Abstract
Although in vivo evidence indicates that salsolinol, the condensation product of acetaldehyde and dopamine, has properties that may contribute to alcohol abuse, the underlying mechanisms have not been fully elucidated. We have reported previously that salsolinol stimulates dopamine neurons in the posterior ventral tegmental area (p-VTA) partly by reducing inhibitory GABAergic transmission, and that ethanol increases glutamatergic transmission to VTA-dopamine neurons via the activation of dopamine D1 receptors (D1Rs). In this study, we tested the hypothesis that salsolinol stimulates dopamine neurons involving activation of D1Rs. By using whole-cell recordings on p-VTA-dopamine neurons in acute brain slices of rats, we found that salsolinol-induced increase in spike frequency of dopamine neurons was substantially attenuated by DL-2-amino-5-phosphono-valeric acid and 6, 7-dinitroquinoxaline-2, 3-dione, the antagonists of glutamatergic N-Methyl-D-aspartic acid and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Moreover, salsolinol increased the amplitude of evoked excitatory postsynaptic currents (EPSCs) and the frequency but not the amplitude of spontaneous EPSCs. Additionally, SKF83566, a D1R antagonist attenuated the salsolinol-induced facilitation of EPSCs and of spontaneous firing of dopamine neurons. Our data reveal that salsolinol enhances glutamatergic transmission onto dopamine neurons via activation of D1Rs at the glutamatergic afferents in dopamine neurons, which contributes to salsolinol's stimulating effect on p-VTA dopamine neurons. This appears to be a novel mechanism which contributes toward rewarding properties of salsolinol.
Highlights
The racemic mixture of salsolinol ((R) + (s)-salsolinol) is formed by nonenzymatic Pictet-Spengler condensation of dopamine with acetaldehyde, the major metabolite of ethanol in the brains of mammals [1,2]
While the brain was kept in ice-cold glycerol-based artificial cerebrospinal fluid (GACSF) – containing 252 mM glycerol, 1.6 mM KCl, 1.2 mM NaH2PO4, 1.2 mM MgCl2, 2.4 mM CaCl2, 18 mM NaHCO3, and 11 mM glucose, and oxygenated with 95% O2/5% CO2. 200–250 mm thick slices were cut in the coronal plane
Whole-cell recording was performed in posterior VTA (p-VTA)-DA neurons in coronal midbrain slices of rats
Summary
The racemic mixture of salsolinol ((R) + (s)-salsolinol) is formed by nonenzymatic Pictet-Spengler condensation of dopamine with acetaldehyde, the major metabolite of ethanol in the brains of mammals [1,2]. More recent studies showed that rats self-administer salsolinol into posterior VTA (p-VTA), a key region in the brain reward system [7,8], and that microinjection of salsolinol into the p-VTA of rats induces conditioned place preference [9]. Such behaviors seem to depend on activation of dopaminergic (DA) neurons [8] and associated with enhanced dopamine levels in the ipsilateral nucleus accumbens shell [9]. Gabazine (10 mM) failed to completely abolish salsolinol-induced increase in DA neuron firing, indicating that other mechanisms may be involved
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