Actions of cocaine on rat dopaminergic neurones in vitro

Abstract

1 Intracellular recordings were made from neurones in vitro in the rat substantia nigra zona compacta and ventral tegmental area; the neurones had the characteristic properties of dopamine-containing cells, and fired action potentials spontaneously. 2 Cocaine (1-104uM) inhibited spontaneous firing, hyperpolarized the membrane and (in neurones voltage-clamped at -60 mV) caused an outward membrane current; the minimally effective concentration was 1 pm. These effects were blocked by sulpiride (30 nM-iIM).3 Dopamine (3-100yM) also inhibited firing, hyperpolarized and caused an outward current. These effects of dopamine were potentiated about five fold by cocaine (10 pM).4 It is concluded that cocaine (1-10pM) inhibits the firing and hyperpolarizes substantia nigra zona compacta neurones in vitro by blocking the uptake of dopamine which the cells continuously release.

Electrophysiologic Changes in Ventral Midbrain Dopaminergic Neurons Resulting from (+/−) -3,4-Methylenedioxymethamphetamine (MDMA—“Ecstasy”)

“…A similar leftward shift of the DA concentration effect curve has been observed with other uptake blockers, suggesting that this value is a typical feature encountered when DAT is pharmacologically inhibited (Federici et al 2005;Lacey et al 1990;Mercuri et al 1991).…”

“…Consequently, during the action of MDMA, DA, normally released from the soma and dendrites of the dopaminergic cells in the extracellular space (Cheramy et al 1981), is not properly cleared by the blocked DAT. Actions similar to those caused by MDMA on the dopaminergic neurons, which are also reserpine-resistant and carbidopa-sensitive, have been described at the neuronal level and said to be caused by the DA uptake blockers cocaine, amineptine, and methylphenidate (Federici et al 2005;Lacey et al 1990;Mercuri et al 1991). Thus, cocaine-like actions of MDMA could be consistent with the firing inhibition of the mesencephalic DAergic neurons (Einhorn et al 1988;Lacey et al 1990).…”

“…Actions similar to those caused by MDMA on the dopaminergic neurons, which are also reserpine-resistant and carbidopa-sensitive, have been described at the neuronal level and said to be caused by the DA uptake blockers cocaine, amineptine, and methylphenidate (Federici et al 2005;Lacey et al 1990;Mercuri et al 1991). Thus, cocaine-like actions of MDMA could be consistent with the firing inhibition of the mesencephalic DAergic neurons (Einhorn et al 1988;Lacey et al 1990). Furthermore, the concentration of MDMA potentiating DA responses is in a micromolar range comparable to the inhibition of DA reuptake into striatal synaptosomes (Crespi et al 1997) and the control of MPPϩ release in recombinant cellular systems (Pifl et al 2005).…”

“…More interesting is the evidence that MDMA 1) potentiates the cellular responses to exogenously applied DA by impeding catecholamine reentering the cells (Pifl et al 1995) and 2) reduces the electrophysiologic actions of amphetamine by inhibiting a DAT-mediated DA efflux (Scarponi et al 1999), suggesting that it behaves, at least electrophysiologically, as a classical DA uptake blocker (Lacey et al 1990). In addition, the observation that an amphetamine-inhibiting concentration of MDMA does not significantly attenuate but augments the peak cellular response to cocaine supports the concept that both drugs have similar converging effects blocking DAT.…”

Differential Autoreceptor Control of Somatodendritic and Axon Terminal Dopamine Release in Substantia Nigra, Ventral Tegmental Area, and Striatum

“…Neuromodulatory actions of somatodendritic DA include autoreceptor inhibition of impulse propagation (Groves et al, 1975;Aghajanian and Bunney, 1977;Lacey et al, 1987Lacey et al, , 1990Mercuri et al, 1989) and heteroreceptor regulation of nondopamine transmission from systems innervating these regions (Gale et al, 1977;Reubi et al, 1978;Waszczak and Walters, 1983, 1986Lantin Le Boulch et al, 1991;Aceves et al, 1992;Cameron and Williams, 1993). However, somatodendritic signaling may differ from axon terminal transmission in several respects (see Rice et al, 1997).…”