Differential actions of cocaine and amphetamine on dorsal raphe neurons in vitro

Z. Z. Pan, J. T. Williams

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


Intracellular recordings of membrane potential were made from neurons in nucleus dorsal raphe in the rat brain slice. Cocaine (300 nM-30 μM) caused a concentration-dependent hyperpolarization of the membrane potential, with a maximum effect of 13.3 ± 2.2 mV (N = 6) and an EC50 of 4.2 μM. This action was antagonized by spiperone (1 μM), suggesting that the hyperpolarization was mediated indirectly througgh endogenous 5-hydroxytryptamine (5-HT). Cocaine (300 nM) increased the time constant for decay (τ2) of the 5-HT inhibitory postsynaptic potential (IPSP) from 432 ± 57 msec to 708 ± 81 msec (N = 14); 10 μM increased τ2 by about 9-fold. Amphetamine (100 nM-10 μM) caused a depolarization that was antagonized by prazosin (100 nM). In slices taken from reserpine-treated animals (5 mg/kg, 12 hr), the 5-HT-mediated IPSP, the noradrenaline-mediated slow excitatory postsynaptic potential and the amphetamine-induced depolarization were absent. These results indicate that the amphetamine-induced depolarization resulted from the release of endogenous noradrenaline. In the presence of prazosin (100 nM), amphetamine caused a hyperpolarization at a threshold concentration of 10 μM, had an EC50 of 26 μM and a maximum effect of 10 ± 0.9 mV (N = 8). This hyperpolarization as well as the cocaine-induced hyperpolarization were not reduced by prior treatment with reserpine. Amphetamine (10 μM) caused a 2.2-fold increase in the time constant of decay of the IPSP with no change in the amplitude. At a concentration of 30 μM the amplitude was reduced from 12.7 ± 0.9 mV (N = 10) to 2.0 ± 0.2 mV (N = 9) by amphetamine. Cocaine prolonged the IPSP and hyperpolarized the membrane potential. The prolongation of the IPSP resulted from inhibition of 5-HT uptake. The hyperpolarization resulted from the accumulation of spontaneously released 5-HT in the slice. Amphetamine had a similar hyperpolarizing action at about 10-fold higher concentrations and a weak effect on the duration of the IPSP. The results suggest that the major actions of cocaine and amphetamine on dorsal raphe neurons are different. Cocaine was inhibitory by enhancing 5-HT actions, whereas amphetamine caused an excitation through release of noradrenaline.

Original languageEnglish (US)
Pages (from-to)56-62
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - 1989

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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