What is the effect of cocaine on gamma-aminobutyric acid (GABA) in the brain?

Cocaine's Effect on GABA in the Brain

Cocaine acutely inhibits GABA transmission through multiple mechanisms, including direct suppression of GABA(A) receptors and indirect modulation via serotonin pathways, while chronic cocaine use causes persistent alterations in GABA signaling with elevated extracellular GABA levels and desensitized GABA(B) receptors. 1, 2, 3

Acute Effects of Cocaine on GABA

Direct Inhibition of GABA(A) Receptors

• Cocaine directly depresses GABA(A) receptor-mediated currents in hippocampal neurons in a concentration-dependent and voltage-independent manner 3
• This inhibition is mediated through a dephosphorylation mechanism: cocaine increases intracellular calcium, which activates phosphatases that dephosphorylate GABA(A) receptors, reducing their function 3
• The effect is strongly enhanced when intracellular calcium concentration increases from 0.01 to 5 μM 3
• This direct GABAergic disinhibition may contribute to cocaine's convulsant properties and seizure risk 3

Indirect Modulation via Serotonin Pathways

• In the ventral tegmental area (VTA), cocaine inhibits GABA(B)-mediated inhibitory postsynaptic potentials through a serotonin-dependent mechanism 1
• Cocaine blocks serotonin reuptake, increasing serotonin concentrations at presynaptic 5-HT1D receptors on GABAergic terminals 1
• This serotonin-mediated effect reduces GABA release onto dopamine neurons, occurring at lower cocaine concentrations (0.1-10 μM) than those required for dopamine transporter blockade 1
• The reduction in GABAergic inhibition leads to increased activation of dopamine neurons in the reward pathway 1

Chronic Effects of Cocaine on GABA

Elevated Basal GABA Levels

• After 14-28 days of chronic cocaine administration (but not 7 days), basal extracellular GABA levels are significantly elevated in the nucleus accumbens during withdrawal 4, 2
• This elevation persists at 3 weeks after discontinuing cocaine and depends on neuronal activity, as it is normalized by blocking voltage-dependent sodium channels 2

GABA(B) Receptor Desensitization

• The elevated extracellular GABA causes functional desensitization of GABA(B) presynaptic autoreceptors and heteroreceptors 4, 2
• Baclofen-stimulated GTPγS binding is reduced, indicating diminished G-protein coupling 2
• This desensitization results from decreased serine phosphorylation of the GABA(B2) receptor subunit, not from changes in total receptor protein levels 2
• Despite desensitization, the elevated GABA provides increased tone on GABA(B) receptors, as blocking these receptors produces greater elevations in extracellular GABA, dopamine, and glutamate in cocaine-treated versus control subjects 2

Impaired Presynaptic Control

• Chronic cocaine (14-28 days) impairs the effectiveness of presynaptic GABA(B) autoreceptors (controlling GABA release) and heteroreceptors (controlling glutamate release) in the dorsolateral septal nucleus 4
• This results in disinhibition of both inhibitory (GABA) and excitatory (glutamate) neurotransmitter release 4
• Postsynaptic GABA(B) receptor function remains unchanged in this brain region 4

Clinical Implications

Seizure Risk

• The acute inhibition of GABA(A) receptors contributes to cocaine's convulsant effects and explains why seizures are a common manifestation of acute cocaine toxicity 3
• This GABAergic disinhibition provides a mechanistic basis for using benzodiazepines (which enhance GABA(A) receptor function) as first-line treatment for acute cocaine intoxication 5, 6

Therapeutic Targets

• GABAergic medications represent potential pharmacotherapies for cocaine addiction, as the GABA system modulates dopaminergic pathways and cocaine effects 7
• Anticonvulsants with GABAergic effects (tiagabine, topiramate) and GABA(B) receptor agonists (baclofen) have shown promise in clinical trials, particularly in patients with more severe cocaine use 7

Common Pitfalls

• The time course matters: chronic cocaine effects on GABA require at least 14 days of exposure, not shorter durations 4
• Multiple mechanisms are involved: both direct receptor effects and indirect neuromodulatory pathways contribute to cocaine's impact on GABA 1, 3
• Regional specificity exists: different brain regions show distinct patterns of GABA system alterations (e.g., postsynaptic receptors affected in some areas but not others) 4