Synergistic Self-Administration of Ethanol and Cocaine Directly into the Posterior Ventral Tegmental Area: Involvement of Serotonin-3 Receptors

Abstract

Ethanol (EtOH) and cocaine are both self-administered into the posterior ventral tegmental area (VTA). Self-administration of either drug is prevented by coadministration of a serotonin (5-HT 3 ) receptor antagonist. Electrophysiological studies indicated that cocaine and EtOH can act synergistically to stimulate VTA dopamine neurons. The current experiment assessed whether cocaine and EtOH would synergistically interact to produce a reinforcing action within the posterior VTA. Adult female Wistar rats were randomly assigned to one of 13 groups. There were three control groups: artificial cerebrospinal fluid (aCSF), a subthreshold EtOH (100 mg%) group, and a subthreshold cocaine (25 pmol/100 nl) group. The other groups self-administered 50 or 75 mg% EtOH containing 6.25, 12.5, or 25 pmol/100 nl cocaine or 100 mg% EtOH containing 3.12, 6.25, 12.5, or 25 pmol/100 nl cocaine. All rats received the assigned infusate for sessions 1 through 4, aCSF alone in sessions 5 and 6, and the original infusate during session 7. The effects of adding a 5-HT 3 receptor antagonist [tropisetron, C 17 pmol/100 nl) were determined. Rats failed to self-administer aCSF or the subthreshold concentration of EtOH or cocaine. All three concentrations of EtOH (50, 75, and 100 mg%) combined with cocaine (12.5 and 25 pmol/100 nl) supported self-administration. Adding a 5HT 3 receptor antagonist attenuated coadministration of EtOH ϩ cocaine. Overall, the data indicate that the reinforcing properties of EtOH and cocaine interacted synergistically within the posterior VTA, and these synergistic effects were mediated, at least in part, by activation of local 5-HT 3 receptors.

The antero-posterior heterogeneity of the ventral tegmental area

“…Indeed, the co-infusion of the D 2 agonist quinpirole into the pVTA, Rodd et al, 2000Rodd et al, , 2004bRodd et al, (2005d, Ding et al (2014) Supports ICSA Rodd et al (2003Rodd et al ( , 2004aRodd et al ( , 2005b, Ding et al (2009cDing et al ( , 2012c Jhou et al (2009a) Increases motor coordination & motor skill learning (L) Bourdy et al (2014) which would inhibit the dopamine system by stimulating local autoreceptors (Ford, 2014), prevents the local selfadministration of ethanol (Rodd et al, 2004b(Rodd et al, , 2005d. The self-administration can then be reinstated by the co-infusion into the pVTA of the D 2 antagonist sulpiride (Rodd et al, 2004b).…”

“…The intra-pVTA administration of an opioid antagonist prevents the locomotor-activating effects of intra-pVTA ethanol in rats (Sanchez-Catalan et al, 2009), and decreases ethanol-induced conditioned place preference in mice (Bechtholt and Cunningham, 2005). Various intra-pVTA 5-HT 3 antagonists can also reduce the pVTA ethanol self-administration (Rodd-Henricks et al, 2003;Rodd et al, 2005d), the pVTA self-administration of a mixture of ethanol and cocaine (Ding et al, 2012c) and the oral self-administration of ethanol (Rodd et al, 2010), while the 5-HT 3 antagonists had no effect on oral ethanol self-administration when delivered into the aVTA (Rodd et al, 2010). In fact, rats will even self-administer a 5-HT 3 agonist in the pVTA but not in the aVTA (Rodd et al, 2007).…”

Reinforcing Properties and Neurochemical Response of Ethanol within the Posterior Ventral Tegmental Area Are Enhanced in Adulthood by Periadolescent Ethanol Consumption

“…Food and water were available ad libitum at all times, except during microinjection-microdialysis testing, which was performed as previously described (Ding et al, 2012). After PND 75, and under isoflurane anesthesia, a microinjection guide cannula (22-gauge; Plastics One) was implanted in the right hemisphere of each subject, stereotaxically aimed 1.0 mm above the pVTA.…”

Gene expression changes in serotonin, GABA-A receptors, neuropeptides and ion channels in the dorsal raphe nucleus of adolescent alcohol-preferring (P) rats following binge-like alcohol drinking

“…Thus, alterations in receptor expression may be compensating for reduced serotonin function. Selective agonists and/or antagonists for various serotonin receptors affect the alcohol-consuming behavior of rats selected for high alcohol preference (Ding et al, 2012; Lankford et al, 1996; Lankford and Myers, 1996; Long et al, 1996; Overstreet et al, 1997; Rodd-Henricks et al, 2000; Rodd et al, 2010). Other selectively bred high alcohol-consuming rat lines (Alko Alcohol preferring and Sardinian alcohol preferring rats) had higher levels of serotonin in whole brain or selected regions than their low alcohol-consuming counterparts (Alko Non-Alcohol and Sardinian non-preferring rats) (Bell, Sable et al 2012).…”