Case study on features of amphetamine intoxication

Paraphrase the whole passage Question 1 (15 marks) Describe the clinical features of amphetamine intoxication and how amphetamines act on the CNS. Ensure that you identify the neurotransmitters and the structures of the brain that are involved in your answer. Amphetamine can prolong wakefulness, increase focus and feelings of energy as well as decrease fatigue. It can produce euphoria, induce anorexia, and be used to treat narcolepsy and attention deficit/hyperactivity disorder (ADHD). Adverse effects include anxiety, aggression, paranoia, hyperactivity, reduced appetite, tachycardia, hallucination, and others. Amphetamine have fewer hydroxyl groups so are more lipid-soluble and CNS-active. It has weak agonist actions on adreno-receptor sites and are classified as sympathomimetic agent (Bryant & Knights, 2011). Amphetamine producing its effects by increasing the synaptic levels of the biogenic amines, dopamine (DA), norepinephrine (NE) and serotonin (5-HT), through multiple mechanisms. Although amphetamine binds to all monoamine transporters, its behavioural stimulant effects are mediated primarily through dopamine and depend on the dopamine transporter (DAT). Amphetamine blocks the ability of DAT to clear the neurotransmitter from the synapse and facilitates reverse movement of dopamine across the cell membrane (Berman, Kuczenski, McCracken, & London, 2009). Amphetamines also promote DA and 5-HT release from storage vesicles and prevent the uptake into vesicles, thus increasing the cytoplasmic concentrations of the neurotransmitter and making them more readily available for reverse transport. Further more, the amphetamines also increase synaptic levels of monoamines by inhibiting their reuptake. In addition, the brain structures that involved in are brain stem, frontal cortex, limbic areas of brain stem, basal ganglia or striatum, hypothalamus and pituitary gland (Yamamoto, Moszczynska, & Gudelsky, 2010). Question 2 (15 marks) a) In your own words describe the dopamine hypothesis of schizophrenia. The dopamine (DA) system consists of 4 major pathways which included Mesocortical pathway, begins in the ventral tegmental area of the brain stem, and ends in the frontal cortex. This pathway involved in cognitive functions such as work memory. Mesolimbic pathway project from the central tegmental area of the brainstem to limbic areas of the brain stem, such as the nucleus accumbens. This pathway plays an important role in attention, motivation, appetitive behaviour, and affective functions. Nigrostriatal pathway projects from the substantia nigra of the brainstem via axons terminating in the basal ganglia or striatum. This pathway is related to the activity of the motor organs. And Tuberoinfundibular pathway begins with hypothalamus to pituitary gland. Thus, controlling hormone release (prolactin) (Ohara, 2007). DA transmission is deeply affected by drugs of abuse, and alterations in DA function are involved in the various phases of drug addiction and potentially exploitable therapeutically. Hyperactivity of dopamine transmission was the first iteration of the DA hypothesis of schizophrenia, supported by the early observations that DA receptors are activated by psychostimulants and DA antagonists (Toda & Abi-Dargham, 2007). In schizophrenia, it is assumed that hypofunction of the cortical and prefrontal dopamine systems contributes to negative symptoms and cognitive disorders and that hyperactivity of the subcortical and limbic dopamine systems causes positive symptoms (Ohara, 2007). Toda & Abi-Dargham (2007), stated that negative symptoms and cognitive symptoms were resistant to D2 receptor antagonism. Moreover, Functional brain imaging studies suggested that these symptoms might arise from altered prefrontal cortex (PFC) functions. As preclinical studies stressed the importance of prefrontal DA transmission at D1 receptor for optimal PFC performance, the idea of a deficit in DA transmission at D1 receptors underlying cognitive impairments and negative symptoms emerged, whereas the excess DA transmission became associated with “positive” symptoms (hallucinations, delusions). As a result, an imbalance in DA with hyperactive subcortical mesolimbic projections and hypoactive mesocortical DA projections to the PFC became the pre-dominant hypothesis (Toda & Abi-Dargham, 2007). Toda & Abi-Dargham (2007) explained amphetamine-induced psychosis as a continuum that evolves from stimulation of interpretative mental activities to enhancement of perceptual acuity, reversal, and projection onto others (persecution), leading to paranoia and ideas of references. The “enhancement of sensitive acuity” develops into hallucinations. The sensorium remains clear until toxic delirium is reached. Thought disorders manifest toward the end of the continuum, near the toxic stage. b) Identify other neurotransmitters associated with schizophrenia and briefly discuss how the function of each neurotransmitter identified is altered in this disorder Serotonin: The idea that serotonin may play a role in schizophrenia was first postulated when the hallucinogen lysergic acid diethylamide (LSD) was found to block serotonin receptors (Sadock, Sadock & Ruiz, 2017). Gamma-aminobutyric acid (GABA): Studies of postmortem brain tissue have provided strong evidence that the GABAergic system is impaired in schizophrenia. These observations were confirmed and extended in subsequent studies showing alteration in several presynaptic components of the GABAergic system. The GABA deficit does not affect all classes of cortical GABAergic interneurons equally, but is restricted mainly to the interneurons. These interneurons have fast-spiking properties, contain the Ca2+-binding protein parvalbumin, and synapse on the perisomatic region of pyramidal cells. Because they target the spike-initiating region of neurons, fast-spiking interneurons are thought to have a key role in controlling the overall firing properties of brain networks (Lisman, Coyle, Green, Javitt, Benes, Heckers & Grace, 2008). Glutamate: N-methyl-D-aspartate (NMDA) is one of the four glutamate receptor. NMDA has been implicated in long-term potentiation (a process related to memory) in the hippocampus. NMDA blockade can result in neurotoxicity, apparently modulated by interneurons and activation of non-competitive glutamate receptors. Blockade of the NMDA receptor by phencyclidine (PCP), a non-competitive antagonist, produces symptoms similar to those seen in schizophrenia. NMDA receptor activation is excitatory, reducing postsynaptic membrane potential. PCP binds to a site within the open NMDA ion channel, thus blocking ionic flux. Of note, NMDA receptor density is highest in the hippocampus and prefrontal cortex, altered neurotransmission in these regions could also play a role in PCP's effects. Acute intoxication with the NMDA antagonist, PCP, produces hallucinations, thought disorder, negative symptoms, and cognitive deficits (Sadock, Sadock & Ruiz, 2017). Norepinephrine, acts at two receptor families (adrenergic and β-adrenergic receptors) in exert their effects via changes in G-protein–mediated second messenger systems, including cAMP and phosphoinositol. Norepinephrine and its co-transmitters (galanin and neuropeptide Y) are involved in a number of physiological and behavioral processes including the sleep-wake cycle, arousal, stress, and memory. nitial studies of norepinephrine examined concentrations in plasma, CSF, and brain tissue. Both plasma and CSF concentrations of norepinephrine and its metabolite appear to be increased in patients with schizophrenia, although this has not been a consistent finding. Neuropeptides: Neurotensin's appeal is due in part to its endogenous antipsychotic-like properties. Not only is it colocalized in dopaminergic neurons, but infusions of neurotensin into the nucleus accumbens block the excitatory effects of stimulants and reduce behavioral activation. Question 3 (10 marks) Describe how auditory hallucinations manifest and describe the areas of the brain that are thought to be involved in auditory hallucinations. Auditory/verbal hallucinations (AVHs) of spoken speech occur in patients with schizophrenia. The patients with schizophrenia were characterised by volume reductions of the superior temporal gyrus (STG) in addition to larger ventricles. In particular, hallucination severity was inversely correlated with left STG volume. These hallucinations often produce high levels of distress, behavioural dyscontrol, and functional disability that are refractory to antipsychotic drugs (Vercammen, Knegtering, den Boer, Liemburg & Aleman, 2010). Neuroimaging studies have associated occurrences of AVHs with activation in diverse brain regions involved in (inner) speech processing and verbal thought, encompassing the temporo-parietal junction (TPJ), inferior frontal gyrus (IFG) (consisting of Broca’s area and the right hemisphere homotope), anterior cingulate cortex (ACC), amygdala, and insula (Allen, Larøi, McGuire & Aleman, 2008). A more recent study has reported that increased severity of AVH is correlated with reduced left anterior STG and middle temporal gyrus (MTG) grey matter volumes. Compared to the non-hallucinating brain, the hallucinating brain is characterised by reduced grey matter volumes in the temporal cortex, stronger activation in subcortical centres, reduced control by the dorsolateral prefrontal cortex, aberrant activation from emotional attention centres, attenuated activation of the dorsal anterior cingulate, supplementary motor area and cerebellum. Dysfunction in this ‘top-down’ network applies to hallucinations in any modality and can account for the often-emotional content, sense of externality and non-volition that accompany the experience. In addition, from researches, used a computational morphometric technique to analyze whole brain grey and white matter in hallucinating and non-hallucinating patients in same age and gender matched controls. When patients with and without AVH were compared reduced grey matter tissue was seen in the left insula and adjacent temporal pole in hallucinators. They found severity of hallucinations to be correlated with volume loss in the left transverse temporal gyrus of Heschl and left (inferior) supramarginal gyrus, as well as the right dorsolateral prefrontal cortex. The volume loss in the right prefrontal cortex is of interest given the role that has been ascribed to frontotemporal interactions in volitional auditory perception. That is, impairments in this network could erase the volitional signature of subjective perceptual awareness arising from frontotemporal interactions, and thus explain why hallucinations are experienced as involuntary (Allen, Aleman & Mcguire, 2007). Question 4 (15 marks) List three different medications which may assist in the alleviating Andy’s symptoms as described in the case study above; then describe two side effects for each medication identified and the biological reasons for each side effect identified. Antipsychotics are classified as being typical and atypical antipsychotics, which have different profiles of actions (Bryant & Knights, 2011). 1. Aripiprazole (atypical): its partial agonist actions at dopamine D2 and 5-HT1A receptors, plus antagonist actions at 5-HT2A receptors (Bryant & Knights, 2011). Side effects: orthostatic hypotension: Initial Orthostatic Hypotension (IOH) is defined as symptoms of cerebral and retinal hypoperfusion (e.g. light-headedness) within 15 seconds after standing up from a supine, sitting or squatting position caused by an abnormally large transient blood pressure (BP) decrease [e.g. >40 mmHg Systolic BP]. Standing up causes an initial increase in venous return through the effects of contraction of leg and abdominal muscles. The consequent sudden increase in right atrial pressure may contribute to the fall in systemic vascular resistance through a reflex effect (Wieling et al., 2007). Hyperprolactinaemia: aripiprazole cause hyperprolactinaemia by blocking D2 receptors on pituitary lactotroph cells, thereby removing the tonic inhibition on prolactin release provided by dopamine secreted by the hypothalamus (Haddad & Sharma, 2007). 2. Clozapine (atypical): clozapine antagonises 5-HT2, α1-adrenoceptors and histamine H1 receptors (Kim et al., 2007). Side effects: weight gain: Kim et al. (2007) stated that the appetite stimulation–weight gain associated with AAPD is mediated by activation of hypothalamic activated protein kinase(AMPK) linked to blockade of the histamine H1R. In the periphery, AMPK activation is associated with decreased lipid formation, because AMPK phosphorylates acetyl-CoA carboxylase (ACC) inhibiting the generation of malonyl-CoA. Malonyl-CoA is a substrate for fatty acid synthase so that inhibition of ACC diminishes formation of fatty acids and lipid. In the hypothalamus, AMPK acts in a seemingly reciprocal fashion to regulate food intake. AMPK activity is inhibited by anorexigenic agents such as leptin and augmented by the orexigenic agouti-related protein (AGRP) (Kim et al., 2007). Type 2 diabetes: AAPDs can impair glycaemic control as based on animal models showing that 5-HT1A antagonism decreases pancreatic b-cell responsiveness, thereby decreasing insulin secretion and increasing serum glucose levels. Work in healthy volunteers has since shown that 5-HT2 antagonists can significantly de- crease insulin sensitivity compared with placebo, an effect possibly mediated by the suppression of 5-HT2A receptor-mediated glucose uptake in skeletal muscle (Nasrallah, 2008). 3. Chlorpromazine (typical antipsychotics): it blocks receptors for acetylcholine, noradrenaline, histamine, and 5-HT (Bryant & Knights, 2011). Side effects: seizures: Different dopamine receptors mediate opposing influences on neuronal excitability and seizure susceptibility. Blocking the D2 receptor is associated with seizure precipitation, while D1 antagonists are known to protect against seizures (Kumlien & Lundberg, 2010). Extrapyramidal: Even though the exact mechanism underlying extrapyramidal is not clear, striatal dopamine D2 receptor blockade is believed to be the principal cause. Another predictor of extrapyramidal is the antipsychotic dosage and consequently the drug plasma concentration, as more than 75–80% blockade of the D2 receptor results in acute EPS (Güzey et al., 2007).