question: what does it mean to down regulate and why does the brain down regulate dopamine?
comment: Downregulate in biology just refers to something else (X) making Y go down. It can also refer to the number of receptors for Y. So for dopamine specifically, if you have a ton of dopamine in your brain, that would lead to a very strong dopamine signal and it might downregulate the number of dopamine receptors to try and maintain a balance. Likewise, a small amount of dopamine would upregulate, or increase the number of receptors to maintain transmission. If you take a drug that releases dopamine in your brain, it could desensitize the dopamine receptors and make them go back into the cell.
passages: Section::::Regulation.
   The mesocortical pathway is primarily involved in the regulation of executive functions (e.g., attention, working memory, inhibitory control, planning, etc.), so it is particularly relevant to ADHD. The mesolimbic pathway regulates incentive salience, motivation, reinforcement learning, and fear, among other cognitive processes. 
   Other laboratories have now shown that STEP activity is also reduced in several additional disorders. Thus, STEP levels or activity is decreased in Huntington’s disease, cerebral ischemia, alcohol abuse, and stress disorders. The emergent model suggests that an optimal level of STEP is required at synaptic sites, and that both high and low levels disrupt synaptic function.
  
  Section::::Inhibition.
   Mesocorticolimbic pathways, as mentioned above in relation to the basal ganglia, are thought to mediate learning. Various models have been proposed, however the dominant one is that of temporal difference learning, in which a prediction is made before a reward and afterwards adjustment is made based on a learning factor and reward yield versus expectation leading to a learning curve.
   Section::::Downregulation and upregulation of receptors.
   The dopaminergic pathways that project from the substantia nigra pars compacta and ventral tegmental area into the striatum (i.e., the nigrostriatal and mesolimbic pathways, respectively) form one component of a sequence of pathways known as the cortico-basal ganglia-thalamo-cortical loop. This method of classification is used in the study of many psychiatric illnesses. The nigrostriatal component of the loop consists of the SNc, giving rise to both inhibitory and excitatory pathways that run from the striatum into the globus pallidus, before carrying on to the thalamus, or into the subthalamic nucleus before heading into the thalamus. The dopaminergic neurons in this circuit increase the magnitude of phasic firing in response to positive reward error, that is when the reward exceeds the expected reward. These neurons do not decrease phasic firing during a negative reward prediction (less reward than expected), leading to hypothesis that serotonergic, rather than dopaminergic neurons encode reward loss. Dopamine phasic activity also increases during cues that signal negative events, however dopaminergic neuron stimulation still induces place preference, indicating its main role in evaluating a positive stimulus. From these findings, two hypotheses have developed, as to the role of the basal ganglia and nigrostiatal dopamine circuits in action selection. The first model suggests a "critic" which encodes value, and an actor which encodes responses to stimuli based on perceived value. However, the second model proposes that the actions do not originate in the basal ganglia, and instead originate in the cortex and are selected by the basal ganglia. This model proposes that the direct pathway controls appropriate behavior and the indirect suppresses actions not suitable for the situation. This model proposes that tonic dopaminergic firing increases the activity of the direct pathway, causing a bias towards executing actions faster.
   The mesolimbic pathway is involved in motivation cognition. Depletion of dopamine in this pathway, or lesions at its site of origin, decrease the extent to which an animal is willing to go to obtain a reward (e.g., the number of lever presses for nicotine or time searching for food). Dopaminergic drugs are also able to increase the extent an animal is willing to go to get a reward, and the firing rate of neurons in the mesolimbic pathway increases during anticipation of reward. Mesolimbic dopamine release was once thought to be the primary mediator of pleasure, but is now believed to have only a minor role in pleasure perception.
   The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain, to the ventral striatum of the basal ganglia in the forebrain. The ventral striatum includes the nucleus accumbens and the olfactory tubercle. The release of dopamine from the mesolimbic pathway into the nucleus accumbens regulates incentive salience (i.e., motivation and desire for rewarding stimuli) and facilitates reinforcement and reward-related motor function learning; it may also play a role in the subjective perception of pleasure. The dysregulation of the mesolimbic pathway and its output neurons in the nucleus accumbens plays a significant role in the development and maintenance of an addiction.
   Section::::Pathways.
  
  There are a number of dopaminergic pathways in the human brain. The six major ones are listed in the table below.
  
  Major pathways (same as above)
  
  Other pathways
  
  BULLET::::- VTA → Amygdala
  
  BULLET::::- VTA → Hippocampus
  
  BULLET::::- VTA → Cingulate cortex
  
  BULLET::::- VTA → Olfactory bulb
  
  BULLET::::- SNc → Subthalamic nucleus
  
  The mesocortical and mesolimbic pathways are sometimes referred to simultaneously as the mesocorticolimbic projection, system, or pathway.
  
  Section::::Function.
   BULLET::::- Movement, motivation, attention, neurological and psychiatric disorders and addictive behavior have a strong influence by Dopaminergic signalling.
  
  BULLET::::- The dopaminergic neurons have a low irregular basal firing frequency in 1–8 Hz range "in vivo" in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). This frequencies can dramatically increase in response to a cue predicting reward or unpredicted reward. The actions that preceded the reward are reinforced by this burst or phasic signal.
   BULLET::::- The projections from the ventral tegmental area (VTA) are a network of dopaminergic neurons with co-localized postsynaptic glutamate receptors (AMPAR and NMDAR). These cells respond when stimuli indicative of a reward are present. The VTA supports learning and sensitization development and releases DA into the forebrain. These neurons also project and release DA into the nucleus accumbens, through the mesolimbic pathway. Virtually all drugs causing drug addiction increase the dopamine release in the mesolimbic pathway, in addition to their specific effects.
   All living cells have the ability to receive and process signals that originate outside their membranes, which they do by means of proteins called receptors, often located at the cell's surface imbedded in the plasma membrane. When such signals interact with a receptor, they effectively direct the cell to do something, such as dividing, dying, or allowing substances to be created, or to enter or exit the cell. A cell's ability to respond to a chemical message depends on the presence of receptors tuned to that message. The more receptors a cell has that are tuned to the message, the more the cell will respond to it.
   Mechanistically, neuromodulation is increasingly being recognized for its fine-tuning of the PV cell-mediated inhibition of excitatory pyramidal neurons' soma. Central to the neuromodulatory regulation of PV cell activity is the existence of distinct subsets of inhibitory neurons, which are responsive to activation by neuromodulators and which inhibit PV cells. Within these cells, some also inhibit specific pyramidal cell dendrites. By inhibiting PV cells activity, the neuromodulator-sensitive inhibitory cells such as those expressing Vasoactive intestinal peptide (VIP) or somatostatin (SST) lift the inhibition of the pyramidal neurons; in other words, the activity of VIP and SST-expressing cells result in the disinhibition of pyramidal neurons. Then, by inhibiting only certain dendritic branches of these now dis-inhibited pyramidal neurons, the neuromodulation-activated cells allow select sensory inputs to excite the pyramidal neurons and be represented in the brain circuitry. Thus, in a landscape of global inhibition by maturing inhibitory signaling, neuromodulation allows windows of dis-inhibition, temporally and spatially, that allow behaviorally important sensory inputs the opportunity to influence the brain.
   In the brain the level of extracellular dopamine is modulated by two mechanisms: phasic and tonic transmission. Phasic dopamine release, like most neurotransmitter release in the nervous system, is driven directly by action potentials in the dopamine-containing cells. Tonic dopamine transmission occurs when small amounts of dopamine are released without being preceded by presynaptic action potentials. Tonic transmission is regulated by a variety of factors, including the activity of other neurons and neurotransmitter reuptake.
  
  Section::::Functions.:Nervous system.
   The second important effect of dopamine is as a "teaching" signal. When an action is followed by an increase in dopamine activity, the basal ganglia circuit is altered in a way that makes the same response easier to evoke when similar situations arise in the future. This is a form of operant conditioning, in which dopamine plays the role of a reward signal.
  
  Section::::Functions.:Nervous system.:Reward.
   The release of dopamine in the nucleus accumbens plays a role in the reinforcing qualities of many forms of stimuli, including naturally reinforcing stimuli like palatable food and sex. Altered dopamine neurotransmission is frequently observed following the development of an addictive state. In humans and lab animals that have developed an addiction, alterations in dopamine or opioid neurotransmission in the nucleus accumbens and other parts of the striatum are evident. Studies have found that use of certain drugs (e.g., cocaine) affect cholinergic neurons that innervate the reward system, in turn affecting dopamine signaling in this region.
  
  Section::::Mechanisms.:Reward system.
   The ventral tegmental area and substantia nigra pars compacta receive inputs from other neurotransmitters systems, including glutaminergic inputs, GABAergic inputs, cholinergic inputs, and inputs from other monoaminergic nuclei. The VTA contains 5-HT receptors that exert a biphasic effects on firing, with low doses of 5-HT receptor agonists eliciting an increase in firing rate, and higher doses suppressing activity. The 5-HT receptors expressed on dopaminergic neurons increase activity, while 5-HT receptors elicit a decrease in activity. The mesolimbic pathway, which projects from the VTA to the nucleus accumbens, is also regulated by muscarinic acetylcholine receptors. In particular, the activation of muscarinic acetylcholine receptor M2 and muscarinic acetylcholine receptor M4 inhibits dopamine release, while muscarinic acetylcholine receptor M1 activation increases dopamine release. GABAergic inputs from the striatum decrease dopaminergic neuronal activity, and glutaminergic inputs from many cortical and subcortical areas increase the firing rate of dopaminergic neurons. Endocannabinoids also appear to have a modulatory effect on dopamine release from neurons that project out of the VTA and SNc. Noradrenergic inputs deriving from the locus coeruleus have excitatory and inhibitory effects on the dopaminergic neurons that project out of the VTA and SNc. The excitatory orexinergic inputs to the VTA originate in the lateral hypothalamus and may regulate the baseline firing of VTA dopaminergic neurons.
   In terms of the gene Opn4, Dopamine (DA) is a factor in the regulation of melanopsin mRNA in ipRGCs.
  
  Section::::Clinical significance.
   Section::::Functions.:Nervous system.:Reward.:Pleasure.
   Section::::Biochemistry.
  
  Section::::Biochemistry.:Synthesis.
  
  Dopamine is synthesized in a restricted set of cell types, mainly neurons and cells in the medulla of the adrenal glands. The primary and minor metabolic pathways respectively are:
   Researching addiction to food, for example, a 2009 Scripps Research Institute study found evidence that the same molecular mechanisms correlated with human drug addiction also exist in compulsive overeating in obese rats. The dopamine D receptor studied is associated with vulnerability to drug addiction in humans. It was found downregulated in obese rats exposed to a high fat diet, and further reductions of the receptor increased compulsive eating. The D receptor responds to dopamine, a central neurotransmitter released in anticipation of rewarding, satiating experiences such as those involving food, sex or psychoactive drugs.
   Section::::Functions.:Cellular effects.:Storage, release, and reuptake.
   Section::::The Overdose Hypothesis.
   Receptors are created, or expressed, from instructions in the DNA of the cell, and they can be increased, or upregulated, when the signal is weak, or decreased, or downregulated, when it is strong. Their level can also be up or down regulated by modulation of systems that degrade receptors when they are no longer required by the cell. 
   Stimulants used regularly in neuroscience experimentation are cocaine and amphetamine. These drugs induce an increase in synaptic dopamine by inhibiting the reuptake of dopamine from the synaptic cleft, effectively increasing the amount of dopamine that reaches the target neuron.
  
  Section::::The reward pathway.
  