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INNOSC Theranostics and
Pharmacological Sciences Ketamine for cocaine use disorder

ketamine increases the firing rate of DAergic neurons in the depression, potassium channels in astrocytes near LHb are
VTA for up to 24 h post-injection, potentially due to its upregulated, leading to hyperpolarization. This change in
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ability to activate D1R 52,53 by inhibiting several microRNAs membrane potential can lead to LHb bursting, a pattern
in the medial prefrontal cortex (mPFC). 54,55 This can correct dependent on the activation of NMDAR. 66,67 This type of
the low dopamine level and depressive symptoms seen bursting increases the likelihood that action potentials will
during cocaine withdrawal, as activating D1R contributes reach the downstream synaptic target, thus enhancing the
to ketamine’s antidepressant effect by promoting inhibitory effect of LHb on midbrain DAergic neurons. 68
spinogenesis and dendritic plasticity. Consistent with In a mouse model, optogenetically inducing this
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this finding, ketamine-induced behavior sensitization is bursting pattern in LHb neurons can lead to depressive-like
abolished by a D2R antagonist, suggesting ketamine may symptoms whereas blocking NMDAR rescued depressive-
activate D2R as well. This supports ketamine’s treatment like symptoms. Consistent with these findings, Ma et al.
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potential for CUD, as the activation of D2-MSN in NAc reported that systemic ketamine injection significantly
suppresses cocaine self-administration. 8,57 reduced bursting neurons in mice brain slices just 1-h
Interestingly, another study found that neither ketamine post-injection, with effects lasting up to 24 h. Although
nor its metabolite showed any antagonist/agonist effect these studies are mostly done using depression models,
on D1R or D2R. Instead, ketamine’s effect on dopamine cocaine’s ability to induce depressive symptoms through
is mediated by its effect on AMPA and NMDA receptors similar pathways underscores ketamine’s potential in
on VTA DAergic neurons. 9,58 It has been shown that acute treating CUD. A study found that cocaine administration
ketamine administration increases DAergic neuron firing increased the phosphorylation at S845 of GluA1, a subunit
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by amplifying AMPA transmission, whereas AMPAR of AMPAR in the LHb. Phosphorylation at this position
antagonists abolish this effect. 59,60 Consistently, chronic can increase AMPAR insertion on the cell surface and the
ketamine administration led to an increase in AMPAR but probability of channel opening, thus increasing the chance
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not NMDAR density, pointing to ketamine’s direct impact of NMDAR activation. Interestingly, although blocking
on AMPARs. 60 AMPAR did not decrease burst firing in LHb neurons,
increased AMPAR current or administration of AMPA
Despite ketamine’s therapeutic potential, there is still increased burst frequency. These findings suggest that
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concern about its abuse risk, especially as it activates cocaine may cause depressive symptoms by trafficking
D1R, increases DAergic neuron activity, and inhibits AMPARs to cell membranes, thus increasing LHb neuron
DAT similarly to cocaine. 61-63 However, ketamine does not bursting activity. Ketamine can then target this process by
induce the same drug-evoked synaptic plasticity, especially blocking the downstream NMDAR to stop the bursting
at a subanesthetic dose. This is because synaptic plasticity of LHb neurons, thus assisting in CUD remission. These
generally requires NMDAR activation for excitatory studies demonstrate that ketamine may reverse the
synapse potentiation onto VTA DAergic neurons, while depressive symptoms associated with CUD by preventing
ketamine blocks NMDARs. In addition, ketamine’s fast LHb bursting.
off-kinetic profile prevents prolonged dopamine increases
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that would otherwise promote synaptic plasticity. Thus, 5.3. Ketamine modulates brain-derived
despite its similarity with other addictive substances, neurotrophic factor (BDNF) levels
ketamine’s mechanism of action suggests a lower abuse A third mechanism by which ketamine may aid in CUD
potential. Nonetheless, more research needs to be done to treatment is through its modulation of the BDNF level,
elucidate the best method to take advantage of ketamine’s the most abundant neurotrophic factor in the nervous
therapeutic effect in clinical settings. system. By binding to its receptor tropomyosin kinase B
(TrkB), BDNF can modulate addiction-related neuronal
5.2. Ketamine modulates lateral habenula (LHb) plasticity. Cocaine’s effect on BDNF varies depending on
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neuron bursting
the stage of the addiction cycle. 73,74 Research indicates that
Another mechanism through which ketamine can alleviate serum or plasma BDNF levels increase with acute cocaine
depressive symptoms is by blocking neuronal bursting use and during periods of cocaine abstinence but decrease
activity in the LHb. The LHb is associated with negative with prolonged cocaine use. 75-79 This is consistent with the
reward processing, as it stimulates the rostromedial co-occurrence between cocaine use and depression since
tegmental nucleus, which inhibits VTA DAergic neurons a decrease in BDNF is also associated with depression.
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(Figure 1). Based on their activity, LHb neurons Interestingly, during withdrawal, a high level of BDNF
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could be categorized as: silent, tonic-firing, and burst- is associated with cocaine craving, and cocaine-induced
firing. Several studies found that, in animal models of depression has a higher BDNF level compared to primary
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Volume 8 Issue 1 (2025) 36 doi: 10.36922/itps.4458