology

Neurobiological research offers an understanding of the transition between occasional controlled drug use and the loss of behavioural control over drug seeking and drug taking that defines chronic addiction.

While there are many definitions of substance dependence or drug addiction, most entail: (i) descriptions of compulsive drug use or “overwhelming involvement with the use of a drug” (Jaffe 1990, p. 524) and (ii) several criteria or symptoms that are indicative of a loss of control in as far as drug use is concerned, and a reduction in the number of various drug-seeking response behaviours (World Health Organization 1990).

Koob (2008) defines drug addiction as a chronically recurring disorder that manifests in: (i) the urge to look for and consume the drug, (ii) lack of control in reducing drug intake, and (iii) the occurrence of such negative emotional state as anxiety, irritability, and dysphoria. This last element reveals dependence or a motivational withdrawal disorder in the event that access to the drug is averted (Koob & Le Moal 1997). Through neurobiological researcher, researchers, scholars and critics are in a better position to gain an in-depth understanding of how an individual is likely to transition from an occasional drug use into chronic addition, and the consequent problem of relapse.

While both the WHO (World Health Organization) (1990) and APA (American Psychiatric Association) recognise withdrawal by itself as constituting their diagnostic criteria for drug addiction (APA 2010), from a historical context, this has denoted somatic and physical symptoms.

On this, Koob (2008) forwards the theory that the withdrawal state is significant for addiction is not somatic or physical symptoms but a motivational withdrawal sign that reveals “dysregulation of hedonic homeostatic processes that form the bases of not only the motivational drive of acute withdrawal from chronic drugs of abuse but also a background state change that extends into protracted abstinence and contributes to reinstatement of drug seeking” (p. 2).

Koob and Le Moal (2008) opine that the conception of drug addiction has been that it is a disorder that entails aspects of compulsivity and impulsivity. Once the compulsivity and impulsivity cycles have been broken it results in an amalgamated cycle made up of three phases namely, intoxication/binge, anticipation/preoccupation, and negative affect/withdrawal.

The intoxication/binge phase and the associated acute reinforcing impacts of drug of abuse in all likelihood entails actions that stress on the extended amygdale inputs and reward system and ventral striatum from the arcuate nucleus and ventral tegmental area of the hypothalamus. Most forms of drug addiction begin with the abuse of substances that an individual seeks on account of their hedonic properties.

Nonetheless, experimentation with drugs could also come out owing to the reinforcing impacts of peer pressure and this reinforcing effect in turn motivates the individual to take more of the drug (Koob 2008). Occasionally, the first time that an individual uses a drug could be associated with the therapeutic properties of the drug in question, such as the use of stimulants, in case of attention-deficient hyperactivity disorder.

Clinical studies reveal that a fundamental aspect of the reinforcing consequences of drugs is largely established to encompass their capability to prompt significant rise in extracellular dopamine activities within the limbic regions. Brain imaging studies involving humans reveal an increase in dopamine activity in the striatum region as induced by drug use, is linked to such subjective reward descriptors as euphoria, pleasure, and high (Volkow et al. 2008).

These studies have further established a link of fast dopamine changes to subjective perception of reward while stable but slow increase in dopamine have not been seen to induce such subjective responses (Volkow & Swanson 2003).

Pharmacokinetic properties of drugs responsible for their time of action and speed at which they move to the brain, also act as crucial aspects of their addition potential (Kolb & Volkow 2010). For instance, an assessment of brain pharmacokinetics of methamphetamine and cocaine indicates that the two drugs reach the brain at a very fast rate, while methamphetamine has been shown to take longer than cocaine to clear out of the brain. This variation might perhaps explain why during a binge, the individual takes cocaine every 30-60 minutes, while it may be a few hours before the individual takes methamphetamine (Fowler et al. 2008).

Clinical studies further reveal that the expectation that an individual has regarding the effects of a drug greatly determines the reading response he/she is likely to receive from taking the drug. Consequently, the regional brain activation and behavioural response is more likely to be powerful in case the individual expects a rewarding in comparison with when rewarding is anticipated (Volkow & Swanson 2003).

Acute withdrawal symptoms such as increased anxiety and negative affect that are significant for addiction and are linked to the negative affect/withdrawal phase, almost certainly entail reduced functionality of the individual’s extended amygdale reward system. Moreover, it also involves brain stress neurocircuitry recruitment. Following the drug intoxication phase, the ensuing response varies significantly from one drug to another and is determined by the frequency and chronicity of its abuse (Kolb & Volkow 2010).

In case of chronic drug use, the discontinuation of such drugs as alcohol, opiates and sedative hypnotics is likely to prompt acute, intense physical withdrawal symptoms that could be fatal if severe or poorly managed (Volkow et al. 2008). All drugs of abuse are linked to a motivational withdrawal condition that manifests in the form of irritability, sleep disturbances, dysphoria, and emotional distress that continue even after prolonged withdrawal. It is important to note that there is a distinctive difference in terms of the neurobiology of motivational or prolonged withdrawal from acute withdrawal.

Nevertheless, both types of withdrawal cause relapse. Only a limited number of imaging studies have been conducted to capture acute withdrawal.

The underlying mechanisms of acute drug withdrawal are thought to be drug specific, and that they point towards adaptations in the specific molecules targeted by the drugs in question. For instance, after a few days of withdrawal from cocaine, it has been noted that the brain is normally increasingly sensitive to GABA-enhancing drugs effects, and that this could be an indication that the neurotransmitter has been downregulated due to chronic cocaine use (Volkow et al 2004).

In the case of protracted withdrawal, the moment the symptoms and signs of acute withdrawal drop, imaging studies reveal a reduction in the release of dopamine and D2 receptor expression, usually depicted as hypofunction in dopamine pathways. These events could play a role in reduced sensitivity to the rewarding stimuli (anhedonia), as well as motivation that drug-addicted individuals report during protracted withdrawal (Volkow et al, 1997; Volkow et al 2007; Martinez et al 2005).

Unlike the reduced sensitivity to rewards reported during withdrawal, imaging studies show increased sensitivity to conditioned cues during detoxification. McClermon et al. (2009) report that abstaining from smoking has the potential to considerably enhance neural responses to cues related to smoking.

Such conditioned responses are thought to maintain the abstinence-relapse cycle as manifested in substance use disorders (Kolb & Volkow 2010).

This stage is also known as the craving stage and is triggered by increased sensitivity to conditioned cues and manifests itself in the form of increased craving for drugs. The anticipation/preoccupation (craving) phase entails stress-induced reinstatement or “intrinsic brain stress systems in the extended amygdala” (Koob 2008, p. 2).

The main afferent protrusions to the nucleus accumbens and extended amygdala and in particular, the basolateral amygdala that is involved in cue-induced reinstatement and the prefrontal cortex that plays an active role in drug-induced reinstatement are involved as well. Koob and LeMoal (1997) and Koob and LeMoal (2008) hypothesize that compulsive drug-seeking behavior engages ventral striatal-ventral pallidal-thalamic-cortical loops. It is also hypothesized that these loops so engage in turn engage other loops known as dorsal striatal-pallidal-thalamic-cortical loops (Koob & LeMoal 1997; Koob & LeMoal 2008).

According to Koob and Le Moal (2005), the attendant reduction of the reward function, along with brain stress systems activation that occurs in the extended amygdala exaggerate both of these effects.

Early stages are characterised by the dominance of impulsivity, even as the terminal stages are dominated by compulsivity (Koob 2008). As a person transitions from impulsivity to compulsivity, there is a resultant shift from positive reinforcement to negative reinforcement of the motivated behaviour (Koob & Le Moal 2008). Koob (2008) defines negative reinforcement as the practice of increasing the likelihood of such a response as dependence-induced drug intake by eliminating an aversive motivation, such as the negative emotional state that characterizes drug withdrawal. The aforementioned phases are perceived as acting in unison, becoming increasingly strong, and eventually resulting in the pathological condition referred to as addiction (Koob & Le Moal 1997).

Neurobiology of the positive drug reinforcement appears to be on the mesocorticolimbic dopamine system along with the association with the basal forebrain (Koob & Le Moal 1997). In the case of amphetamine, nicotine and cocaine, triggering of the mesocorticolimbic dopamine system via dopamine neurotransmission is of significance in reinforcing the drugs. This reinforcement activity also entails several dopamine receptors such as D-3, D-2, and D-1 (10, 11).

However, findings from neuro pharmacological studies support a dopamine-independent and dopamine-dependent involvement in the positive-reinforcing influences of such opiates as heroin (Koob 2009). On the other hand, ethanol seems to associate with elements sensitive to it in various neurotransmitter receptor systems. Such associations are thought to play a role in the positive-reinforcement actions of ethanol (Hyttia & Koob 1995). The receptor systems and neurotransmitters involved include activities on glutamate, serotonin, GABA (γ-aminobutyric acid), and opioid peptide systems. All of these receptors and neurotransmitter systems are to be found within the mesocorticolimbic dopamine system, along with the associated amygdale and nucleus accumbens (Koob 2009).

Nonetheless, not many studies have linked the positive-reinforcing activity of THC (tetrahydrocannabinol) to dopamine release in the nucleus accumbens (Hyman 1996). A key question that seems to challenge drug abuse research, nonetheless, is if there is alteration in the neurobiology of drug and reward reinforcement when an abstinence syndrome manifests itself at a time when there is no more self-administration of the drug.

Previously, substance dependence appears to have emphasized more on the manifestation of abstinence syndrome following sudden termination of drug administration hitherto manifested in such psychical signs as autonomic hyperactivity and well-documented tremor that accompanies ethanol withdrawal, as well as the pain and discomfort linked to opiate withdrawal. Nonetheless, the latest hypotheses of abstinence signs have started to emphasize on elements of abstinence that are frequently encountered in all drugs of abuse. There is a growing realization therefore, that such elements could be regarded as being more motivational and might actually be interpreted as being of a negative affective nature (Paterson & Markou 2003). Examples of such symptoms are different negative emotions like depression, anxiety, dysphoria, and irritability (Paterson & Markou 2003).

In line with the aforementioned clinical observations, studies on animals whereby intracranial self-stimulation acted as the standard for reward function have indicated significant reduction in reward (or enhanced reward threshold) linked to withdrawal for the main drugs of abuse that have thus far been tested (Koob 2008). Such effects differ in terms of duration of exposure and dose but animal models have shown that they could last for up to 96 hours following the withdrawal of the drug.

Early work on self-administration of drugs revolved around drug-taking behaviours as among dependent animals, usually primates. However, later studies seem to have duplicated similar behaviours among nondependent animals, manly Rodents (Koob, Sanna & Bloom 1996). Given that rodents tend to be exceedingly more tractable from an experimental context, they thus offer useful insights into the relevant transductive mechanisms and circuits involved in acute reinforcing impact of drug abuse. Based on the findings of neuropharmacological studies, the dopaminergic system is actively involved in acute reinforcing impact of cocaine.

There are two key projections of the midbrain dopamine system namely, the mesocorticolimbic dopamine system and the nigrostriatal system. While the mesocorticolimbic dopamine system protrudes from the VTA (ventral tegmental area) to the olfactory tubercle, amygdala, nucleus accumbens and frontal cortex, in contrast, the nigrostriatal system protrudes from the substantia nigra towards the corpus striatum (Koob et al. 1996).

The mesocorticolimbic system is mainly associated with the reinforcing activities of drugs of abuse. Such psychostimulants as d-amphetamine and cocaine have been shown to increase extracellular dopamine by means of hindering dopamine reuptake by dopamine transporters. With regard to d-amphetamine, they also enhance reversed dopamine transport. During the self-administration of cocaine intravenously, the use of in vivo microdialysis helps to detect increased dopamine. Moreover, the use of 6-OHDA (6-hydroxydopamine) neurotoxin as a selective means of destroying mesocorticolimbic dopamine neurons has also been shown to get rid of cocaine self-administration (Koob & LeMoal. 1997) have also been implicated in blocking the intravenous self-administration of nicotine, while opioid antagonists can also induce nicotine withdrawal.

Neurochemical actions that trigger a drug’s positive reinforcing impact is hypothesised to cause negative reinforcement linked to addiction. Nonetheless, an extra form of reinforcement is thought to be necessary in making the transition from occasional use of a drug to drug addiction in the form of a decrease in the negative (aversive) emotional state that come about due to repeated use (Wang et al. 2007). In this case, drug use is thought to eliminate the anxiety, dysphoria, irritability, as well as other unwanted feelings brought about by drug abstinence. Such other somatic physical signs like temperature changes, sweating, tremors, which are also indicative of drug dependence, possibly have limited motivating effect on the use of drugs (Koob & Le Moal 1997).

A key defining aspect of drug addiction is believed to be the formation of a negative emotional state of this kind. In line with this contextualization, research findings have revealed that during acute abstinence, all leading drugs of abuse “produce a negative emotional state in dependent humans” (Koob, Sanna & Bloom 1998, p. 469). A possible mechanism for such a negative emotional state could be a decline in brain reward function (Murray 2007). In the study of brain reward circuits involving the use of intracranial self-stimulation behaviour in animals, chronically dependent animals have been shown to depict decreased reward or enhanced reward thresholds (Kolb & Le Moal 1997). Such reductions in reward have been noted after opiates, ethanol, psycho-motor stimulants, nicotine, and THC have been withdrawn. These are also related to the drug dose administered prior to withdrawal.

Duncan et al (2007) opine that stress plays a dominant role in triggering relapse to drug taking behaviours. It does so by triggering brain circuits responsible for rewards processing, as well as in the mnemonic and attentional bias involved in drug use reminders (Duncan et al, 2007). Langleben et al (2008) opine that this chronic relapsed trend is widely renowned to be among the most demanding problems encountered in the fight against drug addiction. Addicted individuals are prone to going back to compulsive drug-taking even after having endured acute withdrawal symptoms for a long time (Vowkow et al. 2006).

Chronic drug abuse is thought to trigger a gradual reorganization of memory and reward routes, a development that is theorized to be significant in the escalation of these responses. Clinical studies have identified both glutamate and dopamine as playing a key role in the neuroplastic changes responsible for conditioned responses (Vowkow et al. 2006). In addition, plastic changes in both glucorticoid and CRF receptors are hypothesized to play a role in increased sensitivity to stressors. Lack of appropriate radiotracers to determine glutamate neurotransmission, as well as deficiency in glucocorticoid or CRF receptors have restricted studies of craving in humans generally to the dopamine system.

Key neurobiological changes in drug use noted in animal and human studies entail overactivated brain stress systems, compromised reward system as well as compromised prefrontal/orbitofrontal cortex function. Seeing as drug addiction tends to be a chronic relapsing disorders it has proven to be especially challenging to study the vulnerability of individuals to drug relapse. In addition, it is also not easy to define the biological basis of drug craving, as well as protracted abstinence.

The vulnerability associated with a reinstatement of drug-use behaviour, and finally the prolongation of habitual drug taking yields a dependence syndrome that manifests in subjective and behavioural signs of withdrawal behaviour. Eventually, an extension of the compulsive use of drugs possibly acts as a pointer to a basic protracted perturbation that materializes long after the easing of the withdrawal reactions. Even as we do not have any biological markers of disorders related to substance abuse, we nevertheless have numerous promising neurobiological elements of substance abuse disorders that shall ultimately play a key role in the diagnoses of key drug misuse, use and dependence.

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