Dopamine Pathways

Dopamine pathways, sometimes called dopaminergic projections, are the sets of projection neurons in the brain that synthesize and release the neurotransmitter dopamine. Individual neurons in these pathways are referred to as dopamine neurons.

Dopamine neurons have axons that run the entire length of the pathway. The neurons’ somata produce the enzymes that synthesize dopamine, and they are then transmitted via the projecting axons to their synaptic destinations, where most of the dopamine is produced.

Dopaminergic nerve cell bodies in such areas as the substantia nigra tend to be pigmented due to the presence of the black pigment melanin. Dopaminergic pathways are involved in many functions such as executive function, learning, reward, motivation, and neuroendocrine control.

Dysfunction of these pathways and nuclei may be involved in multiple diseases and disorders such as Parkinson’s disease, attention deficit hyperactivity disorder, obsessive compulsive disorder, and addiction.

There are eight dopaminergic pathways. The four major ones are the Mesolimbic pathway, the Mesocortical pathway, Nigrostriatal pathway, and the Tuberoinfundibular pathway. The mesocortical and mesolimbic pathways are sometimes referred to simultaneously as the mesocorticolimbic projection, system, or pathway.

Dopamine Pathways Function

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 illness.

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 hypothesis 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.

These models of the basal ganglia are thought to be relevant to the study of ADHD, Tourette syndrome, Parkinson’s Disease, schizophrenia, OCD, and addiction. For example, Parkinson’s disease is hypothesized to be a result of excessive inhibitory pathway activity, which explains the slow movement and cognitive deficits, while Tourettes is proposed to be a result of excessive excitatory activity resulting in the tics characteristic of Tourettes.

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.

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. 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. Two hypothesized states of prefrontal cortex activity driven by D1 and D2 pathway activity have been proposed; one D1 driven state in which there is a barrier allowing for high level of focus, and one D2 driven allowing for task switching with a weak barrier allowing more information in.

Regulation

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-HT1A receptors that exert a biphasic effects on firing, with low doses of 5-HT1A receptor agonists eliciting an increase in firing rate, and higher doses suppressing activity.

The 5-HT2A receptors expressed on dopaminergic neurons increase activity, while 5-HT2C 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.[29][30]

Image: RCSB Protein Data Bank, Wellcome Images