Serotonin-3 receptors in the posterior ventral tegmental area regulate ethanol self-administration of alcohol-preferring (P) rats

Abstract

Several studies indicated the involvement of serotonin-3 ([5-hydroxy tryptamine] 5-HT(3)) receptors in regulating alcohol-drinking behavior. The objective of this study was to determine the involvement of 5-HT(3) receptors within the ventral tegmental area (VTA) in regulating ethanol self-administration by alcohol-preferring (P) rats. Standard two-lever operant chambers (Coulbourn Instruments, Allentown, PA) were used to examine the effects of seven consecutive bilateral microinfusions of ICS 205-930 (ICS), a 5-HT(3) receptor antagonist, directly into the posterior VTA on the acquisition and maintenance of 15% (vol/vol) ethanol self-administration. P rats readily acquired ethanol self-administration by the fourth session. The three highest doses (0.125, 0.25, and 1.25 microg) of ICS prevented acquisition of ethanol self-administration. During the acquisition postinjection period, all rats treated with ICS demonstrated higher responding on the ethanol lever, with the highest dose producing the greatest effect. In contrast, during the maintenance phase, the three highest doses (0.75, 1.0, and 1.25 microg) of ICS significantly increased responding on the ethanol lever; after the 7-day dosing regimen, responding on the ethanol lever returned to control levels. Microinfusion of ICS into the posterior VTA did not alter the low responding on the water lever and did not alter saccharin (0.0125% wt/v) self-administration. Microinfusion of ICS into the anterior VTA did not alter ethanol self-administration. Overall, the results of this study suggest that 5-HT(3) receptors in the posterior VTA of the P rat may be involved in regulating ethanol self-administration. In addition, chronic operant ethanol self-administration and/or repeated treatments with a 5-HT(3) receptor antagonist may alter neuronal circuitry within the posterior VTA.

Fig. 1

Representative injection sites in the anterior and posterior VTA of P rats. Overlapping injection sites are not indicated. Closed circles represent injection sites within the posterior VTA (defined as –5.3 to –6.0 mm Bregma), and closed squares represent injection sites within the anterior VTA (defined as –4.8 to –5.2 mm Bregma). On the right hand side are photomicrographs which indicate an anterior (top) and posterior (bottom) VTA dual placement.

Fig. 2

Number of EtOH responses (FR1) ± SEM following microinjections of ICS205-930 into the posterior VTA during acquisition of ethanol self-administration. Asterisks (*) indicate that rats bilaterally infused with 0.125, 0.25 or 1.25 μg/side of ICS responded significantly less than all other groups. Plus (+) symbol indicates that rats bilaterally infused with 0.125 or 1.25 μg/side of ICS responded significantly less than all other groups. Pound (#) symbols indicate that rats that received ICS during the injection period responded more for ethanol than no injection and aCSF controls.

Fig. 3

Number of water responses (FR1) ± SEM following microinjections of ICS into the posterior VTA during acquisition of ethanol self-administration. ICS did not alter water responding.

Fig. 4

Number of ethanol responses (FR5) ± SEM following microinjections of ICS205-930 into the posterior VTA during maintenance of ethanol self-administration. Single asterisk indicates that rats bilaterally infused with 1.25 μg/side of ICS responded significantly more than the aCSF group. Plus symbols indicate that rats that received bilaterally microinjections of 1.0 and 1.25 μg/side of ICS responded more for ethanol than aCSF controls and 0.25, 0.5 μg/side of ICS groups. Pound symbols indicate that rats that received 0.75, 1.0 and 1.25 μg/side of ICS responded more for ethanol than all other groups. Double Asterisks indicate that rats that received 0.75 and 1.0 μg/side of ICS responded more for ethanol than all other groups.

Fig. 5

Number of saccharin responses (FR5) ± SEM following microinjections of ICS205-930 into the posterior VTA during maintenance of Saccharin self-administration. Microinjections of ICS into the posterior VTA did not alter saccharin self-administration.

Fig. 6

Number of ethanol responses (FR5) ± SEM following microinjections of ICS205-930 into the anterior VTA during maintenance of ethanol self-administration. Microinjections of ICS into the anterior VTA did not alter ethanol self-administration.