Cocaine Pharmacology and Effects on the Brain

Cocaine Pharmacology and Effects on the Brain Cocaine is a highly addictive substance abused worldwide. Its primary mechanism of action involves blockage of dopamine, norepinephrine and serotonin transporters in specific brain regions, mainly the dopamine reuptake system located on mesolimbic neurons. Cocaine increases the dopaminergic neurotransmission and triggers adaptive changes in several neuronal circuits underlying reinforcement, reward, sensitisation and the high addictive potential of cocaine. However, the long-lasting behavioural effects associate with cocaine addiction show there is complex neurotransmitters interaction within the reward circuit. Excitatory amino acid and inhibitory GABA transmitters also play a part in these changes. Glutamatergic systems regulate dopamine function, while GABAergic modulate the release of basal dopamine and glutamate. Understanding of the molecular and cellular mechanisms that lead to cocaine addiction has given new treatment methods in the pharmacological field to develop better med icine. Especially, useful monoamine agonists treatment may be successfully in controlling behaviour and lead to long term moderation of drug taking. However, more studies are needed in order to identify safe and efficacious pharmacotherapy. Introduction Cocaine, an alkaloid derived from the leaves of Erythroxylon coca is a psychostimulant drug linked to human addiction (Dackis et al., 2001). Cocaine acts as a local anaesthetic with sympathomimetic and vasoconstrictor properties (White and Lambe, 2003). In addition, cocaine is a potent uptake blocker for dopamine (DA), norepinephrine and serotonin (Carrera et al., 2004). As shown in figure one, the chemical structure of cocaine molecule contains two rings, the six-carbon phenyl ring shown on the right and the unusual nitrogen (N)-containing ring shown on the left, both necessary for its biological activity (Meyer and Quenzer, 2005). Cocaine acts by blocking the dopamine transporter within the mesocorticolimbic reward system. Blockade of the transporter increases the level of dopamine in this region of the brain. Increased dopamine level is responsible for the euphoric effect of cocaine (Butterner et al., 2003). However, the long lasting effects of behavioural characteristics of cocaine addiction, such as sensitisation and the vulnerability to the reinstatement of drug seeking years after the acute rewarding effects of the drug have disappeared, shows that there must be complex interactions between additional neurotransmitter systems (Kalivas, 2004). In contrast to dopaminergic system, excitatory amino acid and inhibitory GABA transmitters also play a role in these changes. Glutamatergic systems regulate dopamine function, while GABAergic modulate the release of basal dopamine and glutamate (Baler and Volkow, 2006). Additionally, cocaine can also interact with several receptors and ion channels, including nicotin ic acetylcholine, and opioid receptors coupled to voltage-gated Ca2+ and K+ channels (Kobayashi et al., 2007), resulting in prolonged elevation of extracellular dopamine. The potential abuse of cocaine is mainly based on the rapid development of tolerance to the euphoric effects (Butter et al., 2003). Cocaine addiction is an uncontrollable and continually relapsing drug taking disorder (Torregrossa and Kalivas, 2008). The behavioural manifestation of addiction is mediated by adaptations that chronic administration of drug abuse elicits at the level of individual neurons in the CNS. These adaptations alter the functional properties of neurons, which in turn change the properties of the functioning of neural circuits in the brain in which these neurons are involved (Nestler, 1997). The probability that one will become addicted to cocaine depends on the method, the frequency and the duration of ones cocaine intake (Carrea et al., 2004). Historical aspect of cocaine use The use of cocaine for personal satisfaction dated back over thousands of years ago, when Erythroxylon coca, the plant from which cocaine is extracted was used by indigenous people from Andes and South America for religious, mystical, social, and medical purposes (Dackis et al., 2001). The coca leaf was chewed by these communities because of its euphoric effects and its ability to reduce fatigue and hunger and to enable sustained periods of heavy labour (White and Lambe, 2003). This leaf was introduced in Europe in 1492 by the Spaniards, when they conquered South America and discovered that this leaf would be useful for performing hard labour (Julien et al., 2008). Eventually, the Spaniards started using the coca leaf as a method of payment for the native worker in gold and silver mine, who would take the leaf to reduce appetite and increase physical stamina. Cocaine alkaloid was first isolated by a German chemist Friedrich Gaedche in 1855 (Julien, 2008). The ability of cocaine in reducing fatigue and hunger were recognised by Sigmund Freud who used cocaine himself. Freud and others also recognised the ability of cocaine to cure opioid addiction. As a result, Freud prescribed cocaine to his patients who were addicted to morphine (Boghdadi and Henning, 1997). Unfortunately, many of these patients became addicted to cocaine themselves (Grilly, 1998). Morphine, which is similar to cocaine in reducing hunger, was extracted from opium in the early 1800s by Friedrich Wilhelm Adam Sertà ¼rner. But its use spread in 1853 when the hypodermic needle was developed (Grilly, 1998). Morphine was used as a pain reliever and as a cure for opium and alcohol addiction. Its extensive use during the American Civil war resulted with people suffering from the soldiers disease (addiction), (Julien et al, 2008). Forms of cocaine The use of crack cocaine, or crack, was first reported in 1980 in Europe and the US as a new drug with rapid stimulating effects. Crack cocaine is a by-product of cocaine, C17H21NO4 (figure 1). However, crack is formed through different processes. First, the coca leaves are transformed into a product known as basic cocaine paste. The paste is then turned into either crack cocaine through chemical treatment with sodium bicarbonate, or into a less potent water soluble salt, cocaine hydrochloride when it is refined with either acetone or sulphuric and hydrochloric acids. The powdered hydrochloride salt can be snorted, and because it is water soluble, it can be injected intravenously (Boghdadi et al., 1997). However, in the hydrochloride form, cocaine decomposes when it is heated and is destroyed to temperature, making it unsuitable for use by inhalation. In contrast, crack cocaine is converted to a stable vapour by heating it (Julien et al., 2008), making it more potent than the concentrated form. The paste and crack cocaine forms can be smoked either on their own or together with tobacco or cannabis-marijuana and sometime mixed with heroin and sold on the street (Goldstein et al., 2009). Cocaine hydrochloride compared to crack cocaine, is less potent and it is used as a local anaesthetic. Its use as anaesthetic first came about in 1884, after Niemann described its anaesthetic properties such as bitter taste and the resultant unusual numbness when applied to the tongue (Goldstein et al., 2009). By the late 1800s, when morphine was already used as a pain reliever, the use of cocaine for its analgesic properties which includes nerve blocking anaesthesia, epidural, and spinal anaesthesia has began to spread (Goldstein et al., 2009). Both cocaine hydrochloride and morphine are still used medically today as anaesthetic, despite their addictive properties. Cocaine hydrochloride is used as a vasoconstricting anaesthetic agent in surgery for ears, nose, and throat (White et al., 2003), while morphine is used as anaesthetic to relieve severe pain. Morphine acts through mu, kappa, and delta opioid receptor to block pain messages to the central and peripheral nervous system (Jul ien et al., 2008), However, morphine produces euphoria by interacting mainly with the mu opioid receptor (rosin et al., 2000). Aim: The aim of this project is to view the complex interaction between cocaine and cocaine receptors and the mechanisms of action of cocaine. Special emphasis will be placed on cocaine tolerance and addiction. To begin with, an overview will be provided on the pharmacokinetics of cocaine by discussing how it is absorbed, distributed, metabolised and excreted. Then, a discussion on how cocaine-induced changes in the peripheral and central nervous system contribute to the euphoric effect and addiction. Finally, an overview of how cocaine dependency could be treated. Pharmacokinetics of cocaine The effect of cocaine on the body depends heavily on the rate of accumulation and the concentration of cocaine at its site of action (the brain) and the duration of contact at these sites (Grilly, 1998). The pharmacokinetics of cocaine refers to its movement in the body with respect to its absorption, distribution, metabolism and excretion from the body and this is dependent on multiple factor such as, route of administration, genetics, and consumption of cocaine (Goldstein et al., 2009). Route of Administration/ Absorption As illustrated in figure two, cocaine is rapidly absorbed from the mucous membranes, the stomach and the lungs. Therefore, cocaine can be snorted, smoked, taken orally, or injected intravenously (Julien et al., 2008). However, the onset and duration of cocaine depends on the method of intake (Grilly, 2006). Cocaine hydrochloride poorly crosses the mucosal membranes when snorted, due to its vasoconstriction properties, thereby constricting blood vessels and limiting its own absorption. Because of the slow absorption of cocaine, its euphoric effect is prolonged when administered intranasally (Boghdadi et al., 1997). Cocaine can be also smoked in the form of crack. Because of its rapid absorption in the pulmonary vascular bed, crack produces an intense high in seconds, peaks at 5 minutes and persists for about 30 minutes. Intravenous injection of cocaine hydrochloride bypasses all the barriers to absorption, placing the total dose of drug immediately into the bloodstream. It produces euphoria in 30-45 seconds (Julien et al., 2008). Distribution After administration, cocaine rapidly penetrates the brain. Initial brain concentrations far exceed the concentration in plasma (Julien et al, 2008). After it penetrates the brain, cocaine is rapidly redistributed to other tissues such as the spleen, kidney, and lungs. Cocaine also binds to plasma protein, albumin and also to ÃŽÂ ±1-acid glycoprotein (Boghdadi et al., 1997). Metabolism Drugs taken orally initially pass through the liver (Figure 2), where they may be metabolised before entering the blood. Cocaine is metabolised primarily into ecgonine methyl ester and benzoylecgonine (Figure 3), the main urinary metabolite of cocaine and can be detected in urine for about 48 hours and up to 2 weeks in chronic users (Butttner et al., 2003). Cocaine is catalysed to ecgonine methyl ester by serum and liver cholinesterases, while benzoylecgonine is hydrolysed non-enzymaticaly (Carrera et al., 2004). Benzoylecgonine have vasoconstrictive properties, however it does not appear to cross the blood-brain barrier readily (Goldstein et al., 2009.). In addition, cocaine is demethylated to formed norcocaine (Figure 3) (Carrera et al., 2004), the only metabolite of cocaine that crosses the blood-brain barrier (Flowler et al., 2001). In the presence of ethanol, cocaine is metabolized to cocaethylene (Buttner et al, 2003). Cocaethylene is as active as cocaine in blocking the presynaptic dopamine reuptake transporter, thereby potentiating the euphoric effect of cocaine, increasing the risk of dual dependency and the severity of withdrawal with chronic patterns of use. This metabolite is more toxic than cocaine and aggravates cocaines toxicity. The half-life of cocaethylene is about 150 minutes, outlasting cocaine in the body (Julien et al., 2008). Even though cocaines plasma half-life is about 50 minutes, several metabolites can be detected by way of urinalysis for up to 2 to 5 days after cocaine overdose (Grilly, 2006). Mechanism of actions of cocaine Cocaines euphoric and reinforcing properties are the result of the obstruction of dopamine transporter (Butterner et al., 2003), thus, increasing dopamine level within the mesolimbic dopamine pathways. The mesolimbic dopamine pathways, shown in figure4, are composed of ventral tegmental area (VTA), the prefrontal cortex (PFC), Hipocampus, amygdale, and the nucleus accumbens (NAc) (Cornish and Kalivas, 2001) (figure 5). The nucleus accumbens (NAc) which consists of two sub-regions, the core and the shell, is believed to be the site for both the primary reinforcing properties of drugs of abuse and conditioned control over drug seeking (Kalivas, 2004). Normally, Dopamine is released into the synapse from an axon terminal in response to a pleasurable signal (Dackis and OBrien, 2001). Once this neurotransmitter is released, it diffuses across the synaptic cleft to bind to their respective receptors, D1 and D2 receptors (Howell* and Kimmel, 2008), which are linked to the cAMP second messengers system via membrane-bound G-proteins. D1family receptors (D1 and D5) are coupled to a stimulatory G-protein (Gs), which when activated increases the production of adenylate cyclase and cAMP and stimulation of the D2 family receptors (D2, D3, and D4) leads to the inhibition of adenylate cyclase through activation of an inhibitory G-protein (Gi/Go) (Cunningham and Kelley, 1993). Dopamine is taking back into the presynaptic neurons through the dopamine transporter, as a result shutting off the signal between neurons by preventing new dopamine to be formed (Howell* and Kimmel, 2008). Cocaine, on the other hand, blocks the dopamine transporter (figure 5), preventing the reuptake of dopamine into the presynaptic neurons of the VTA. Blockade of the transporter augment dopamine level in the synaptic clefts, producing continuous stimulation of dopamine receptors (Anderson and Pierce, 2005). Increasing dopamine concentration in the nucleus accumbens is responsible for the euphoric and reinforcing effects of cocaine. Behavioural sensitisation Repeated cocaine treatment increases dopamine levels in the synaptic cleft, which could lead to further stimulation of the dopamine receptors, causing more intense but shorter behavioural responses (Anderson and Pierce, 2005). This progressive change in behavioural response following repeated cocaine administration is known as behavioural sensitisation or reverse tolerance. The enduring neuronal adaptation in the reward circuit that occur after repeated cocaine administration is believed to be associated with motive and reward (Morgan and Roberts, 2004). The neuroadaptations that result in behavioural sensitization is characterised by two processes, known as initiation and expression (Anderson and Pierce, 2005). Initiation, which takes place in the VTA, is referred to as temporary cellular and molecular changes, such as alteration in various genes, second messenger cascades and receptors densities, which occur in response to psychostimulant administration, while expression is the lon g-lasting neuronal changes that start from the VTA and progress to the nucleus accumbens and striatum to increase behavioural response (Pierce and Kalivas, 1997). It has been reported that repeated cocaine treatment for two weeks increases the sensitivity of dopamine D1 receptors in the olfactory tubercle, nucleus accumbens, ventral pallidum, and substantia nigra and subsensitivity of D2 receptor (Unterwald et al., 1996). Activation of D1 receptors stimulates adenylyl cyclase activity via activation of Gs; increasing sensitivity of D1 and also increased adenylate cyclase and cyclic AMP-dependent protein Kinase (PKA) activity in the nucleus accumbens due to continual activation of Gs protein (Cunningham and Kelley, 1993). However, continuous cocaine treatment decreased D1-like receptor density and function, thereby initiated behavioural tolerance (Keys, and Ellison, 1994). Increased release of dopamine in the nucleus accumbens is also calcium-dependent and relies upon activation of calcium-dependent proteins, calmodulin and calcium-calmodulin kinase II (CaM-KII (Pierce and Kalivas, 1997). It is generally believed that increased calcium conductant and activation of calcium-dependent protein kinase are involved in the release of neurotransmitters in presynaptic nerve terminals and initiation of gene transcription (Evans and Zamponi, 2006). Therefore, continuous activation of calmodulin and CaM-KII by cocaine in the nucleus accumbens may mediate the release of dopamine or other neurotransmitters such as glutamate and GABA that are associated with expression of behavioural sensitisation (Pierce and Kalivas, 1997). D1 receptors located on GABA and glutamate afferents to the VTA are responsible for the release of these neurotransmitters in the nucleus accumbens when activated. Interaction between these neurotransmitters in the VTA changes the regulation of dopamine cell, which initiate long-term neuroadaptations (Cornish and Kalivas, 2001). Glutamatergic systems Excitatory amino acid such as glutamate acts as the main mediators of excitatory signals in the central nervous system (Baler and Volkow, 2006). Glutamate is known to produce its action through ionotropic (NMDA and non-NMDA) and metabotropic (mGluR) subclasses receptors (Danbolt, 1997). Although cocaine does not have a direct influence on brain glutamate systems, repeated exposure to cocaine results in alterations in glutaminergic transmission in the nucleus accumbens (Schmidt et al., 2005). However, the PFC, which transmits major glutaminergic projections to the nucleus accumbens (figure 4) has been most implicated in the regulation of dopamine released from dopamine cell terminals through NMDA and non-NMDA receptors (Kalivas, 1997). It is believed that stimulation of NMDA receptors through a voltage-dependent calcium channel initiate burst firing model in dopamine cells, as a result increasing accumbal dopamine release which is similar to what occurs in behavioural sensitisation (E vans and Zamponi, 2006). Administration of cocaine increases dopamine release presynaptically, which stimulates dopamine D1 receptors, located on descending glutamatergic afferent terminals from the prefrontal cortex (PFC). The D1 receptor in turn, stimulates the release of glutamate in the prefrontal cortex postsynaptic neuron. The released glutamate activates NMDA receptors on the dopaminergic dendrites in this brain area. This sequence of events is augmented by the fact that repeated cocaine administration desensitises dopamine D2 autoreceptors. Desensitisation of D2 receptor reduces the hyper-polarisation of dopamine cells, thereby allowing a further augmentation of dopamine release, which causes supersensitivity of D1 receptors, hence, increasing NMDA activity (Johnson and North, 1992). Because the neuronal circuits are interconnected (figure 5), a reduction in PFC dopamine transmission will activate the nucleus accumbens dopamine release, leading to expression of behavioural sensitisation. Increased glutamate release from the PFC to nucleus accumbens core is associated with cocaine-induced reinstatement and expression of locomotor sensitisation (Torregrossa and Kalivas, 2008). Both Glutamatergic and GABAergic neurons are also joined in the prefrontal cortex, indicating a possible interaction between glutamate and GABA. Therefore, the PFC GABA transmission may also be involved in the development of behavioural sensitisation (Giorgi et al., 2005). GABA systems It has been reported that cocaine sensitisation is linked with a cocaine-induced increased glutamate and GABA levels in the PFC. This was supported by Jayaram and Steketee (2005), who observed an increase in both glutamate and GABA concentration in the prefrontal cortex of animals withdrawn from repeated daily cocaine after the first week following repeated exposure to cocaine, but increase in these neurotransmitters were not observed after prolonged withdrawal. Furthermore, Jayaram and Steketee reported that the AMPA/KA receptor antagonist, (DNQX) prevent cocaine from increase the concentration of GABA in the prefrontal cortex in cocaine-sensitised animals. Therefore, increasing the response of GABAergic neurons in the PFC is a consequence of enhance glutamate level in prefrontal cortex. Because the AMPA/KA receptor antagonists seem to block cocaine from augmenting GABA levels, it can be concluded that glutamate acts mainly through AMPA/KA receptors to increase GABAergic activity in the prefrontal cortex. However, decrease in GABAÃŽÂ ² receptors function in the PFC is also associated with sensitisation of locomotors. It is believed that a loss in GABAÃŽÂ ² function in the prefrontal cortex would lead to a decrease in inhibitory modulation of excitatory pyramidal output neurons in the PFC (Badran et al., 1997), and therefore, a simultaneous increase in glutamatergic transmission in subcortical regions associated with the expression of behavioural sensitisation (McFarland et al., 2003). Glutamatergic, GABAergic and midbrain dopamine neurons are joined onto dendritic spines of medium spiny neurons that contain GABA, and endogenous opioid peptides. These opioid-containing neurons project directly to the substantia nigra and VTA to synapse on dopamine cells (Yung and Bolam, 2000). Therefore, alteration of endogenous opioid may participate in the development of drug abuse. Opioid systems It has been suggested that dopamine and opioid act together to modulate locomotion, mood and motivated behavioural, therefore, modification of the endogenous opioids participate in the development of drug of abuse. In addition the opioid system could also influence drug craving and relapse by altering stress physiology (Rosin et al. 2000). Apart from dopaminergic system, the endogenous opioid system is also a major player in addiction. Opioid system consists of three G-protein coupled receptors, termed mu (ÃŽÂ ¼), kappa (ÃŽÂ º), and delta (ÃŽÂ ´) opioid receptors. They act through G-protein second messenger systems (Go/Gi) to inhibit adenylate cyclase and cyclic AMP (Contet et al., 2004). Activation of these receptors on presynaptic axon terminals inhibits the Ca2+ influx that underlies release of neurotransmitters (Evans and Zamponi, 2006). At the postsynaptic membrane, their activation hyperpolarises the membranes by enhancing K+ flow out of neurons (Taddese et al., 1995) mu ( µ)-opioid receptor Mu ( µ) opioid receptors mediate positive reinforcement following direct morphine or indirect alcohol, cannabinoids and nicotine activation (Jullien et al, 2008). The positive reinforcing and euphoric effect of morphine involved dopaminergic as well as mu opioid receptors. Morphine activates ÃŽÂ ¼-opioid receptors through inhibitory Go/Gi protein, which decreases the level of adenylate cyclase and the cAMP pathways in the VTA (Contet et al, 2004). Because opioid and GABA containing-neurons also project in the VTA, activation of  µ receptor inhibits the release of GABA on dopamine, leading to high level of dopamine in the nucleus accumbens and other area. The increase in dopamine level in the nucleus accumbens leads to the positive reinforcement of opioid addiction (Bartoletti et al., 1999), which is also related to cocaine reinforcing effect (Julien et al., 2008). Stimulation of  µ opioid receptor in the VP is thought to promote motor activity, in part, by red ucing presynaptic release of GABA (Torregrossa and Kalivas, 2008). Repeated cocaine administration results in reduced extracellular GABA in the VP due to increasing stimulation of presynaptic  µ opioid receptors (Tang, et al. 2005). 2. K-opioid receptors ÃŽÅ ¡-opioid receptor system is essential in regulating presynaptic dopamine release and administration of dynorphin (DYN) within the nucleus accumbens (Shippenberg and Rea, 1997). DYN, endogenous ligand for the ÃŽÂ º-opioid receptor prevents the sensitisation that develops to locomotor stimulatory and conditioned reinforcing effect of cocaine. Anatomical studies have shown interaction between the mesolimbic dopamine neurons and neurons containing the opioid peptide dynorphin (Yung and Bolam, 2000. As mentioned above, dynorphin are found in dentritic spine of medium spiny neurons and project to the VTA and nucleus accumbens in which ÃŽÂ º-opioid receptors are expressed. However, the accumbens shell express high density of ÃŽÂ º-opioid receptors (Jayaram and Steketee,). Microdialysis studies have shown that the systemic administration of selective ÃŽÂ º-opioid receptor agonists such as U50488 and U69593 depress the firing rate of mesolimbic dopamine neurons and decreases dopamine overflow in the nucleus accumbens (Shippenberg and Rea, 1997). Therefore, activation of ÃŽÂ º-opioid receptor will inhibit dopamine release in the nucleus accumbens. However, Kuzmin et al., 1997 showed that acute administration of selective ÃŽÂ º-opioid receptor antagonist, nor-binaltorphimine increases dopamine overflow within the nucleus accumbens. In addition to these findings, it is believed that dopamine D1 or D2 receptor agonist, apomorphine, increases dynophin immunoreactivity and prodynorphin mRNA in the nucleus (Li et al., 1990). Therefore, repeated administration of cocaine increases prodynorphin mRNA in the nucleus accumbens and striatum. Taken in to account all these findings, and the role of ÃŽÂ º-opioid receptors in presynaptic modulation of dopamine release, it can be concluded that an increase in the extracellular level of dopamine within the nucleus accumbens results in a compensatory increase in the activity of dynorphinergic neurons. However, this increase is insufficient to prevent the development of behavioural sensitisation. Because many of the above intracellular adaptation involve changes in protein levels, it can be though that regulation of gene expression may be involved in the long-lasting effects of cocaine. Cocaine regulates gene expression It has been reported that one of the early molecular events following cocaine administration is the activation of nuclear protein (CREB) (Konradi et al., 1994). CREB control the changing that occur in synaptic neurons through modulation of the expression of several cAMP-inducible genes. CREB is regulated via phosphorylation at serine-133 (Konradi et al., 1994) The kinase inducible domain (KID) that contains serine-133 amino acid residue is phosphorylated by cAMP-dependent protein kinase A (PKA), and Ca2+/calmodulin-dependent protein kinases II and IV (CaMK II and IV) (Lonze and Ginty, 2002). Phosphorylation of CREB by PKA and CaMK II and IV results in the expression of immediate early genes (IEGs) including Fos and Jun, which are members of the transcription factor activator protein-1 (AP-1) family (Soderling, 1999). Acute cocaine administration activates DNA-binding activity of the AP-1 and expression c-Fos, FosB and JunB proteins (Hope et al., 1992). Chronic cocaine exposure is believed to reduce the capability of cocaine to express c-Fos, JunB and FosB proteins. This results in prolonged accumulation of à ¢Ã‹â€ Ã¢â‚¬  FosB proteins (a shorter splice-variant of FosB), which produces more persistent AP-1 complex (Hiroi et al., 1997). Prolonged accumulation of à ¢Ã‹â€ Ã¢â‚¬  FosB was reported in a variety of knockout and transgenic mice studies. Hiroi et al (1997) showed that mice lacking Fos-B and its shorter splice- variant à ¢Ã‹â€ Ã¢â‚¬  Fos-B had reduced AP-1 complexes following chronic cocaine exposure and increases cocaine-mediated hyper-locomotion and conditioned place (CPP) preference. They also observed that the long-term over expression of à ¢Ã‹â€ Ã¢â‚¬  Fos-B increases AP-1 complexes and behavioural sensitisation in both the nucleus accumbens and striatum. Increased neuronal expression of Fos in these regions after cocaine treatment is mediated by increasing D1 dopamine receptor activation, due to high level of extracellular dopamine. Desensitisation Chronic cocaine administration repeatedly stimulates dopamine receptors, as a result, decreases the concentration of dopamine within mesolimbic system and the remaining receptors become less sensitive to dopamine. Decrease in dopamine concentration leads to tolerance. This has been reported in several studies. For example, Maisonneuve et al (1995) observed a reduction in the basal dopamine concentration of rats nucleus accumbens when 10 or 15 mg/kg of cocaine was administered three times every day per hour for 13 days. Additionally, Inada et al (1992) showed that repeated cocaine administration in rats, reduced dopamine response to cocaine striatum 24 h after withdrawal. Decrease in dopaminergic level also leads to behavioural tolerance. Tolerance Tolerance refers to a decrease in response to cocaine due to repeated exposure of the drug (Maisonneuve et al., 1995). The major contributory factor to tolerance is the supersensitivity of D2-like autoreceptors as a result of D1 receptors desensitisation after chronic cocaine treatment (King et al., 1994). King et al showed that following chronic administration of 40 mg/kg of cocaine per day, for 7 days, increases sensitivity of D2-1ike receptors in the nucleus accumbens. Increasing D2 receptors leads to a transient decrease in the levels of GiÃŽÂ ± and GoÃŽÂ ± proteins linked to these receptors (King et al., 1994). Continuous cocaine administration produces tolerance to the inhibitory effects of cocaine on dopamine uptake in striatum and nucleus accumbens. Therefore, blockade of dopamine uptake by cocaine produces a compensatory increase of dopamine reuptake transporters (Letchworth et al, 2001). However, repeated cocaine treatment decreases the mRNA expression of dopamine transporter in the VTA neurons that project to the limbic brain regions during withdraw (Hammer et al., 1997). Polymorphism in the genes of dopamine transporter (DAT1) and receptors could be implicated in the genetic susceptibility to the complications of long-term development use in different individual (Wang et al., 2004). There are two main types of DAT1 genes, the SLC6A3 gene and the 3 untranslated VNTR polymorphism. The SLC6A3 is localised to chromosome 5p15.3 and genetic variation in SLC6A3 are thought to change the expression of DAT1 (Fuke et al., 2001). The variable number tandem repeat (VNTR) polymorphism in the 3untranslated region of DAT1 consists of a 40-bp repetitive sequence and can vary from 3 to 12 repeats. However the two most common alleles are the 9-repeat and the 10-repeat, and several studies have linked these polymorphisms to prolonged psychosis following stimulant withdrawal. Fuke et al (2001) reported that the 10-repeat allele (10R) enhances the expression of the DAT1 protein, while Michelhaugh et al (2001) claimed that the 9-repeat allele (9R) enhanced the DAT1 expression. However both studies found that the DAT1 VNTR is associated with drug addictions. The gene for D2 dopamine receptor (DRD2), TaqI A (rs1800497) is a single-nucleotide polymorphism (SNP) with two variant; A1, the less frequent allele, and A2, the commoner allele. Accumulative evidence from post-mortem brain samples using a [3H] binding ligand and in living subjects using positron emission tomography (PET) showed that the presence of the A1 allele leads to a decrease in D2 dopamine receptor density, as a consequence of chronic cocaine treatment (Thompson et al. 1997). Therefore, the DRD2 A1 allele is implicated in addictive behaviours. Several studies on different populations suggested that the involvement of TaqI A and VNT

Heat of the Day By Elizabeth Bowen Essay

â€Å"Heat of the Day† by Elizabeth Bowen is the reflection of the complexities in the relationships across the generations, in love and war, set at the backdrop of 1942 World War. The story is about a life of Londoners and the traumatic experience they had to undergo when the city was being bombarded during war. â€Å"The Heat of the Day† sees the city being shattered and in this scenario of devastation, how the people try to make the sense of their lives? â€Å"The Heat of the Day† follows with same intensity the flow of the wartime stories written by Bowen in 1945. The story is though about warfare yet there is very little description about the war and that only one instance of the air raid, which happens close to the end of novel. The description of impressions of war and the London has been explicitly referred through the voice of characters with the reality transformed through visionary approach of the city. As described by Neil Corcoran, â€Å"The ‘Heat of the Day’ is a novel in which the panic of possibly losing identity, and of others deceiving you about their identities, operates not only as an agency of plot but as the very texture of style.† (Corcoran, 169) Within the context of the centrally located story is woven several others stories told by protagonists to one another with the purpose to retain their identity which they themselves had found in peril. Stella herself tells false story about her marriage to Roderick, as she wants him to believe that his father Victor was the abandoned party rather than she herself. She does so partly to increase the image of his dead father in the eyes of Roderick and secondly to make herself appear as a femme fatale instead of being a victim. The impression of the war scene can very well be seen in one of the scenes where Harrison is standing in the street and the flames appearing from the distance are helping him to read Stella’s address mentioned on the envelop. The depiction of the fire has been made through the use of image chandelier: â€Å"the Chandelier flare makes the street like a mirrored drawing-room† (Bowen, 315). Inside the flat when the two characters are involved in the conversations, the sounds of guns can be heard seeming to be welcomed, as they made Stella to remain quite. â€Å"The guns rested her by opening up once more† and soon they faded, â€Å"The guns, made fools of, died out again, askance† (Bowen, 319). The importance of war seems to be considered very less with Stella and Harrison being hardly aware of any danger. The language has been used in a very poetic way giving a vivid, lucid and a very realistic touch to the nature and the objects surrounding the characters. Bowen penetrates into the physical objects and events manifesting in the human behaviors and their dreams and missions. With great subtlety, complexity and force, she is able to make characters come alive making them have real experience of the terrific upheavals of the warfare. Her prose is beautifully contrived to give meaning and depth to life experiences of the characters, which continues to follow us after the last page has been read and has been placed down. At many occasions, the scenes are shifted from war torn London to the peace and tranquility of the countryside. The difference is clearly seen between the country life in England around the Victorian hulk and in the neutral Ireland. While reading it, we are made to remember about the blackouts, characters forgetting the names of the places during their train journey, continuous alike confusions between the friend and foe, and the direction to which war is taking in the passing years. Amidst this scenario lies the gripping version of the story of woman and the way she comes to term and understanding of the intolerable situations. In the first chapter itself, we are introduced to Harrison and his rude behavior towards woman who is trying to have a casual conversation with him. From the second chapter onwards, we are introduced to the heroine and with that her ongoing situation of crises and dilemma she has to undergo and her interaction and influence of Harrison on her. Their relationship with each other cannot be judged very easily but when the scenes are read carefully then only the realization of the base on which they are building their terrible relationship is felt that even before Robert makes his entry. The relationship between Stella and her son Roderick is also very beautifully carved while he takes over the Irish inheritance. On the other hand Robert’s mother and sister are both very confusing personalities making fuss all the time on whom Stella would never be able to leave good impression according to Robert. All the characters are very wonderfully drawn. There is also a scene where two women are sharing one apartment at the same time enjoying each other’s company and exchanging own tales of woes to each other. They contribute their bit in easing tension of the main protagonists. Amidst all the surviving lives of the protagonists, tensions ensue, as it becomes known that Robert is giving his support to the opponents. His disillusionment with Dunkirk induces him to adopt the title of a traitor. Climactic is the reason given by Robert for this decision of his, and on the other hand wants to enlighten himself with the most meaningful future by the war ends. In the last chapter, we are introduced to Louie who is artless girl at the Bandstand. She is a widow as her husband succumbs to the vagaries of the war. She with her child now would like to spend rest of her life at the devastated seaside where she had spent all her life as a child. An essence of the reality being transferred can be felt by the way characters have been visualizing many places in the city. All through the novel, Bowen has made special reference to the seasons, time and the lucid description of light. This aspect shows her creative spree in impressionistic technique. How the way Stella is mystified can very well be seen in the following scene: The two stations also, in Stella’s mind, became epitomes of the two most poignant seasons — in spring, in autumn everything telegraphs its mystery to your senses; nothing is trite. And more: in these years the idea of war made you see any peaceful scene as it were through glass (Bowen, 104). This passage is a manifestation of the transfer of reality in the form of metaphor. With the help of the impressions and metaphors, Bowen gives vivid description of the city London after the bombardment. The whole city is broken with almost several of the landmarks lost. As critics said there is great exposure of irony in the fiction retold and the sense of solidity and individualization in characterization increase the credibility of the most sensuous fiction. Bowen has captured London with such a great dexterity and with greatest blitz that even after reading the whole novel, the memories of this wartime London would haunt the readers for a long time.

Heart of Darkness in Relation to its Title Essay - 1360 Words

The Parallel meaning of the novella with its title- Heart of Darkness The title, Heart of Darkness, aptly chosen, can be very strongly linked to the novel. IT can be used to describe Joseph Conrad’s views on civilization, the individual mind and the land into which he ventures. These sum up his opinions on the bourgeoise society, uncivilized society and the faults of human nature, linking them to the land under one common theme and thus establishing the title. ‘Heart of Darkness’ can most noticeably describe Marlow’s journey into the heart of the land. A dominant symbol in the novel is of the river- the snake- â€Å"But there was in it one river especially, a mighty big river, that you could see on the map, resembling an immense snake†¦show more content†¦Surrounded by dark jungle and distant mist, he knows his journey will be a blind one, one where he is new and possibly unwelcome. Also, by saying he felt he was headed towards the center of the earth rather than the continent, he refers to the earth’s core, where in religion and folklore hell resides. With this, all he knows about his impending journey is that it will be a voyage into chaos and, ultimately, death. Where the setting depicts heading into the heart of darkness, one can only begin to grasp the relationship of inside to outside, of hell to the norm. This is even existent in civilization as well as individuals, who are hosted and somewhat intensified by Conrad’s use of the land. Although Conrad wrote this novella before the psychological era of Freud (and in some cases Jung), the two shared many similarities. Relating to the phrase â€Å"Heart of Darkness,† Freud believed everyone was born primitive, and in some senses, there is always a primitive aspect waiting to be shown, being covered up in a constant struggle to keep it locked away inside. 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The Psychology Of Existential Counseling - 1066 Words

Corey (2009) argues that to reach these treatment goals, the therapist must strive to reach three phases in existential counseling. The first phase is understood to be to challenge the perception of the client of their presenting issues or symptoms. â€Å"They may focus on what other people â€Å"make them feel† or on how others are largely responsible for their actions or inaction† (Corey, 2009). It is the role of the therapist to teach the client about the role they have in their own lives and how they contribute to their own problems. During the middle stage, the therapist will encourage the client to explore their current value system. With this self-exploration, the client can find a new internal value process once they have taken responsibility of their actions. In the final phase, the client ins encouraged to take the newly learned information and thought processing into action. Between sessions and after treatment is terminated, he client is to recognize their s trengths they have in their newly discovered internalized values which they can use to make the adjustments in their life. It is through the adjustments that are successfully made can lead to a purposeful existence. In regards to Humanistic theory, specifically Person-Centered theory, it is the theory’s ability to what Corey (2009) describes as the ability to provide a subjective view of human experiencing. In the initial stages of therapy, the therapist can allow the client to have time to express their unique andShow MoreRelatedFactors Affecting Students in Terms of Comprehension and Literature1495 Words   |  6 PagesExistential counselling  is a  philosophical  form of  counselling  which addresses the situation of a persons life and situates the person firmly within the predictable challenges of the human condition. 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While the theories presented have brought up interesting and valid points on what causes personality, there are others that have taken a different approach to its study. There is the Humanistic-Dynamic theory by Abraham Maslow, the Person-Centered theory by Carl Rogers, and the Existential Psychology made popular by Rollo May. Analyze how humanistic