Regional Heterogeneity for the Intracranial Self-Administration of Ethanol and Acetaldehyde within the Ventral Tegmental Area of Alcohol-Preferring (P) Rats: Involvement of Dopamine and Serotonin

Abstract

The meso-limbic dopamine (DA) system has an important role in regulating alcohol drinking. Previous findings from our laboratory indicated that Wistar rats self-administered ethanol (EtOH) directly into the posterior, but not anterior, ventral tegmental area (VTA), and that coadministration of a DA D 2,3 receptor agonist or a serotonin-3 (5-HT 3 ) receptor antagonist blocked EtOH self-administration. In addition, we reported that alcohol-preferring (P) rats self-administered acetaldehyde (ACD), the first metabolite of EtOH, into the posterior VTA. The objectives of this study were to compare the reinforcing effects of EtOH and ACD within the VTA of P rats to examine the possibility that the reinforcing effects of EtOH within the VTA may be mediated by its conversion to ACD. Adult female P rats were stereotaxically implanted with guide cannulae aimed at either the posterior or anterior VTA. At 1 week after surgery, rats were placed in standard two-lever (active and inactive) experimental chambers for a total of seven to eight sessions. The 4-h sessions were conducted every other day. The results indicated that (a) 75-300 mg% (17-66 mM) EtOH and 6-90 mM ACD were self-administered into the posterior, but not anterior, VTA; (b) the self-administration of 150 mg% EtOH was not altered by coinfusion of a catalase inhibitor; (c) coadministration of the D 2/3 agonist quinpirole (100 mM) blocked the self-infusions of 150 mg% EtOH and 23 mM ACD into the posterior VTA; and (d) coadministration of 200 mM ICS205,930 (5-HT 3 receptor antagonist) prevented the self-infusion of 150 mg% EtOH, whereas concentrations of ICS 205,930 up to 400 mM had no effect on the self-infusion of 23 mM ACD into the posterior VTA. Overall, the results of this study indicate that EtOH and ACD can independently produce reinforcing effects within the posterior VTA, and that activation of DA neurons mediates these effects. Furthermore, activation of 5-HT 3 receptors within the posterior VTA is involved in the self-infusion of EtOH, but not ACD.

Motor Stimulant Effects of Ethanol Injected into the Substantia Nigra Pars Reticulata: Importance of Catalase-Mediated Metabolism and the Role of Acetaldehyde

“…The notion that ethanol metabolism in the brain is important for some of the behavioral effects of ethanol is supported by the reports that manipulations of catalase activity exert a powerful effect on ethanol-induced behavior (Aragon et al, 1992a;Aragon and Amit, 1993;Correa et al, 1999aCorrea et al, , b, 2000Correa et al, , 2001Correa et al, , 2004aSanchis-Segura et al, 1999a-c;Pastor et al, 2002). Additional support is provided by studies showing behavioral effects of acetaldehyde after central administration (Myers and Veale, 1969;Brown et al, 1978Brown et al, , 1979Brown et al, , 1980Smith et al, 1984;Arizzi et al, 2003;Correa et al, 2003b, c;Rodd-Henricks et al, 2002;Rodd et al, 2005). The central administration of acetaldehyde avoids the issue of brain penetrability, and therefore more directly assesses the effects of central acetaldehyde on distinct aspects of behavior.…”

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

“…Likewise, examination of drugs affecting GABA A receptor function implicated differing brain regions for self-administration and ethanol discrimination of ethanol (Hyytia and Koob, 1995;McBride et al, 1999;Roberts et al, 1996;Rodd et al, 2004Rodd et al, , 2005. In further support of a regional specificity of ethanol on GABA transmission, work demonstrated that chronic ethanol treatment altered expression of GABA A receptor subunit mRNAs in some brain regions, but not others Grobin et al, 2000a, b;Montpied et al, 1991;Morrow et al, 1992;Mhatre and Ticku, 1992;Papadeas et al, 2001).…”

“…The effect of drugs influencing GABA function implicated the extended amygdala in ethanol self-administration (Hyytia and Koob, 1995;Roberts et al, 1996). Utilizing intracranial self-administration of ethanol, Rodd et al (2005) described regional heterogeneity within the ventral tegmental area. To define sites that support the discriminative stimulus for ethanol, Hodge and Cox (1998) found that muscimol substituted for ethanol when microinjected into the amygdala, but not when microinjected in the prelimbic cortex.…”

What is in that Drink: The Biological Actions of Ethanol, Acetaldehyde, and Salsolinol

“…However, EtOH self-administration directly into the posterior VTA is not altered by co-administration of a catalase antagonist (3-amino-1,2,4-triazole; triazole; Rodd et al, 2005). Yet, ACD could have been produced within the posterior VTA following self-infusion of EtOH through a catalase-independent pathway.…”