Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Drug design wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Polysubstance dependence wikipedia , lookup
Toxicodynamics wikipedia , lookup
NK1 receptor antagonist wikipedia , lookup
Neuropharmacology wikipedia , lookup
Theralizumab wikipedia , lookup
Prenatal Cannabis Exposure Increases Heroin Seeking with Allostatic Changes in Limbic Enkephalin Systems in Adulthood M.Sabrina Spano, Maria Ellgren, X. Wang, Yasmin L. Hurd • THC exposure in prenatal development: – Higher rates of fetal distress – Growth retardation • Transferred from mother to offspring via placental blood during gestation and via maternal milk during lactation • CB1 receptors mediate neural actions of cannabinoids & emerge early in development – synaptogenesis, proliferation and migration of neuronal cells • Clinical studies indicate in utero exposure is associated – impulsive behavior, cognitive impairment, psychiatric disorders (schizophrenia, anxiety) in later life • Kandel 03 suggested potential for cannabis to increase the risk of consumption of other drugs of abuse • hypothesized that long lasting neurobiological changes in neuronal systems linked with limbic function might be affected by in utero THC exposure – Gateway….? Opioids • Endogenous opioid system shares neuroanatomical and neurochemical characteristics with the cannabinoid system; tightly linked • 3 families – Enkephalin from preproenkephalin (PENK) – Dynorphin from preprodynorphin – Endorphin from proopiomelanocortin (POMC) • Cannabinoids stimulate release of enkephalin in the NAc and VTA – NAc is part of the mesocorticolimbic circuit – VTA is origin of DA mesocorticolimbic circuit • PENK widely dist. (NAc, amygdala, PFC) • Previous human studies show sig. impairment of PENK and meso-limbic DA genes in association with in utero CB exposure – Enduring effects into adulthood? – Influence adult behavior relative to addiction disorders? • In rats, perinatal THC exposure alters opioid gene expression, opioid receptor binding and morphine self-administration – Differs between males and females • treated with THC through gestation & entire lactation period – Dams treated with THC orally, different pharmacokinetic property than alternate routes of ingestion e.g. smoking, iv Methods Fear Leads to Anger---Anger Leads to Stress Stress Leads to Doobies—Doobies lead to Twinkies Test animals • • • • Female Long-Evans rats Reversed light/dark cycle Permanent right jugular catheter for IV Following surgery were mated with a male to induce pregnancy Admin of drug • Drug exposure limited to prenatal period – Gestational day5 to post-natal day 2 – Corresponds with mid-gestation period in humans ~ week 20 • THC given IV to better mimic the pharmacokinetics of smoking cannabis in pregnant human females – THC injected .15mg/kg daily During Drug Treatment • Maternal weight gain, gestational length and fetal weights were recorded • PND 2 pups from both groups cross fostered; some brains taken at this time • PND 21 males weaned; housed 4/cage • PND 55 iv catheter implanted – Housed individually, 7 day recovery • These are the test animals – More brains taken PND 62 prior to behav studies Heroin Self Admin • Active lever press = 15ug/kg in 85 ml fluid • Fixed Ratio 1, 10s timeout, 3 hour sessions during dark cycle • After 6 days, dose increased to 30 mg/kg • Baseline= <15% change in # bar presses for 3 consecutive days • During training food=20g/day – Ad libitum after stable response reached Dose Response • Between session dose response test • Rats now receive either higher 60,100mg or lower 7.5, 15 mg doses – Self admin as normal for 3 days, order of presentation was random • Following test, back to 30mg maintenance for 5 more days Food Stress • Food deprived for 24 hours • Response measured following day Extinction and Reinstatement • First week of extinction = saline • Following days = no fluid injected • Decrease in bar presses of 85% baseline for 3 days = extinction • Priming: – saline – heroin 0.25 mg/kg sc 10 min prior – CB1 antagonist 3 mg/kg ip + heroin Results • No significant change between groups in – % weight gain in pregnant dams – Gestational length – Pup length at PND 2 – Pup weight – Weight between groups at PND 62 • Start of heroin self adminstration training 15 mg/kg/infusion 30 mg/kg/infusion • No self admin at 15 mg/kg dose • Both THC and Vehicle groups self admin at 30 mg/kg dose • THC animals show shorter latency to first active response 34 ± 0.84s vs 115 ± 0.91s Dose Response Test • Dose-dependant decrease in responding with increasing heroin dose • THC animals show higher responding at lower doses (7.5 & 15 mg/kg) • No diff in responding at 30, 60 or 100 mg doses between groups Response after Stress Test • THC animals respond to food deprivation stress with more active lever presses Extinction, Priming, SR Treatment • THC group responded to active bar more during first day of extinction (more than maintenance, more than vehicle group) • Heroin priming reinstated active bar presses – THC group responded to active bar sig more than they had during maintenance • SR treatment abolished priming induced reinstatment Locomotion Response • THC group showed less locomotion during acquisition and maintenance phases – No diff during extinction phase • Differences are due to heroin intake CB1 and m Opioid Receptor G-Protein Coupling • Agonist-stimulated GTPgS binding • No change in m or CB1 binding at PND2 • In adults, prenatal THC exposure significantly associated with – decreased m opioid binding in NAc shell – Increased binding in SN – No change in CB1 receptor coupling 1=NAc shell, 2=NAc core, 3=CP, 4=VTA, 5=SN PENK mRNA Expression • Prenatal THC Exposure decreased PENK mRNA expression in NAc at PND2 – No reliable measurements from amygdala • No change in preprodynorphin which is colocalized in the NAc • HOWEVER… • Prenatal THC exposure increased PENK mRNA in Adults at PND 62 in – NAc core and shell – Central and medial amygdala nuclei • Compensation? 1=NAc shell 2=NAc core 3=CP 4=m.amy 5=c.amy Increased PENK mRNA in cAmy Discussion • Hyperactivity of the mesocorticolimbic enkephalinergic system in adult animals may be due to the blunted PENK gene expression during early development Self Administration • No diff in self admin of heroin between groups in adulthood – THC group showed • • • • Shorter latency to first active lever press Higher response to lower doses of heroin Increased response following food stress Higher level of seeking during extinction • Suggests long term vulnerability in the motivation to self-administer heroin Relapse! • Following 21 days of drug extinction – Heroin primed THC group responded with higher number of bar presses than maintenance (increased seeking) – CB1 antagonist SR141716A completely blocked heroin primed relapse in both groups – Cross talk between opioid and cannabinoid systems m opioid receptor binding • THC group show less mOR binding in NAc – Key region in reward processing – also modulates locomotion • THC group showed less loco when on heroin • Similar to mOR deficient animals Take-Home Message • THC administered during prenatal period significant affects PENK mRNA expression during prenatal period and adulthood • Alterations of the opioid system last into adulthood and enhance vulnerability to opiate-seeking behavior