A neuroanatomical substrate for alcohol drinking: identification of tetrahydropapaveroline (THP)-reactive sites in the rat brain.

Abstract Certain endogenously synthesized adducts, derived from a condensation reaction of a catechol- or indole-amine with a biogenic aldehyde, act in the brain to augment or suppress the drinking of ethyl alcohol. When infused directly into the cerebral ventricles, a tetrahydro-isoquinoline such as tetrahydropapaveroline (THP) can enhance markedly the consumption of alcohol even in noxious concentrations. The present study was undertaken to isolate and identify specific anatomical structures in the limbic-midbrain, limbic-forebrain which mediate the changes in the ingestion of alcohol induced by THP. In adult male Sprague-Dawley rats, a 23 ga guide tube was implanted stereotaxically either unilaterally or bilaterally in cerebral regions extending from coronal planes AP 1.0–10.0. Following recovery, each animal was tested by a standard screen for its self-selection of water versus an alcohol solution offered in 10 concentrations increased on each of 10 days from 3 to 30%. THP was dissolved in an artificial CSF vehicle containing Na 2 S 2 O 5 or ascorbate and then microinjected in a volume of 1.5–2.0 μl at a depth 1.0–1.5 mm beneath the tip of the guide. After a set of 5 microinjections of THP in a dose of 25, 50 or 250 ng was given over 3 days, the same 10-day alcohol preference sequence was repeated. In nearly all rats, the microinjection series was repeated at either one or two depths 1.0–1.5 mm ventral to the first, after which the same alcohol test was repeated. The results showed that THP induces or sustains significant increases in alcohol intake when the adduct was injected at 16 sites within caudal AP planes 1.0–5.0. Structures sensitive to THP included the substantia nigra, reticular formation, medial lemniscus, zona incerta and medial forebrain bundle. When injected at 21 sites located more rostrally within AP planes 6.5–10.0, THP also evoked significant increments in alcohol intake of a similar magnitude. The reactive loci included the N. accumbens, olfactory tubercle, lateral septum, preoptic area, stria terminalis, medial forebrain bundle and rostral hippocampus. In terms of the efficacy of the dose of THP microinjected, 25, 50 and 250 ng induced alcohol self-selection in 81%, 5% and 14% of the sites, respectively. Repeated microinjections following identical procedures of two control solutions at 46 homologous sites within corresponding coronal planes from AP 1.5–10.0 produced no significant alterations in g/kg or proportional intakes of alcohol. Composite anatomical maps of the THP-reactive sites revealed their integral overlap with dopaminergic pathways which originate in the ventral tegmentum and substantia nigra and project rostrally to structures within the limbic-forebrain. Since the loci also encompass regions containing enkephalin receptors, it is envisaged that a dopamine-enkephalinergic link underlies the mechanism responsible for the initial onset of the aberrant intake of alcohol induced by the aldehyde adduct. Further, we hypothesize that the transient presence of endogenous THP within the diffuse anatomical pathways of the amine-opioid systems likewise modifies permanently their respective receptor populations. This would explain why the reinforcing property and subsequent addictive liability of alcohol are irreversibly maintained.