#neuropharmacology

The human reward system is made up of neural structures responsible for incentive salience (desire), associative learning (primarily positive reinforcement and classical conditioning), and positive/pleasure emotions (e.g. euphoria). 

• Dopamine is the primary neurotransmitter of the brain’s reward mechanisms
• Most important reward pathway is the mesolimbic dopamine pathway.
• Thisconnects the ventral tegmental area (VTA) of the midbrain, to the nucleus accumbens (NAc) and olfactory tubercle, which are located in the ventral striatum 
• Theprojections from the VTA are a network of dopaminergic neurons with co-localized postsynaptic glutamate receptors.
• The NA itself consists mainly of GABAergic medium spiny neurons. 

When a rewarding stimulus, such as eating food, or direct stimulation by a drug occurs, dopaminergic neurons in the VTA are activated. These neurons project to the NAc, and their activation causes dopamine levels in the NAc to rise,activating dopamine receptors and generating a reward response, thus encouraging repetition and learning. –> any activity that resulted in a reward from your brain will therefore be one you want to repeat. This is essentially how your brain keeps you alive and reproducing.

 Another major dopamine pathway, the mesocortical pathway, also originates in the VTA but travels to the prefrontal cortex, and is thought to integrate information which determines whether a behavior will be elicited.Thebasolateral amygdala projects into the NAc and is thought to also be important for motivation, while the hippocampus plays a role in learning and memory. 

Even though increased dopamine in the brain reward system is generally thought to be the final common pathway for the reinforcing properties of drugs, other neurotransmitters such as serotoninare involved in the modulation of both drug self-administration and dopamine levels.  Serotonin may be important in modulating motivational factors, or the amount of work and individual is willing to perform to obtain a drug. Serotonergic neurons project both to the NA and VTA and appear to regulate dopamine release at the NA.  

• Excessive intake of addictive drugs  –> repeated release of high amounts of dopamine –>increased dopamine receptor activation. 
• The intrinsic purpose of an endogenous reward center is to reinforce behaviors that promote survival, so when a drug stimulates this center, drug-seeking behavior is also promoted - induced by glutamatergic projections from the prefrontal cortex to the nucleus accumbens
• Prolonged and abnormally high levels of dopamine in the synaptic cleft can induce receptor downregulation, resulting in a decrease in the sensitivity to natural stimuli. 
• Alongside the positive reinforcement, these withdrawal symptoms can be considered negative reinforcing factors. 
• Discontinued drug use will often induce various negative responses such as chronic irritability, physical pain, emotional pain, malaise, dysphoria, alexithymia, and loss of motivation for natural rewards.

Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms. The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP), (CREB), (NF-κB). Overexpression of ΔFosB in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in drug self-administration and reward sensitization) seen in drug addiction. This means an individuals actual genes are changed by chronic drug use to make them even more addicted  - not just a case of being able to stop when they chose.