guanosine-5--o-(3-thiotriphosphate) and Heroin-Dependence

Prenatal cannabis exposure is a growing concern with little known about the long-term consequences on behavior and neural systems relevant for reward and emotional processing.. We used an animal model to study the effects of prenatal exposure to Delta(9)-tetrahydrocannabinol (THC) on heroin self-administration behavior and opioid neural systems in adult males (postnatal day 62). Rats were exposed to THC (.15 mg/kg) or vehicle from gestational day 5 to postnatal day 2.. Both pretreatment groups showed similar heroin intake, but THC-exposed rats exhibited shorter latency to the first active lever press, responded more for low heroin doses, and had higher heroin-seeking during mild stress and drug extinction. THC exposure reduced preproenkephalin (PENK) mRNA expression in the nucleus accumbens during early development, but was elevated in adulthood; no adult striatal changes on preprodynorphin mRNA or PENK in caudate-putamen. PENK mRNA was also increased in the central and medial amygdala in adult THC-exposed animals. THC animals had reduced heroin-induced locomotor activity and nucleus accumbens mu opioid receptor coupling.. This study demonstrates enduring effects of prenatal THC exposure into adulthood that is evident on heroin-seeking behavior during extinction and allostatic changes in mesocorticolimbic PENK systems relevant to drug motivation/reward and stress response.

Topics: Analysis of Variance; Animals; Autoradiography; Behavior, Animal; Cannabis; Conditioning, Operant; Dynorphins; Enkephalins; Female; Guanosine 5'-O-(3-Thiotriphosphate); Heroin Dependence; In Situ Hybridization; Limbic System; Pregnancy; Prenatal Exposure Delayed Effects; Protein Binding; Protein Precursors; Rats; Rats, Long-Evans; Reaction Time

Methadone maintenance therapy has been the mainstay of treatment for heroin addiction since the 1970s. Recent studies indicate that methadone is of greater relative intrinsic efficacy than the active metabolites of heroin at mu-opioid receptors and that the extent of mu-opioid receptor desensitization is dependent upon agonist efficacy. Regional differences have been found for mu-opioid receptor desensitization with chronic heroin self-administration, and a similar paradigm was employed to compare regional differences between the effects of heroin and methadone. Rats were trained to self-administer heroin i.v., and the dose available was increased incrementally to a terminal value of 6 mg/kg for each infusion. Half of these rats were allowed to continue to self-administer heroin, while dependence was maintained in the others by hourly infusions of 3 mg/kg of methadone. A separate group of animals was kept on a low dose of heroin. Activation of G-proteins by the high efficacy agonist DAMGO was decreased to a greater extent in animals treated chronically with methadone compared with those allowed to self-administer heroin in amygdala, periaqueductal gray, and subicular nucleus. Activation of G-proteins by the partial agonist endomorphin was decreased in striatum, thalamus, and amygdala in rats from all drug treatment groups, but to a greater extent in the striatum in methadone treated rats compared with the heroin groups. Elucidating the mechanisms by which methadone induces differential desensitization of mu-opioid receptors across brain regions compared with heroin could provide insights to improve the pharmacotherapy of heroin addiction.

Topics: Animals; Binding, Competitive; Brain; Dose-Response Relationship, Drug; Drug Tolerance; Eating; Guanosine 5'-O-(3-Thiotriphosphate); Heroin; Heroin Dependence; Injections, Intravenous; Male; Methadone; Narcotics; Radioligand Assay; Rats; Rats, Inbred F344; Receptors, G-Protein-Coupled; Receptors, Opioid, mu; Reinforcement, Psychology; Self Administration

In previous studies from our laboratory, chronic noncontingent morphine administration decreased mu opioid receptor-activated G-proteins in specific brainstem nuclei. In the present study, mu opioid receptor binding and receptor-activated G-proteins were examined after chronic heroin self-administration. Rats were trained to self-administer intravenous heroin for up to 39 d, achieving heroin intake up to 366 mg. kg(-1). d(-1). mu opioid-stimulated [(35)S]GTPgammaS and [(3)H]naloxone autoradiography were performed in adjacent brain sections. Agonist-stimulated [(35)S]GTPgammaS autoradiography also examined other G-protein-coupled receptors, including delta opioid, ORL-1, GABA(B), adenosine A(1), cannabinoid, and 5-HT(1A). In brains from heroin self-administering rats, decreased mu opioid-stimulated [(35)S]GTPgammaS binding was observed in periaqueductal gray, locus coeruleus, lateral parabrachial nucleus, and commissural nucleus tractus solitarius, as previously observed in chronic morphine-treated animals. In addition, decreased mu opioid-stimulated [(35)S]GTPgammaS binding was found in thalamus and amygdala after heroin self-administration. Despite this decrease in mu-activated G-proteins, [(3)H]naloxone binding demonstrated increased mu opioid receptor binding in several brain regions after heroin self-administration, and there was a significant decrease in mu receptor G-protein efficiency as expressed as a ratio between agonist-activated G-proteins and mu receptor binding. No effects on agonist-stimulated [(35)S]GTPgammaS binding were found for any other receptor examined. The effect of chronic heroin self-administration to decrease mu-stimulated [(35)S]GTPgammaS binding varied between regions and was highest in brainstem and lowest in the cortex and striatum. These results not only provide potential neuronal mechanisms that may contribute to opioid tolerance and dependence, but also may explain why various chronic effects of opioids develop to different degrees.

Topics: Animals; Autoradiography; Brain; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Heroin; Heroin Dependence; Kinetics; Male; Naloxone; Organ Specificity; Rats; Rats, Inbred F344; Receptors, Opioid, mu; Self Administration; Sulfur Radioisotopes; Tritium