Novel psychoplastogen DM506 reduces cue-induced heroin-seeking and inhibits tonic GABA currents in the Prelimbic Cortex.

Opioid use disorder is a major public health crisis that is manifested by persistent drug-seeking behavior and high relapse frequency. Most of the available treatments rely on targeting opioid receptors using small molecules that do not provide sustained symptom alleviation. Psychoplastogens are a novel class of non-opioid drugs that produce rapid and sustained effects on neuronal plasticity, intended to produce therapeutic benefits. Ibogalogs are synthetic derivatives of iboga alkaloids that lack hallucinogenic or adverse side effects. In the current study, we examine the therapeutic potential of DM506, a novel ibogalog lacking any cardiotoxic or hallucinogenic effects, in cue-induced seeking behavior following heroin self-administration. At a single systemic dose of 40 mg/kg, DM506 significantly decreased cue-induced seeking in both male and female rats at abstinence day 1 (AD1) following heroin self-administration. Upon re-testing for cue-induced seeking at AD14, we found that males receiving DM506 continued to show decreased cue-induced seeking, an effect not observed in females. Since there is evidence of psychedelics influencing tonic GABA currents, and opioid and psychoplastogen-mediated neuroadaptations in the medial prefrontal cortex (PrL) underlying its functional effects, we performed patch-clamp recordings on PrL slices of drug-naïve rats with an acute application or chronic incubation with DM506. Tonic GABA current was decreased in slices incubated with DM506 for 2 h. qPCR analysis did not reveal any differences in the mRNA levels of GABAA receptor α and δ subunits at AD14 in heroin and saline self-administered animals that received vehicle or DM506 at AD1. Overall, our data indicate that DM506 attenuates cue-induced heroin seeking and inhibits tonic GABA current in the prelimbic cortex.

Synthetic contraceptive hormones occlude the ability of nicotine to reduce ethanol consumption in ovary-intact female rats.

Rates of tobacco and alcohol use in women are rising, and women are more vulnerable than men to escalating tobacco and alcohol use. Many women use hormonal birth control, with the oral contraceptive pill being the most prevalent. Oral contraceptives contain both a progestin (synthetic progesterone) and a synthetic estrogen (ethinyl estradiol; EE) and are contraindicated for women over 35 years who smoke. Despite this, no studies have examined how synthetic contraceptive hormones impact this pattern of polysubstance use in females. To address this critical gap in the field, we treated ovary-intact female rats with either sesame oil (vehicle), the progestin levonorgestrel (LEVO; contained in formulations such as Alesse®), or the combination of EE+LEVO in addition to either undergoing single (nicotine or saline) or polydrug (nicotine and ethanol; EtOH) self-administration (SA) in a sequential use model. Rats preferred EtOH over water following extended EtOH drinking experience as well as after nicotine or saline SA experience, and rats undergoing only nicotine SA (water controls) consumed more nicotine as compared to rats co-using EtOH and nicotine. Importantly, this effect was occluded in groups treated with contraceptive hormones. In the sequential use group, both LEVO alone and the EE+LEVO combination occluded the ability of nicotine to decrease EtOH consumption. Interestingly, demand experiments suggest an economic substitute effect between nicotine and EtOH. Together, we show that chronic synthetic hormone exposure impacts nicotine and EtOH sequential use, demonstrating the crucial need to understand how chronic use of different contraceptive formulations alter patterns of polydrug use in women.

Ovarian Hormones Regulate Nicotine Consumption and Accumbens Glutamatergic Plasticity in Female Rats.

Women report greater cigarette cravings during the menstrual cycle phase with higher circulating levels of 17ß-estradiol (E2), which is metabolized to estrone (E1). Both E2 and E1 bind to estrogen receptors (ERs), which have been highly studied in the breast, uterus, and ovary. Recent studies have found that ERs are also located on GABAergic medium spiny neurons (MSNs) within the nucleus accumbens core (NAcore). Glutamatergic plasticity in NAcore MSNs is altered following nicotine use; however, it is unknown whether estrogens impact this neurobiological consequence. To test the effect of estrogen on nicotine use, we ovariectomized (OVX) female rats that then underwent nicotine self-administration acquisition and compared them to ovary-intact (sham) rats. The OVX animals then received either sesame oil (vehicle), E2, or E1+E2 supplementation for 4 or 20 d before nicotine sessions. While both ovary-intact and OVX females readily discriminated levers, OVX females consumed less nicotine than sham females. Further, neither E2 nor E1+E2 increased nicotine consumption back to sham levels following OVX, regardless of the duration of the treatment. OVX also rendered NAcore MSNs in a potentiated state following nicotine self-administration, which was reversed by 4 d of systemic E2 treatment. Finally, we found that E2 and E1+E2 increased ERα mRNA in the NAcore, but nicotine suppressed this regardless of hormone treatment. Together, these results show that estrogens regulate nicotine neurobiology, but additional factors may be required to restore nicotine consumption to ovary-intact levels.

Rabies virus modifies host behaviour through a snake-toxin like region of its glycoprotein that inhibits neurotransmitter receptors in the CNS.

Rabies virus induces drastic behaviour modifications in infected hosts. The mechanisms used to achieve these changes in the host are not known. The main finding of this study is that a region in the rabies virus glycoprotein, with homologies to snake toxins, has the ability to alter behaviour in animals through inhibition of nicotinic acetylcholine receptors present in the central nervous system. This finding provides a novel aspect to virus receptor interaction and host manipulation by pathogens in general. The neurotoxin-like region of the rabies virus glycoprotein inhibited acetylcholine responses of α4ß2 nicotinic receptors in vitro, as did full length ectodomain of the rabies virus glycoprotein. The same peptides significantly altered a nicotinic receptor induced behaviour in C. elegans and increased locomotor activity levels when injected into the central nervous system of mice. These results provide a mechanistic explanation for the behavioural changes in hosts infected by rabies virus.

Superagonist, Full Agonist, Partial Agonist, and Antagonist Actions of Arylguanidines at 5-Hydroxytryptamine-3 (5-HT3) Subunit A Receptors.

Introduction of minor variations to the substitution pattern of arylguanidine 5-hydroxytryptamine-3 (5-HT3) receptor ligands resulted in a broad spectrum of functionally-active ligands from antagonist to superagonist. For example, (i) introduction of an additional Cl-substituent(s) to our lead full agonist N-(3-chlorophenyl)guanidine (mCPG, 2; efficacy % = 106) yielded superagonists 7-9 (efficacy % = 186, 139, and 129, respectively), (ii) a positional isomer of 2, p-Cl analog 11, displayed partial agonist actions (efficacy % = 12), and (iii) replacing the halogen atom at the meta or para position with an electron donating OCH3 group or a stronger electron withdrawing (i.e., CF3) group resulted in antagonists 13-16. We posit based on combined mutagenesis, crystallographic, and computational analyses that for the 5-HT3 receptor, the arylguanidines that are better able to simultaneously engage the primary and complementary subunits, thus keeping them in close proximity, have greater agonist character while those that are deficient in this ability are antagonists.

Stenting for coronary artery spasm.

We evaluated coronary stenting in nine patients with clinically severe, angiographically documented spasm refractory to aggressive pharmacologic management. No patient subsequently developed unstable ischemia requiring hospitalization as a consequence of recurrent spasm within the stent. Mechanisms of therapeutic failure included both persistent spasm and spasm in a different artery in one patient. Restenosis occurred in three patients who subsequently underwent repeat revascularization. In the rare, carefully selected patient, stents may represent an adjunct in the management of focal coronary artery spasm, although currently medical therapy remains the standard initial approach.