The interaction of cocaine with serotonin dorsal raphe neurons: Single-unit extracellular recording studies

Cocaine potently inhibits the spontaneous activity of dorsal raphe serotonin (5-hydroxytryptamine [5-HT]) neurons which possess impulse-modulating receptors of the 5-HT_1A subtype. In an investigation of the neuropharmacologic mechanisms underlying this electrophysiologic effect, we have compared cocaine with structurally and functionally similar compounds, attempted to reverse cocaine-induced suppression of 5-HT dorsal raphe nucleus (DRN) neuronal activity, and assessed the effects of 5-HT depletion on the response to cocaine. Extracellular recordings in chloral hydrate-anesthetized rats were obtained using single-unit recording techniques; drugs were infused intravenously (IV) in a cumulative dose manner. The active isomer (-)-cocaine (ID₅₀ = 0.5 ± 0.15 mg/kg) and the phenyltropane analogue WIN 35428 (ID₅₀ = 0.17 ± 0.03 mg/kg) that share the ability of cocaine to block monoamine uptake also inhibit impulse activity in 5-HT neurons. In contrast, the inactive isomers (+)-cocaine, (+)-pseudococaine and the metabolite benzoylecgonine do not exhibit the same range of potency (maximal 20% to 30% inhibition at a cumulative dose of 8 to 16 mg/kg). A selective inhibitor of uptake for 5-HT (fluoxetine; ID₅₀ = 1.8 ± 0.5 mg/kg), but not norepinephrine (desipramine) or dopamine (GBR 12909), mimicked cocaine, as did the monoamine releaser amphetamine (ID₅₀ = 2.86 ± 0.46 mg/kg). The putative 5-HT_1A autoreceptor antagonist spiperone reversed the cocaine-induced depression of firing rate in 64% of 5-HT neurons tested whereas receptor antagonists for dopamine D₂ (haloperidol), 5-HT₂ (ketanserin), γ-aminobutyric acid (picrotoxin) and 5-HT₁/ β-adrenergic (propranolol) were ineffective. Following treatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (100 mg/kg/day of the base for 3 days), impulse depression induced by cocaine was significantly attenuated as compared to control, which suggests that the effects of cocaine may be dependent on endogenous 5-HT stores. In summary, these findings support the hypothesis that the inhibitory effects of cocaine on 5-HT DRN neurons are mediated by increased 5-HT available for interaction with 5-HT_1A impulse-regulating autoreceptors in the DRN, as a consequence of cocaine-induced blockade of 5-HT reuptake processes. Further studies are required to clarify the relative contribution of cocaine-5-HT interactions to the behavioral and physiologic effects of this psychostimulant.