Peer-induced cocaine seeking in rats: Comparison to nonsocial stimuli and role of paraventricular hypothalamic oxytocin neurons.

The purpose of this study was to determine if social vs nonsocial cues (peer vs light/tone) can serve as discriminative stimuli to reinstate cocaine seeking. In addition, to assess a potential mechanism, an oxytocin (OT) promoter-linked hM3Dq DREADD was infused into the paraventricular nucleus of the hypothalamus to determine whether peer-induced cocaine seeking is decreased by activation of OT neurons. Male rats underwent twice-daily self-administration sessions, once with cocaine in the presence of one peer (S+) and once with saline in the presence of a different peer (S-). Another experiment used similar procedures, except the discriminative stimuli were nonsocial (constant vs flashing light/tone), with one stimulus paired with cocaine (S+) and the other paired with saline (S-). A third experiment injected male and female rats with OTp-hM3Dq DREADD or control virus into PVN and tested them for peer-induced reinstatement of cocaine seeking following clozapine (0.1 mg/kg). Although acquisition of cocaine self-administration was similar in rats trained with either peer or light/tone discriminative stimuli, the latency to first response was reduced by the peer S+, but not by the light/tone S+. In addition, the effect of the conditioned stimulus was overshadowed by the peer S+ but not by the light/tone S+. Clozapine blocked the effect of the peer S+ in rats receiving the OTp-hM3Dq DREADD virus, but not in rats receiving the control virus. These results demonstrate that a social peer can serve as potent trigger for drug seeking and that OT in PVN modulates peer-induced reinstatement of cocaine seeking.

Primed for addiction: A critical review of the role of microglia in the neurodevelopmental consequences of adolescent alcohol drinking.

Alcohol is one of the most widely used recreational substances worldwide, with drinking frequently initiated during adolescence. The developmental state of the adolescent brain makes it vulnerable to initiating alcohol use, often in high doses, and particularly susceptible to alcohol-induced brain changes. Microglia, the brain parenchymal macrophages, have been implicated in mediating some of these effects, though the role that these cells play in the progression from alcohol drinking to dependence remains unclear. Microglia are uniquely positioned to sense and respond to central nervous system insult, and are now understood to exhibit innate immune memory, or "priming," altering their future functional responses based on prior exposures. In alcohol use disorders (AUDs), the role of microglia is debated. Whereas microglial activation can be pathogenic, contributing to neuroinflammation, tissue damage, and behavioral changes, or protective, it can also engage protective functions, providing support and mediating the resolution of damage. Understanding the role of microglia in adolescent AUDs is complicated by the fact that microglia are thought to be involved in developmental processes such as synaptic refinement and myelination, which underlie the functional maturation of multiple brain systems in adolescence. Thus, the role microglia play in the impact of alcohol use in adolescence is likely multifaceted. Long-term sequelae may be due to a failure to recover from EtOH-induced tissue damage, altered neurodevelopmental trajectories, and/or persistent changes to microglial responsivity and function. Here, we review critically the literature surrounding the effects of alcohol on microglia in models of adolescent alcohol misuse. We attempt to disentangle what is known about microglia from other neuroimmune effectors, to which we apply recent discoveries on the role of microglia in development and plasticity. Considered altogether, these studies challenge assumptions that proinflammatory microglia drive addiction. Alcohol priming microglia and thereby perturbing their homeostatic roles in neurodevelopment, especially during critical periods of plasticity such as adolescence, may have more serious implications for the neuropathogenesis of AUDs in adolescents.

[3H]Dopamine Uptake through the Dopamine and Norepinephrine Transporters is Decreased in the Prefrontal Cortex of Transgenic Mice Expressing HIV-1 Transactivator of Transcription Protein.

Dysregulation of dopamine neurotransmission has been linked to the development of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND). To investigate the mechanisms underlying this phenomenon, this study used an inducible HIV-1 transactivator of transcription (Tat) transgenic (iTat-tg) mouse model, which demonstrates brain-specific Tat expression induced by administration of doxycycline. We found that induction of Tat expression in the iTat-tg mice for either 7 or 14 days resulted in a decrease (∼30%) in the V max of [3H]dopamine uptake via both the dopamine transporter (DAT) and norepinephrine transporter (NET) in the prefrontal cortex (PFC), which was comparable to the magnitude (∼35%) of the decrease in B max for [3H]WIN 35,428 and [3H]nisoxetine binding to DAT and NET, respectively. The decreased V max was not accompanied by a reduction of total or plasma membrane expression of DAT and NET. Consistent with the decreased V max for DAT and NET in the PFC, the current study also found an increase in the tissue content of DA and dihydroxyphenylacetic acid in the PFC of iTat-tg mice after 7 days' administration of doxycycline. Electrophysiological recordings in layer V pyramidal neurons of the prelimbic cortex from iTat-tg mice found a significant reduction in action potential firing, which was not sensitive to selective inhibitors for DAT and NET, respectively. These findings provide a molecular basis for using the iTat-tg mouse model in the studies of NeuroHIV. Determining the mechanistic basis underlying the interaction between Tat and DAT/NET may reveal novel therapeutic possibilities for preventing the increase in comorbid conditions as well as HAND. SIGNIFICANCE STATEMENT: Human immunodeficiency virus (HIV)-1 infection disrupts dopaminergic neurotransmission, leading to HIV-associated neurocognitive disorders (HANDs). Based on our in vitro and in vivo studies, dopamine uptake via both dopamine and norepinephrine transporters is decreased in the prefrontal cortex of HIV-1 Tat transgenic mice, which is consistent with the increased dopamine and dihydroxyphenylacetic acid contents in this brain region. Thus, these plasma membrane transporters are an important potential target for therapeutic intervention for patients with HAND.

GZ-11608, a Vesicular Monoamine Transporter-2 Inhibitor, Decreases the Neurochemical and Behavioral Effects of Methamphetamine.

Despite escalating methamphetamine use and high relapse rates, pharmacotherapeutics for methamphetamine use disorders are not available. Our iterative drug discovery program had found that R-N-(1,2-dihydroxypropyl)-2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), a selective vesicular monoamine transporter-2 (VMAT2) inhibitor, specifically decreased methamphetamine's behavioral effects. However, GZ-793A inhibited human-ether-a-go-go-related gene (hERG) channels, suggesting cardiotoxicity and prohibiting clinical development. The current study determined if replacement of GZ-793A's piperidine ring with a phenylalkyl group to yield S-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11608) diminished hERG interaction while retaining pharmacological efficacy. VMAT2 inhibition, target selectivity, and mechanism of GZ-11608-induced inhibition of methamphetamine-evoked vesicular dopamine release were determined. We used GZ-11608 doses that decreased methamphetamine-sensitized activity to evaluate the potential exacerbation of methamphetamine-induced dopaminergic neurotoxicity. GZ-11608-induced decreases in methamphetamine reinforcement and abuse liability were determined using self-administration, reinstatement, and substitution assays. Results show that GZ-11608 exhibited high affinity (Ki = 25 nM) and selectivity (92-1180-fold) for VMAT2 over nicotinic receptors, dopamine transporter, and hERG, suggesting low side-effects. GZ-11608 (EC50 = 620 nM) released vesicular dopamine 25-fold less potently than it inhibited VMAT2 dopamine uptake. GZ-11608 competitively inhibited methamphetamine-evoked vesicular dopamine release (Schild regression slope = 0.9 ± 0.13). GZ-11608 decreased methamphetamine sensitization without altering striatal dopamine content or exacerbating methamphetamine-induced dopamine depletion, revealing efficacy without neurotoxicity. GZ-11608 exhibited linear pharmacokinetics and rapid brain penetration. GZ-11608 decreased methamphetamine self-administration, and this effect was not surmounted by increasing methamphetamine unit doses. GZ-11608 reduced cue- and methamphetamine-induced reinstatement, suggesting potential to prevent relapse. GZ-11608 neither served as a reinforcer nor substituted for methamphetamine, suggesting low abuse liability. Thus, GZ-11608, a potent and selective VMAT2 inhibitor, shows promise as a therapeutic for methamphetamine use disorder. SIGNIFICANCE STATEMENT: GZ-11608 is a potent and selective vesicular monoamine transporter-2 inhibitor that decreases methamphetamine-induced dopamine release from isolated synaptic vesicles from brain dopaminergic neurons. Results from behavioral studies show that GZ-11608 specifically decreases methamphetamine-sensitized locomotor activity, methamphetamine self-administration, and reinstatement of methamphetamine-seeking behavior, without exhibiting abuse liability. Tolerance does not develop to the efficacy of GZ-11608 to decrease the behavioral effects of methamphetamine. In conclusion, GZ-11608 is an outstanding lead in our search for a therapeutic to treat methamphetamine use disorder.

Environmental enrichment and drug value: a behavioral economic analysis in male rats.

Rats raised in an enriched condition (EC) show decreased stimulant self-administration relative to rats reared in an isolated condition (IC). However, few studies have examined the behavioral mechanisms underlying this environment-induced difference in self-administration. Because economic demand for drugs of abuse predicts addiction-like behavior in both humans and animals, we applied a behavioral economic analysis to cocaine self-administration data in EC and IC rats. During cocaine self-administration, the dose decreased across blocks of trials (0.75-0.003 mg/kg/inf), which allowed for a determination of demand intensity and demand elasticity. Demand intensity did not differ between EC and IC rats; however, cocaine was more elastic in EC rats relative to IC rats (i.e. EC rats were less willing to respond for cocaine as the unit price increased). When EC rats were placed in an isolated condition, demand elasticity decreased, whereas elasticity increased for IC rats placed in an enriched condition. Additionally, we applied behavioral economic analyses to previously published self-administration data and found that our results replicate past findings with cocaine and methylphenidate. To determine if differences in demand elasticity are specific to drug reinforcement, a separate group of rats was tested in sucrose or saccharin self-administration. Results showed that sucrose and saccharin were more elastic in EC rats relative to IC rats, and demand intensity was lower for saccharin in EC rats relative to IC rats. Overall, drug and nondrug reinforcers are more elastic in EC rats, which may account for the protective effects of environmental enrichment against stimulant self-administration.

Reduction of Cocaine-Induced Locomotor Effects by Enriched Environment Is Associated with Cell-Specific Accumulation of ΔFosB in Striatal and Cortical Subregions.

Background: Early exposure to enriched environments has been shown to decrease the locomotor effects induced by repeated injections of cocaine and modify basal and cocaine-induced total protein levels of the transcription factor ΔFosB in the whole striatum of mice. In this study, we aimed at characterizing whether the profile of ΔFosB accumulation induced by enriched environments and cocaine would be similar or different in terms of brain areas and cell type. Methods: We used mice expressing the eGFP protein in D1 receptor positive (D1R(+)) neurons to determine whether Δ FosB induced by enriched environment or cocaine injections (5×15 mg/kg) would occur in selective subpopulations of neurons in several subregions of the striatum and prefrontal cortex. Results: We found that: (1) exposure to enriched environment reduces cocaine-induced locomotor activation, confirming our previous findings; (2) exposure to enriched environment by itself increases the accumulation of Δ FosB mostly in D1R(-) cells in the shell part of the nucleus accumbens and dorsal striatum, whereas in the nucleus accumbens core, Δ FosB accumulates in both D1R(+) and D1R(-) neurons; (3) in standard environment mice, cocaine induces accumulation of Δ FosB selectively in D1R(+) cells in the nucleus accumbens, dorsal striatum, and infralimbic cortex; and (4) the effects of enriched environments and cocaine on accumulation of Δ FosB were reciprocally blocked by their combination. Conclusions: Altogether, these results suggest that the enriched environment-induced reduction in behavioral effects of cocaine might result from 2 distinct effects on ΔFosB in striatal medium-sized spiny neurons belonging to the direct and indirect pathways.

Nicotine self-administration remodels perineuronal nets in ventral tegmental area and orbitofrontal cortex in adult male rats.

Nicotine, a major psychoactive component of tobacco smoke, alters gamma-aminobutyric acid (GABA) modulation of dopamine neurons in the ventral tegmental area (VTA). Changes in structural neuroplasticity can occur in GABAergic parvalbumin (PRV) positive neurons, which are enveloped by structures of the extracellular matrix called perineuronal nets (PNNs). In the current study, rats were trained to self-administer intravenous nicotine (0.03 mg/kg/infusion) for 21 days in 1-hour daily sessions with an incrementing fixed ratio requirement; a control group received saline infusions. At either 45 minutes or 72 hours after the last session, immunofluorescence measurements for PNNs, PRV and c-Fos were conducted. In VTA, nicotine self-administration reduced the number of PRV+ cells surrounded by PNNs at 45 minutes, as well as reducing the intensity of PNNs, suggesting a remodeling of GABA interneurons in this region; the number of PRV+ cells surrounded by PNNs was also reduced at 72 hours. A similar reduction of PNNs occurred in orbitofrontal cortex (OFC) but not in medial prefrontal cortex (prelimbic or infralimbic), 45 minutes after the last session; PNNs were not detected in nucleus accumbens (shell or core). The reduction of PNNs in VTA and OFC was unrelated to c-Fos + cells, as the percent of wisteria floribunda agglutinin + cells co-expressing c-Fos was decreased in OFC but not in VTA. Thus, nicotine self-administration remodeled PNNs surrounding GABA interneurons in VTA and its indirect connections to OFC, suggesting a new possible molecular target where nicotine-induced neuroplasticity takes place. PNN manipulations may prevent or reverse the different stages of tobacco addiction.

r-bPiDI, an α6ß2* Nicotinic Receptor Antagonist, Decreases Nicotine-Evoked Dopamine Release and Nicotine Reinforcement.

α6ß2* nicotinic acetylcholine receptors (nAChRs) expressed by dopaminergic neurons mediate nicotine-evoked dopamine (DA) release and nicotine reinforcement. α6ß2* antagonists inhibit these effects of nicotine, such that α6ß2* receptors serve as therapeutic targets for nicotine addiction. The present research assessed the neuropharmacology of 1,10-bis(3-methyl-5,6-dihydropyridin-1(2H)-yl)decane (r-bPiDI), a novel small-molecule, tertiary amino analog of its parent compound, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI). bPiDI was previously shown to inhibit both nicotine-evoked DA release and the reinforcing effects of nicotine. In the current study, r-bPiDI inhibition of [(3)H]nicotine and [(3)H]methyllycaconitine binding sites was evaluated to assess interaction with the recognition binding sites on α4ß2* and α7* nAChRs, respectively. Further, r-bPiDI inhibition of nicotine-evoked DA release in vitro in the absence and presence of α-conotoxin MII and following chronic in vivo nicotine administration were determined. The ability of r-bPiDI to decrease nicotine self-administration and food-maintained responding was also assessed. Results show that r-bPiDI did not inhibit [(3)H]nicotine or [(3)H]methyllycaconitine binding, but potently (IC50 = 37.5 nM) inhibited nicotine-evoked DA release from superfused striatal slices obtained from either drug naïve rats or from those repeatedly treated with nicotine. r-bPiDI inhibition of nicotine-evoked DA release was not different in the absence or presence of α-conotoxin MII, indicating that r-bPiDI acts as a potent, selective α6ß2* nAChR antagonist. Acute systemic administration of r-bPiDI specifically decreased nicotine self-administration by 75 %, and did not alter food-maintained responding, demonstrating greater specificity relative to bPiDI and bPiDDB, as well as the tertiary amino analog r-bPiDDB. The current work describes the discovery of r-bPiDI, a tertiary amino, α-conotoxin MII-like small molecule that acts as a potent and selective antagonist at α6ß2* nAChRs to specifically decrease nicotine self-administration in rats, thus, establishing r-bPiDI as a lead compound for development as a treatment for nicotine addiction.

Vesicular monoamine transporter-2 inhibitor JPC-141 prevents methamphetamine-induced dopamine toxicity and blocks methamphetamine self-administration in rats.

Previous research has demonstrated therapeutic potential for VMAT2 inhibitors in rat models of methamphetamine use disorder. Here, we report on the neurochemical and behavioral effects of 1-(2-methoxyphenethyl)-4-phenethypiperazine (JPC-141), a novel analog of lobelane. JPC-141 potently inhibited (Ki = 52 nM) [3H]dopamine uptake by VMAT2 in striatal vesicles with 50 to 250-fold greater selectivity for VMAT2 over dopamine, norepinephrine and serotonin plasmalemma transporters. Also, JPC-141 was 57-fold more selective for inhibiting VMAT2 over [3H]dofetilide binding to hERG channels expressed by HEK293, suggesting relatively low potential for cardiotoxicity. When administered in vivo to rats, JPC-141 prevented the METH-induced reduction in striatal dopamine content when given either prior to or after a high dose of METH, suggesting a reduction in METH-induced dopaminergic neurotoxicity. In behavioral assays, JPC-141 decreased METH-stimulated locomotor activity in METH-sensitized rats at doses of JPC-141 which did not alter locomotor activity in the saline control group. Moreover, JPC-141 specifically decreased iv METH self-administration at doses that had no effect on food-maintained responding. These findings support the further development of VMAT2 inhibitors as pharmacotherapies for individuals with methamphetamine use disorder.

Searching for Synthetic Opioid Rescue Agents: Identification of a Potent Opioid Agonist with Reduced Respiratory Depression.

While in the process of designing more effective synthetic opioid rescue agents, we serendipitously identified a new chemotype of potent synthetic opioid. Here, we report that conformational constraint of a piperazine ring converts a mu opioid receptor (MOR) antagonist into a potent MOR agonist. The prototype of the series, which we have termed atoxifent (2), possesses potent in vitro agonist activity. In mice, atoxifent displayed long-lasting antinociception that was reversible with naltrexone. Repeated dosing of atoxifent produced antinociceptive tolerance and a level of withdrawal like that of fentanyl. In rats, while atoxifent produced complete loss of locomotor activity like fentanyl, it failed to produce deep respiratory depression associated with fentanyl-induced lethality. Assessment of brain biodistribution demonstrated ample distribution of atoxifent into the brain with a Tmax of approximately 0.25 h. These results indicate enhanced safety for atoxifent-like molecules compared to fentanyl.

Effects of VMAT2 inhibitors lobeline and GZ-793A on methamphetamine-induced changes in dopamine release, metabolism and synthesis in vivo.

Vesicular monoamine transporter-2 (VMAT2) inhibitors reduce methamphetamine (METH) reward in rats. The current study determined the effects of VMAT2 inhibitors lobeline (LOB; 1 or 3 mg/kg) and N-(1,2R-dihydroxylpropyl)-2,6-cis-di(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A; 15 or 30 mg/kg) on METH-induced (0.5 mg/kg, SC) changes in extracellular dopamine (DA) and its metabolite dihydroxyphenylacetic acid (DOPAC) in the reward-relevant nucleus accumbens (NAc) shell using in vivo microdialysis. The effect of GZ-793A (15 mg/kg) on DA synthesis in tissue also was investigated in NAc, striatum, medial prefrontal cortex and orbitofrontal cortex. In NAc shell, METH produced a time-dependent increase in extracellular DA and decrease in DOPAC. Neither LOB nor GZ-793A alone altered extracellular DA; however, both drugs increased extracellular DOPAC. In combination with METH, LOB did not alter the effects of METH on DA; however, GZ-793A, which has greater selectivity than LOB for inhibiting VMAT2, reduced the duration of the METH-induced increase in extracellular DA. Both LOB and GZ-793A enhanced the duration of the METH-induced decrease in extracellular DOPAC. METH also increased tissue DA synthesis in NAc and striatum, whereas GZ-793A decreased synthesis; no effect of METH or GZ-793A on DA synthesis was found in medial prefrontal cortex or orbitofrontal cortex. These results suggest that selective inhibition of VMAT2 produces a time-dependent decrease in DA release in NAc shell as a result of alterations in tyrosine hydroxylase activity, which may play a role in the ability of GZ-793A to decrease METH reward.

Distinct effects of enriched environment on dopamine clearance in nucleus accumbens shell and core following systemic nicotine administration.

Environmental enrichment during development may reduce drug abuse liability by modulating dopamine transporter (DAT) function. Nucleus accumbens (NAc) shell and core respond differentially to regulate the rewarding properties and locomotor stimulant effects of psychostimulants. The current study evaluated dopamine (DA) clearance (CL(DA) ) in the NAc shell and core using in vivo voltammetry in rats raised in an enriched condition (EC) or an impoverished condition (IC) and determined the effect of nicotine (0.4 mg/kg) on CL(DA) . Baseline CL(DA) in NAc shell and core was not different between EC and IC rats. In the saline control group, CL(DA) in NAc shell was greater across time in IC when compared with EC rats, whereas CL(DA) in NAc core was greater in EC rats when compared with IC rats. Consistent with these findings, opposite effects of enrichment on DA clearance in shell and core were obtained following acute nicotine administration. In NAc shell, nicotine increased CL(DA) in EC rats, but not in IC rats. Conversely, in NAc core, nicotine increased CL(DA) in IC rats, but not in EC rats. The current results demonstrate that environmental enrichment differentially regulates the response to nicotine in NAc shell and core via alterations in DAT function, which may explain how environmental enrichment reduces the behavioral response to nicotine.

Renewal of cocaine seeking using social and nonsocial contextual stimuli.

RATIONALE: Various nonsocial cues have been used as stimuli to examine the contextual control of drug seeking behavior, but little is known about the role of social stimuli. OBJECTIVES: This study determined if renewal of cocaine seeking is differentially controlled using a context consisting of either a social peer and/or house light illumination. METHODS: In Experiment 1, male and female rats trained to self-administer cocaine in the presence of a same-sex social peer and house light illumination (context A). Following self-administration, rats were randomly assigned to either an AAA (control) or ABA (renewal) group for extinction. For AAA rats, extinction consisted of the same context A as self-administration; for ABA rats, extinction occurred without the peer or house light (context B). Following extinction, renewal of cocaine seeking occurred by testing the peer alone, house light alone, and the peer + house light combination. Experiment 2 was conducted to ensure that the house light alone was sufficiently salient to produce renewal. RESULTS: Both experiments showed that rats acquired cocaine self-administration and extinguished lever pressing. In Experiment 1, the ABA group renewed cocaine seeking to the peer and peer + house light, but not to the house light alone. In Experiment 2, ABA rats renewed cocaine seeking to the house light alone, indicating it was sufficiently salient to produce renewal. The AAA group did not show renewal in either experiment. CONCLUSION: Social peers serve as powerful stimuli that can overshadow nonsocial visual stimuli in the renewal of cocaine seeking.

PT150 blocks the rewarding properties of ethanol and attenuates ethanol-induced reduction of egg laying in Coturnix quail.

RATIONALE: Alcohol use disorder (AUD) has been shown to be associated with a dysregulated stress system. Reducing the stress hormone corticosterone (CORT), that binds to glucocorticoid receptors, may attenuate the rewarding properties of drugs of abuse. However, the effect of blocking corticosterone receptors on ethanol reward has yet to be investigated. OBJECTIVES: The current study investigated whether the stress hormone receptor antagonist, PT150, would block the rewarding properties of ethanol via the glucocorticoid receptor system and attenuate other ethanol-induced effects. METHODS: A conditioned place preference (CPP) procedure was used to examine the rewarding properties of ethanol in an avian preclinical model. Ethanol was paired with the least preferred chamber. On alternate days, water was paired with the preferred chamber. After eight pairings, a place preference test was given that allowed subjects to have access to both chambers. Half of the subjects received PT150 prior to ethanol administration. The other half received vehicle. Time spent in each chamber during the preference tests, locomotor activity during the pairings, and egg production in female birds was recorded. RESULTS: Ethanol treatment resulted in a CPP and pretreatment of PT150 blocked the acquisition of the ethanol-induced place preference. Neither ethanol nor PT150 altered locomotor activity. Pretreatment of PT150 also increased egg production in female quail treated with ethanol. CONCLUSIONS: These findings suggest repeated ethanol pairings with visual cues can produce a CPP. Furthermore, pretreatment of PT150 may be a potential pharmacotherapy for blocking the rewarding properties of ethanol and may enhance egg production in female quail treated with ethanol.

Effect of the glucocorticoid receptor antagonist PT150 on acquisition and escalation of fentanyl self-administration following early-life stress.

There is comorbidity between posttraumatic stress disorder (PTSD) and opioid use disorder (OUD), perhaps because PTSD-like stressful experiences early in life alter the hypothalamic-pituitary-adrenal stress axis to increase the risk for OUD. The present study determined if the glucocorticoid receptor antagonist PT150 reduces the escalation of fentanyl intake in rats exposed to a "two-hit" model of early-life stress (isolation rearing and acute stress). Male and female rats were raised during adolescence in either isolated or social housing and then were given either a single acute stress (restraint and cold-water swim) or control treatment in young adulthood. Rats were then treated daily with PT150 (50 mg/kg, oral) or placebo and were tested for acquisition of fentanyl self-administration in 1-hr sessions, followed by escalation across 6-hr sessions. Regardless of PT150 treatment or sex, acquisition of fentanyl self-administration in 1-hr sessions was greater in isolate-housed rats compared to social-housed rats; the acute stress manipulation did not have an effect on self-administration even though it transiently increased plasma corticosterone levels. During the 6-hr sessions, escalation of fentanyl was observed across all treatment groups; however, there was a significant PT150 Treatment × Sex interaction. While males self-administered more than females overall, PT150 decreased intake in males and increased intake in females, thus negating the sex difference. Although PT150 may serve as an effective treatment for reducing the risk of OUD following early-life stress in males, further work is needed to determine the mechanism underlying the differential effects of PT150 in males and females. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Adolescent Intermittent Ethanol Drives Modest Neuroinflammation but Does Not Escalate Drinking in Male Rats.

During adolescence, the brain is highly susceptible to alcohol-induced damage and subsequent neuroimmune responses, effects which may enhance development of an alcohol use disorder (AUD). Neuroimmune reactions are implicated in adolescent alcohol exposure escalating adulthood drinking. Therefore, we investigated whether intermittent alcohol exposure in male, adolescent rats (AIE) escalated adult drinking via two-bottle choice (2BC). We also examined the influence of housing environment across three groups: standard (group-housed with enrichment during 2BC), impoverished (group-housed without enrichment during 2BC), or isolation (single-housed without bedding or enrichment throughout). In the standard group immediately after AIE/saline and after 2BC, we also examined the expression of microglial marker, Iba1, reactive astrocyte marker, vimentin, and neuronal cell death dye, FluoroJade B (FJB). We did not observe an escalation of adulthood drinking following AIE, regardless of housing condition. Further, only a modest neuroimmune response occurred after AIE in the standard group: no significant microglial reactivity or neuronal cell death was apparent using this model, although some astrocyte reactivity was detected in adolescence following AIE that resolved by adulthood. These data suggest that the lack of neuroimmune response in adolescence in this model may underlie the lack of escalation of alcohol drinking, which could not be modified through isolation stress.

Environmental enrichment during development decreases intravenous self-administration of methylphenidate at low unit doses in rats.

Despite the efficacy and widespread use of methylphenidate (MPH) as a treatment modality for attention deficit hyperactivity disorder, clinical and preclinical findings indicate that it has abuse potential. Environmental enrichment reduces susceptibility to cocaine and amphetamine self-administration and decreases impulsive behavior, but its effects on MPH self-administration are unknown. The present experiments sought to determine the influence of environmental enrichment on MPH self-administration. Male rats were raised in an enriched condition (EC) or isolated condition (IC). They were trained to self-administer MPH (0.3 mg/kg/infusion) and then exposed to varying doses of MPH on either a fixed-ratio (experiment 1) or a progressive-ratio (experiment 2) schedule of reinforcement. EC rats earned significantly fewer infusions of MPH at low doses (0.03 and 0.056 mg/kg/infusion) compared with IC rats under both schedules; however, no differences were observed at high unit doses (0.1-1.0 mg/kg/infusion). During saline substitution at the end of MPH self-administration, EC rats also responded less for saline compared with IC rats, indicative of more rapid extinction. As with other stimulant drugs with different mechanisms of action, environmental enrichment during development protects against self-administration of MPH at low unit doses but not at high unit doses.

Nicotine and opioid co-dependence: Findings from bench research to clinical trials.

Concomitant use of tobacco and opioids represents a growing public health concern. In fact, the mortality rate due to smoking-related illness approaches 50% among SUD patients. Cumulative evidence demonstrates that the vulnerability to drugs of abuse is influenced by behavioral, environmental, and genetic factors. This review explores the contribution of genetics and neural mechanisms influencing nicotine and opioid reward, respiration, and antinociception, emphasizing the interaction of cholinergic and opioid receptor systems. Despite the substantial evidence demonstrating nicotine-opioid interactions within the brain and on behavior, the currently available pharmacotherapies targeting these systems have shown limited efficacy for smoking cessation on opioid-maintained smokers. Thus, further studies designed to identify novel targets modulating both nicotinic and opioid receptor systems may lead to more efficacious approaches for co-morbid nicotine dependence and opioid use disorder.

Neurobehavioral effects of environmental enrichment and drug abuse vulnerability: An updated review.

Environmental enrichment consisting of social peers and novel objects is known to alter neurobiological functioning and have an influence on the behavioral effects of drugs of abuse in preclinical rodent models. An earlier review from our laboratory (Stairs and Bardo, 2009) provided an overview of enrichment-specific changes in addiction-like behaviors and neurobiology. The current review updates the literature in this extensive field. Key findings from this updated review indicate that enrichment produces positive outcomes in drug abuse vulnerability beyond just psychostimulants. Additionally, recent studies indicate that enrichment activates key genes involved in cell proliferation and protein synthesis in nucleus accumbens and enhances growth factors in hippocampus and neurotransmitter signaling pathways in prefrontal cortex, amygdala, and hypothalamus. Remaining gaps in the literature and future directions for environmental enrichment and drug abuse research are identified.

Effects of voluntary adolescent intermittent alcohol exposure and social isolation on adult alcohol intake in male rats.

Initiating alcohol use in adolescence significantly increases the likelihood of developing adult alcohol use disorder (AUD). However, it has been difficult to replicate adolescent alcohol exposure leading to increased adult alcohol intake across differing preclinical models. In the present study, differentially housed male rats (group vs. single cages) were used to determine the effects of voluntary intermittent exposure of saccharin-sweetened ethanol during adolescence on adult intake of unsweetened 20% ethanol. Adolescent male rats were assigned to group- or isolated-housing conditions and underwent an intermittent 2-bottle choice in adolescence (water only or water vs. 0.2% saccharin/20% ethanol), and again in adulthood (water vs. 20% ethanol). Intermittent 2-bottle choice sessions lasted for 24 h, and occurred three days per week, for five weeks. Rats were moved from group or isolated housing to single-housing cages for 2-bottle choice tests and returned to their original housing condition on off days. During adolescence, rats raised in isolated-housing conditions consumed significantly more sweetened ethanol than rats raised in group-housing conditions, an effect that was enhanced across repeated exposures. In adulthood, rats raised in isolated-housing conditions and exposed to sweetened ethanol during adolescence also consumed significantly higher levels of unsweetened 20% ethanol compared to group-housed rats. The effect was most pronounced over the first five re-exposure sessions. Housing conditions alone had little effect on adult ethanol intake. These preclinical results suggest that social isolation stress, combined with adolescent ethanol exposure, may play a key role in adult AUD risk.