Drugs

Numerous research investigations using animal models and functional brain imaging in the human brain, intended at understanding and subsequently defining the underlying mechanisms of drug addiction have been concluded or are underway. While probing the biological basis of drug addiction, what is imperative is the understanding of the pathways in which drugs act, along with the factors that effect alterations in those pathways (Jones & Bonci, 2005).
The affect of all drugs of abuse occurs in the reward circuit of the brain, which is also referred to as the mesolimbic system and is characterised by the interaction of several areas of the brain, which include the ventral tegmental area, the nucleus accumbens, the prefrontal cortex and the basolateral amygdala (Rang, 2003). The principal connected sections are the ventral tegmental area (VTA) and the nucleus accumbens. These are also linked to the prefrontal cortex in the pathway where they communicate through neurons. The ventral tegmental area of the reward circuit consists of dopaminergic neurons that respond to glutamate. These cells respond in the presence of stimuli indicative of a reward. In addition to supporting learning and sensitisation development, the VTA releases dopamine (DA) not just into the forebrain (Jones & Bonci, 2005) but also into the nucleus accumbens (Eisch & Harburg, 2006), an activity that occurs through the mesolimbic pathway. Interestingly, just about all drugs of abuse that result in addiction, increase the release of dopamine into the nucleus accumbens through the mesolimbic pathway (Rang, 2003).
The nucleus accumbens (NAcc) otherwise known as the accumbens nucleus or as the nucleus accumbens septi is a collection of neurons within the forebrain which is believed to play a major role in the sensation of reward, laughter, pleasure, addiction and fear in humans (Schwienbacher, 2004). (Olds and Milner, 1954) were among the first to study electrical stimulation of the brain in rats. Their research suggested that the area is the ‘pleasure centre’ of the brain. The nucleus accumbens consist mainly of spiny outcrop neurons also known as gamma amino butyric acid (GABA) neurons (Kourrich et.al, 2007) and is associated with acquiring and bringing forth conditioned behavioural responses, but perhaps more importantly, involved in the increased sensitivity to drugs as addiction progresses.
Research has advanced significantly and identified that a number of distinctive rewarding events can be rationalised by their abilities to activate a common brain reward mechanism. For instance, the electrical brain stimulation reward, the psychomotor stimulant reward, and the opiate reward all appear to involve an activation of the ventral tegmental dopamine system (Wise & Bozarth, 1984).
Fibiger et.al, (1987) investigated the role of dopamine in intracranial self-stimulation (ICSS) of the ventral tegmental area and observed that ICSS obtained from electrodes in the VTAresulted in significant increases in the dopamine metabolites.
It is important to recognise that amphetamines and cocaine although both included in the stimulant class of drugs may either be active or passive in their role pertaining to the enhancement of the level of dopamine in the brain, in other words either by actively increasing its release or by preventing it from being reabsorbed. Intake of psychostimulants may result in a decrease in dopamine synthesis, increase in the release of dopamine into the synapse, obstruction of dopamine reuptake back into the neuron, and inhibition of monoamine oxidase, an enzyme that breaks down catecholamines. While cocaine primarily effects by inhibiting reuptake of dopamine, amphetamine has most effect in increasing synthesis of dopamine.
Studies give the impression that the innervation of the nucleus accumbens is vital in the underlining characteristics of psychostimulants such as amphetamines and cocaine (Golan et.al, 2007). It is known that positive intracranial self-stimulation sites are confined to dopaminergic areas in the mid brain (mesencephalon). These sites include the nucleus accumbens, the striatum and regions of the prefrontal cortex. The principal area of interest is in the medial forebrain bundle; a region if stimulated will activate the ventral tegmental area. Intracranial self-stimulation also occurs for stimulation of the ventral tegmental area, which causes increased dopamine release in the medial forebrain bundle.
Researchers agree that dopamine neurotransmission in the nucleus accumbens plays an essential role in intracranial self stimulation, a precise definition of which still remains elusive (Cheer et.al, 2005).
Confirmation for dopamine’s importance in intra cranial self stimulation includes the reduced reaction in rats with lesions of dopaminergic neurons (Fibiger, 1987), the blockade of the intra cranial self stimulation by nucleus accumbens microinjections of a dopaminergic competitor (Stellar & Corbett, 1989) and the impaired intra cranial self stimulation in dopamine 1 knockout mice (Tran et.al, 2005).
Nevertheless, evaluation of dopamine release during intra cranial self stimulation reveals that it is not an essential requirement for the stimulation (Miliaressis et.al, 1991).
Research has shown that continuous administration of amphetamine was related to lowering in brain reward thresholds while withdrawal was associated with threshold elevations (Patterson et.al, 2000).

2. Emotion – Fear & Aggression

Psychopathy is defined as a developmental disorder characterised by emotional hypo-responsiveness together with a heightened risk for reactive aggression. Psychopathy is regarded to be the symptomatic result of the lack of sympathy, a reduced aptitude for remorse, an outward display of charisma, unforced susceptibility to boredom along with feeble control over such behaviour (Cleckley, 1967). Anatomically, researchers have suggested an impairment of the septo-hippocampal system (Gorenstein & Newman, 1980), the amygdala (Blair et.al, 1999); and the orbitofrontal cortex (Damasio, 1994) to be the reasons behind the exhibited behaviour of psychopathic individuals. This answer evaluates the claims of Damasio (1994) and Blair (1999) and discusses the impact of such damage on emotional behaviours such as fear and aggression.
Stimulation of certain parts of the brain can induce fear and aggression or can generate forceful defensive responses. In other words, the stimulation can produce the behaviours associated with aggression and / or fear. The explicit behavioural responses and the hormonal secretions associated with these emotional reactions are manipulated by separate neural systems. The integration of these responses appears to be controlled by the amygdala. Considering the claim (Blair et.al, 1999) that the amygdala is damaged in psychopaths, it is important to be aware of the remarkable parallels between the behaviour of psychopathic individuals and patients with abnormalities in the amygdala on neurocognitive measures. In addition to psychopathic individuals exhibiting impairments in handling fearful expressions, which is also displayed in patients with amygdala lesions (Adolphs et al., 1999), the characteristic of psychopathic individuals to exhibit a diminished potential in response to visual threats (Patrick et.al, 1993) along with impairments in aversive conditioning (Hare, 1998), also draws a parallel in patients with amygdala lesions who display both these impairments (Bechara et al., 1995).
It is known that amygdala damage (bilateral) in humans compromises the recognition of fear in facial expressions (Adolphs et al., 1994) which is thought to result from insensitivity to the intensity of fear expressed by faces. The same group reports findings (Adolphs et al., 1999) which suggest that the amygdala is critical in knowledge relating to the arousal of negative emotions. This may explain the impaired recognition of fear and anger in patients with bilateral amygdala damage while remaining consistent with the amygdala’s role in processing stimuli related to threat and danger.
On the other hand, the role of the orbitofrontal cortex being damaged in psychopathic individuals, similar behavioural resemblances have been brought forward between patients with orbitofrontal cortex abnormalities and psychopathic individuals (Damasio, 1994). As an instance, both categories exhibit a strong susceptibility towards aggression (Grafman et.al, 1996). Formulated by Antonio Damasio, the somatic-marker hypothesis puts forward a theory that enables emotional processes to guide behaviour of individuals with particular emphasis to their decision making capabilities thereby proposing a close connection between emotion and cognition in practical decision making. (Damasio et.al, 1994) had put forward the hypothesis indicating a possible link between somatic markers and the behaviour of psychopathic individuals. According to this hypothesis, behavioural options are related to unconscious somatic responses evoked by their previous consequences. The associated somatic responses, or the somatic markers, are activated by the mere thought of an option and either encourage or discourage the option. To test the theory that psychopathic individuals would fail to become risk averse, in consistence with the somatic marker hypothesis, the authors had considered 86 Caucasian and 71 African American male offenders for their analysis. However, the results pointed towards the level of anxiety and not psychopathy being predictive of responsive choices of the subjects. The somatic marker theory and its associated claims have met with criticism and researchers believe the use of somatic-markers would be an inefficient method of influencing behaviour (Rolls, 1999).
However, studies performed with the Iowa Gambling Task [IGT] (Bechara et al., 1994) have provided evidence of the somatic marker hypothesis. The IGT participants were required to serially select a card from four separate decks and receive the monetary outcome (reward and punishment) after each selection. Two (conservative) decks yielded small rewards and small punishments, while the other two (risky) decks yielded large rewards and large punishments. At the start, healthy subjects showed a tendency to select more cards from risky decks. At the later stages however, they preferred conservative decks and generated skin conductance responses (SCRs) before selecting cards from risky decks (Bechara et al., 1999). These SCRs are believed to be an example of defensive somatic markers aimed at preventing risky decisions. In contrast however, subjects with the amygdala lesion preferred risky decks throughout the task and failed to generate anticipatory SCRs (Bechara et al., 1999) leading to an assumption that amygdala damage is associated with an inability to evoke somatic responses.
The results suggest that amygdala damage is associated with impairment in decision-making and that the roles played by the amygdala and orbitofrontal complex with respect to emotional behaviours are disparate.
Recent research stipulates that the developmental origins of psychopathy do not rest with the orbitofrontal cortex (OFC) dysfunction primarily citing the reason that the distinctive functional impairments observed in psychopathic individuals are associated with damage to the amygdala and not the OFC. Nevertheless, the combined functioning of the amygdala and medial OFC and its implications in stimulus-reinforcement learning and decision making is perturbed in psychopathic individuals which, are thought to bring about the impairments in socialisation along with fear and aggression.

3. Emotion – Fear and Aggression

Early research (Bylinsky, 1982) emphasised that emotional responses such as fear and aggression are ‘shaped by the brain’. Biological analyses of the roots of fear and aggression have primarily involved genetic factors, endocrine influences and scrutiny of the brain structure (Lanza, 1983). (Siann, 1985) put forward the fact that neurotransmitters noradrenalin, dopamine and serotonin have been found to be in enhanced amounts in the limbic system of the brain and have a role to play when individuals exhibit fear and aggression.
Aggression, defined as behaviour, deliberately aimed at inflicting physical and/or psychological damage on persons or property, represents a problem of significant clinical and social concern. Aggression is directed towards and more often than not, stems from external stimuli. The areas of the brain that relate to aggression in humans include the amygdala, the hypothalamus, the prefrontal cortex, the hippocampus, the cingulate cortex, the septal nuclei, and the periaqueductal gray. Fear is an emotional response to a perceptive or realistic threat. The amygdala is a key brain structure in the neurobiology of fear. It is involved in the processing of negative emotions such as fear and aggression.
The fear response generated by the amygdala may be alleviated by another brain region known at the rostral anterior cingulate cortex, positioned in the frontal lobe of the brain. Researchers have observed that subjects experienced less activity in the amygdala when they were conscious in their perception of fear stimuli. Comparatively, more activity in the amygdala resulted from unconscious perception of fearful stimuli (Etkin, 2006).
Various neurotransmitters and hormones have been shown to correlate with aggressive behaviour and fearful response behaviour. The fear-reducing properties of testosterone have been firmly established in animals but not in humans (Archer et al., 2005). Criminological research reveals that men are more prone to using physical violence and are more often the victims of physical aggression themselves and biological research has linked this fact to testosterone, the most important male sex hormone which indirectly depicts the social dominance of the male.
Testosterone, although drawn in on many behaviours related to sexual and reproductive function, its role in fear responses is uncertain. Research involving both humans and animals has associated varied testosterone concentrations to external behaviours such as aggression but comparatively less to more internal behaviours like fear. However, some researchers report that low levels of testosterone may have a significant effect on increasing innate fear response and fear-induced enhancement of analgesia in male rats (King et.al, 2005).
Some researchers reported that oestrogen treatment in mice heightened fear responses in a range of fear and anxiety-provoking situations (Morgan & Pfaff, 2001). In contrast, treatment by testosterone was found to sharply reduce fear reactions in ewes that were subject to non-social, fear eliciting conditions (Vandenheede & Bouissou, 1993).
Apparently, there is clear-cut evidence in animals that testosterone is directly associated with aggression, however this correlation is not as strong in human studies. It may be kept in mind that since testosterone is present in males that are not aggressive as well as in those that are aggressive. This brings forward the possibility of other factor(s) being involved, such as cognition and environmental circumstances.
It is becoming increasingly evident that many neurotransmitters and hormones are expressed at early periods of neural development and it is likely that they participate in the structural organization of the nervous system. A major challenge is therefore the identification of specific neural mechanisms that define aggressiveness and impulsivity for the purpose of early identification, prevention and the treatment of individuals who are prone to violent acts.
The brain 5-HT system is the most widely distributed neurotransmitter system in the brain. (Spoont, 1992) claimed that serotonin (5-hydroxytryptamine or 5-HT) alleviates information processing in neural systems, resulting in controlled behavioural output, while discrepancies in 5-HT activity result in transformed information processing abilities. Unfortunately, the influence of 5-HT activity on aggressive or impulsive behaviour in humans is not yet understood, even though reduced functionality of the neurotransmitter is believed to increase aggressive tendencies. There exists substantiation to advocate the role of 5-HT in aggressive behaviour directed either towards others or towards oneself (Tuinier et al., 1996).
It is interesting to note that there is convincing support for an inverse relationship between 5-HT measures and aggression in adults but a comparable straightforward direction of the inverse relationship in children is not observed (Van Goozen et al., 1999) even though it is clear that genetic aspects are involved in the explanation (Foley et al., 2004). Researchers also suggest age of the individual to be an important aspect in clearing up these inconsistent results and propose that aggressive behaviour may be related to developmental abnormalities of the 5-HT system (Halperin et al., 1997).
It has also been hypothesized (Birger et.al, 2003) that the interaction between diminished serotonin levels and increased testosterone levels in the central nervous system has a marked effect on the neural mechanisms involved in the expression of aggressive behaviour. It has been theorised that testosterone modulates serotonergic receptor activity in a way that directly affects aggression, fear and anxiety.

4. Learning and Memory

Memory in the brain is structured into multifaceted memory systems that execute contrasting memory operations and have varied neurological basis. Declarative or relational memory includes attentive memory for facts and occurrences. Declarative memory maintains the ability to recall facts and occurrences and is in evident disparity with non-declarative memory abilities such as skills, habits, uncomplicated training and so forth including other channels by which familiarity modifies the outward interactions of human beings (Purves et.al, 2008).
Declarative memory is the memory for facts (Tulving & Schater, 1990). Studies of patients suffering from amnesia have been the most common form of evidence used to differentiate declarative memory from the other prominent type of long-term memory known as procedural memory. The performance of declarative / relational memory is distinctly correlated with the neural processing in the medial temporal lobes, along with areas of the frontal and parietal lobes and sensory sections throughout the brain (Purves et.al, 2008). The medial temporal lobe and structures in the diencephalons are vital towards the formation of new declarative memories the traces of which are subsequently saved in respective regions of the cerebral cortex. Another region that is linked with declarative memory is the neocortex. Particularly, this comprises the right frontal & temporal lobes for the episodic element, and the temporal lobes for the semantic element (Long, 2000)
The presence of the hippocampus within the medial temporal lobes is crucial in relation to the functioning of the declarative memory. The functions of the hippocampus in declarative memory are not completely established; however regular hippocampal action is evidently significant for encoding spatial, relational, and episodic (an element of declarative memory that refers to memory for personally experienced past events) memories. Medial temporal structures, other than and adjacent to the hippocampus are also critical for the normal operation of declarative memory (Poldrack & Gabrieli, 1997). The perirhinal cortices manipulate both memory for items as such and memory of context.
Various regions of the prefrontal cortex have been specifically implicated in the retrieval of different types of declarative memory (Davachi & Dobbins, 2008). The episodic retrieval is linked to neural activity in anterior prefrontal regions, recall with activity in the left dorsolateral prefrontal regions and awareness with activation of the right dorsolateral prefrontal regions (Purves et.al, 2008). Along with the frontal lobe the basal ganglia too is important in some forms of declarative memory that require reasoning about the contents of memory. Other frontal lobe regions are active in semantic (an element of declarative memory that deals with general knowledge, including language, facts, and the properties of objects) retrieval, these being effectively related to the language areas in the left inferior frontal gyrus. It may be mentioned that posterior lateral parietal and posterior midline regions are also concerned with episodic recovery, nevertheless are typically disabled during episodic encoding (Purves et.al, 2008). Operational communication between diverse brain regions is vital to efficiently encode, save, and recover memories.
On the other hand non-declarative or implicit memory, the three principal forms of which are priming, skill learning, and conditioning is a mixed classification that is identified fundamentally by its disparity with declarative memory. Non-declarative memory comprises each kind of memory that is unrelated to consciousness and the consistency of the medial temporal lobes (Squire & Zola, 1996). Non-declarative forms of memory (dexterity learning, repetition priming, and classical conditioning) do not engage conscious recall and are measured through changes in the way in which tasks are performed and are dependent on the cerebral cortex, basal ganglia and cerebellum.
Analyses of experimental studies in animals propose that declarative memory is more flexible than non-declarative memory (Squire & Zola, 1996). Analyses also reveal that declarative and non-declarative memories vary with respect to the flexibility of the information acquired by each approach. Declarative information is available to multiple response systems whereas non-declarative memory is more encapsulated and hence is less accessible to systems not concerned with the original knowledge.
The hippocampus, a scrolled structure located in the medial temporal lobe is crucial in laying down declarative memory, although it isn’t essential for working memory, procedural memory, or memory storage. Damage to the hippocampus will only affect the formation of new declarative memories. Research on non-human primates reveals that cortical regions neighbouring the hippocampal formation, consisting of entorhinal, perirhinal, and parahippocampal cortices, are key elements of the medial temporal lobe (MTL) memory system. In addition, studies on human subjects reveals that bilateral damage to the hippocampal formation is enough to generate severe anterograde amnesia together with severe, temporally graded retrograde amnesia (Squire & Zola, 1996). (Bayley & Squire, 2003) reported that damage limited for the most part to the hippocampal region weakens the learning of new facts (semantic memory), even as such damage impairs the learning of new events (episodic memory). However, remote memory for factual knowledge is spared and in addition, damage to the medial temporal lobe spares remote memory for autobiographical events (episodic memory).
Perhaps the most significant case of hippocampus damage in humans is the patient named H.M (Corkin et.al, 1997). During an epilepsy surgery, doctors removed nearly all of his medial temporal lobes. Since that surgery, in 1953, H.M. had formed no new memories. He could remember his childhood and facts and events before the surgery, able to use his working memory and had the capacity to form procedural memories but had entirely lost the capability to dictate declarative memory.