Clozapine and cocaine effects on dopamine and serotonin release in nucleus accumbens during psychostimulant behavior and withdrawal.
Level 5 - mechanism / opinion, no new human data
Animal research (non-human experimental study)
PubMed 14687870 · doi:10.1016/j.pnpbp.2003.09.032
What was done
Male Sprague-Dawley rats were administered either cocaine alone (10 mg/kg IP, n=5) or clozapine co-administered with cocaine (20 mg/kg and 10 mg/kg IP, n=6). Real-time dopamine (DA) and serotonin (5-HT) release in the nucleus accumbens was measured via in vivo microvoltammetry using BRODERICK PROBE microelectrodes, while locomotor activity was monitored simultaneously using infrared photobeams. Measurements were recorded acutely following drug injection and subacutely at 24-hour follow-up without further drug administration. Depolarization blockade with gamma-butyrolactone was used to assess release mechanisms.
What was found
Acute cocaine significantly increased DA release, 5-HT release, and locomotor activity above baseline (all P < .001). At 24-hour follow-up, cocaine-treated animals showed DA release significantly below baseline (P < .001) and a maximum 40% decrease in 5-HT release below baseline (P < .05), while locomotor activity remained elevated (P < .05). Clozapine co-administration acutely blocked cocaine-induced increases in DA (P < .001), 5-HT (P < .001), and locomotion (P < .001). Subacutely at 24 hours, the clozapine/cocaine group continued to show decreased DA release (P < .001), but 5-HT release increased significantly above baseline (P < .001), and locomotor activity returned to baseline levels (P > .05).
Why it matters
This study provides mechanistic evidence in a rodent model that clozapine suppresses acute cocaine-induced monoamine surges and hyperlocomotion. It also indicates that clozapine can normalize subacute serotonin depletion associated with cocaine withdrawal, though dopamine suppression persists.
Limits
The findings are derived entirely from a very small sample of male Sprague-Dawley rats (n=5 to 6 per group). As an acute and subacute animal study, it does not capture chronic human cocaine dependence, withdrawal syndromes, or clinical cocaine-induced psychosis, and specific receptor subtype contributions were not directly isolated.
Cited by
- supports Large surges in dopamine from stimulant drugs of abuse (like cocaine or amphetamines) are followed by a drop in dopamine below baseline levels.