Dopaminergic Circuitry of Reward

Dopaminergic circuitry of reward    Produces pleasure for behaviours needed for survival: o Eating. o Drinking. o Sex. o Nurturing. Involves the mesolimbic dopamine system: o Ventral tegmental area  nucleus accumbens  prefrontal cortex. Activated when engaged in activities that further survival, or the continuation of genes. Drugs affecting reward system  Nearly all drugs of abuse increase dopamine in the dopaminergic circuitry of reward.  Direct dopamine effect: o Cocaine. o Amphetamines. o Ecstasy (MDMA).  Indirect effect involving other centres: o Caffeine. o Nicotine. o Alcohol. o Heroin. o Marijuana. General mechanism of action  Increase of dopamine release.  Decrease of dopamine re-uptake.  Lowering threshold of dopamine-mediated activation in postsynaptic neuron (e.g. by co-activation of the opioid receptor). Cocaine  Alkaloid that is obtained from the leaves of the South American coca plant.  Different formulations: o Cocaine: cocaine hydrochloride. o Free base: proton removed with baking soda. o Crack cocaine: proton removed with ammonia; NH4Cl remains in the freebase cocaine after the mixture is evaporated. o Believed that crack cocaine is more addictive than normal cocaine because of the removal of a charge, allowing it to cross the blood-brain barrier more easily.  Mode of action: o Inhibits dopamine, NA and 5-HT transporters with Kd (concentration at which 50% of drug is bound to receptor) of about 300nanomolar, 900nM and 400nM respectively. o This means that 300nM of cocaine is needed to inhibit dopamine re-uptake.    Perceived positive effects: o Potent CNS stimulant. o Effects last from 20 minutes to several hours, depending upon dosage, purity and method of administration. o Initial signs of stimulation are hyperactivity, restlessness, increased BP and HR, euphoria. Negative effects: o Euphoria is followed by discomfort and depression. o There is a craving to experience the drug again. o The drug dose has to be increased due to receptor desensitisation (loss of dopamine receptors). o Other side effects include: increased risk of MI and stroke, reduced attention, insatiable hunger, insomnia, lethargy. With long-term use: o Chronic use is directly related to dysfunction in areas of the brain involved in higher thought and decision-making. o Users can lose the ability to memorise and remember even simple items. o Their decision-making abilities can be impaired. Amphetamines  Related to the plant alkaloid, ephedrine.  Used extensively in combat fatigue and to increase alertness in soldiers.  Different types: o Amphetamine – “speed”. o Methamphetamine – “meth”, “ice”, “crystal meth”. o MDMA – “ecstacy”.  Mechanism of action: o Increase dopamine release in the presynaptic dopaminergic neurones. o Decrease dopamine degradation by binding to MAO in dopaminergic neurones. o Revert the dopamine re-uptake transporter by binding on it, causing it to act in reverse and transport dopamine out of the nerve terminal.  Perceived positive effects: o Increased wakefulness and focus. o Feeling of power or superiority. o Decreased fatigue and appetite.  Negative effects: o Restlessness. o Headache. o o o o o Increase HR, BP and RR. Uncontrollable movements or shaking. Palpitations and arrhythmia. Convulsions. Withdrawal elicits anxiety, depression, agitation, fatigue, excessive sleeping, increased appetite, psychosis and suicidal thoughts. MDMA (Ecstasy)  Clinical trials: o Post-traumatic stress disorder. o Anxiety associated with terminal cancer.  Its mode of action is more complex than amphetamine. o Interacts with several neurochemical systems. o Stimulates dopamine, but also NA and ACH release. o Release 5-HT and blocks its reuptake. o Acts directly on a number of receptors, including α2adrenergic (adrenaline) and 5-HT2A (serotonin) receptors.  Perceived positive effects: o Euphoria. o Decreased hostility and insecurity. o Increased feelings of intimacy and empathy to others. o Ability to discuss anxiety-provoking topics with markedly increased ease. o A strong sense of inner peace and self-acceptance. o Feelings of insightful and mental clarity. o Intensification of sensory experience, particularly proprioception, hearing and touch.  Negative effects: o Hyperthermia and dehydration. o Bruxism (teeth grinding) and trismus (jaw clenching). o Acute renal failure. o Cardiac arrhythmias. o Long term: serotonergic neurotoxicity. o Withdrawal elicits lowered mood or even depression, and an increase in anxiety, stress and other negative emotions. Marijuana (cannabis)  Biologically active chemical compound is Δ9-tetrahydrocannabinol (THC).  Mode of action: o Binds to the cannabinoid receptor CB1 (CNS) and the CB2 receptor (immune system).     o Acts as a partial agonist on both receptors. o Mimics anandamide, 2-arachidonyl glyceride (2-AG) and other related compounds known as endocannabinoids. o Once bound, activates a G-protein cascade that activates and inhibits a number of signal transduction pathways involved. o G-protein directly inhibit N and P/Q-type voltage dependant Ca2+ and Na+ channels, and indirectly inhibit A-type Ca2+ channels via inhibition of adenylyl cyclase. o G-protein also activates inwardly K+ channel and the MAP kinase. o Cumulative effect of these pathways is the euphoric feelings associated with cannabis use. Sidetrack – production of endocannabinoids: o These work through synaptic retrograde transmission. o Binding of glutamate to its receptor on the postsynaptic neuron causes an influex of Ca2+, which induces the production of endocannabinoids in the post-synaptic neuron. o Binding occurs at the cannabinoid receptor (CB1) present on presynaptic neurons, where they modulate neurotransmission. Perceived positive effects: o Relaxation. o Euphoria. o Altered space-time perception. o Alteration of visual, auditory and olfactory senses. o Pain relief in many chronic conditions. Negative effects: o Anxiety. o Disorientation, confusion. o Acute panic reactions, anxiety attacks, fear and a sense of helplessness. o Fatigue appetite stimulation (“the munchies”) due to activity of CB1 in the hunger centres. With long-term use: o Greater risk of developing psychosis. o Brain atrophy in hippocampus and amygdala.