Brain changes in ketamine users
Essentially, ketamine is known to work by being an NMDA antagonist, i.e. it binds to NMDA receptors on GABA neurons (inhibitory neurons). By blocking the action of inhibitory neurons, it leads to increased excitation (i.e, increased firing) - and thus is used as an antidepressant. Ketamine specifically excites thalamic neurons. This region is responsible for dopamine transmission; thus, disinhibiting the thalamic region increases dopamine release. As dopamine is responsible for pleasure, ketamine is effective as an antidepressant.
Although this is the dominant theory, there are various proposed mechanisms, each of which have their own evidence. These involve the suppression of certain ion channels, inhibition of serotonin reuptake (thus increasing serotonin’s activity), and stimulation of opioid receptors. Ketamine has also shown to increase BDNF (Brain-Derived-Neurotrophic-Factor, a protein that increases neural growth - see image below). If interested in these exact mechanisms by which these processes occur, I would suggest the following review - Ketamine: 50 Years of Modulating the Mind
With regards to effects on the brain, evidence suggests that chronic ketamine use has decreased the activity of gamma waves (related to complex cognitive processing) in the brain, has depressed alpha wave activity (associated with semi-arousal or wakefulness).
It has been found that ketamine use increases frontal lobe activity (responsible for planning and decision-making), and lowers activity in the anterior cingulate gyrus (plays a role in emotions). It also lowers activity in the mid-brain(handles involuntary and reflex responses), and raises activity in the striatum (role in motor movement and reward).
Evidence has also shown reduced connectivity in the right sagittal striatum(contains dopaminergic circuits contributing to pleasure and movement), thalamic regions (important for regulating wakeness, and relaying signals to sensory and motor regions), the retrolenticular limb of the internal capsule (contributes to relaying signals from the sensory cortex), superior longitudinal fasciculus (contributes to sensory processing), as well as the temporal (involved in language processing), and frontal regions (response inhibition, decision-making). Additionally, it has shown to reduce activation in the hippocampus (responsible for memory). fMRI studies have also found decreased occipital (visual processing) and precentral (motor movement) activity. Most of these brain regions are shown below.
In terms of neurotransmitter-related regions, ketamine intake has corresponded to reduce activity in serotonic (contributes to pleasure), cholinergic (motor movement, memory), and noradrenergic (responsible for the ‘fight-or-flight’ response) brain circuits. It has also been suggested to increase dopamine, a hallmark for identifying schizophrenia.
Dopaminergic and serotonic pathways:
Noradrenergic pathway (of note is the locus coeruleus):