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Article: Rats Chasing the Dragon: A new heroin inhalation method.

Gutierrez, Arnold / Taffe, Michael A

bioRxiv : the preprint server for biology

2023

Abstract: Rationale: Despite extensive human use of the inhalation route for ingesting opioids, models in rodents have mostly been limited to parenteral injection and oral dosing. Methods using electronic drug delivery systems (EDDS; "e-cigarettes") have shown ... ...

Abstract	Rationale: Despite extensive human use of the inhalation route for ingesting opioids, models in rodents have mostly been limited to parenteral injection and oral dosing. Methods using electronic drug delivery systems (EDDS; "e-cigarettes") have shown efficacy in rodent models but these do not faithfully mimic the most popular human inhalation method of heating heroin to the point of vaporization. Objective: This study was designed to determine if direct volatilization of heroin hydrochloride delivers effective heroin doses to rodents. Methods: Middle aged rats were exposed to vapor created by direct heating of heroin HCl powder in a ceramic e-cigarette type atomizer. Efficacy was determined with a warm water tail withdrawal nociception assay, rectal temperature and self-administration. Results: Ten minutes of inhalation of vaporized heroin slowed response latency in a warm water tail withdrawal assay and increased rectal temperature in male rats, in a dose-dependent manner. Similar antinociceptive effects in female rats were attenuated by the opioid antagonist naloxone (1.0 mg/kg, s.c.). Female rats made operant responses for heroin vapor in 15-minute sessions, increased their response rate when the reinforcement ratio increased from FR1 to FR5, and further increased their responding when vapor delivery was omitted. Anti-nociceptive effects of self-administered volatilized heroin were of a similar magnitude as those produced by the 10-minute non-contingent exposure. Conclusions: This study shows that "chasing the dragon" methods of inhalation of heroin can be modeled successfully in the rat. Inhalation techniques may be particularly useful for longer term studies deep into middle age of rat species.
Language	English
Publishing date	2023-08-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.09.552712
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Article ; Online: Rats chasing the dragon: A new heroin inhalation method.

Gutierrez, Arnold / Taffe, Michael A

Journal of neuroscience methods

2023 Volume 402, Page(s) 110013

Abstract: Background: Despite extensive human use of inhalation for ingesting opioids, models in rodents have mostly been limited to parenteral injection and oral dosing. Methods using electronic drug delivery systems (EDDS; "e-cigarettes") have shown efficacy in ...

Abstract	Background: Despite extensive human use of inhalation for ingesting opioids, models in rodents have mostly been limited to parenteral injection and oral dosing. Methods using electronic drug delivery systems (EDDS; "e-cigarettes") have shown efficacy in rodent models but these do not faithfully mimic the most popular human inhalation method of heating heroin to the point of vaporization. New method: Middle aged rats were exposed to vapor created by direct heating of heroin HCl powder in a ceramic e-cigarette type atomizer. Efficacy was determined with a warm water tail withdrawal nociception assay, rectal temperature and self-administration. Results: Ten minutes of inhalation of vaporized heroin slowed response latency in a warm water tail withdrawal assay and increased rectal temperature in male rats, in a dose-dependent manner. Similar antinociceptive effects in female rats were attenuated by the opioid antagonist naloxone (1.0 mg/kg, s.c.). Female rats made operant responses for heroin vapor in 15-minute sessions, increased their response rate when the reinforcement ratio increased from FR1 to FR5, and further increased their responding when vapor delivery was omitted. Anti-nociceptive effects of self-administered volatilized heroin were of a similar magnitude as those produced by the 10-minute non-contingent exposure. Comparison with existing methods: Inhalation of directly volatilized heroin successfully produces heroin-typical effects, comparable to EDDS inhalation delivery. Conclusions: This study shows that "chasing the dragon" methods of inhalation of heroin can be modeled successfully in the rat. Inhalation techniques may be particularly useful for longer term studies deep into the middle age of rats.
MeSH term(s)	Humans ; Middle Aged ; Rats ; Male ; Female ; Animals ; Heroin/pharmacology ; Electronic Nicotine Delivery Systems ; Naloxone/pharmacology ; Narcotic Antagonists ; Camphor ; Menthol ; Water ; Self Administration
Chemical Substances	Heroin (70D95007SX) ; Naloxone (36B82AMQ7N) ; Narcotic Antagonists ; Camphor (76-22-2) ; Menthol (1490-04-6) ; Water (059QF0KO0R)
Language	English
Publishing date	2023-11-19
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	282721-9
ISSN	1872-678X ; 0165-0270
ISSN (online)	1872-678X
ISSN	0165-0270
DOI	10.1016/j.jneumeth.2023.110013
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Article ; Online: Adult consequences of repeated nicotine and Δ

Gutierrez, Arnold / Creehan, Kevin M / Grant, Yanabel / Taffe, Michael A

Psychopharmacology

2024 Volume 241, Issue 3, Page(s) 585–599

Abstract: Rationale: Use of electronic drug delivery systems (EDDS, "e-cigarettes") to ingest nicotine and Δ: Objectives: This study was conducted to examine the impact of repeated adolescent vapor inhalation of nicotine and THC in rats.: Methods: Female ... ...

Abstract	Rationale: Use of electronic drug delivery systems (EDDS, "e-cigarettes") to ingest nicotine and Δ Objectives: This study was conducted to examine the impact of repeated adolescent vapor inhalation of nicotine and THC in rats. Methods: Female Sprague-Dawley rats were exposed to 30-min sessions of vapor inhalation, twice daily, from post-natal day (PND) 31 to PND 40. Conditions included vapor from the propylene glycol (PG) vehicle, nicotine (60 mg/mL in the PG), THC (100 mg/mL in the PG), or the combination of nicotine (60 mg/mL) and THC (100 mg/mL). Rats were assessed on wheel activity, heroin anti-nociception and nicotine and heroin vapor volitional exposure during adulthood. Results: Nicotine-exposed rats exhibited few differences as adults, but were less sensitive to anti-nociceptive effects of heroin (1 mg/kg, s.c.). THC- and THC + nicotine-exposed rats were less spontaneously active, and obtained fewer nicotine vapor deliveries as adults. In contrast, THC-exposed rats obtained volitional heroin vapor at rates indistinguishable from the non-THC-exposed groups. Repeated THC exposure also caused tolerance to temperature-disrupting effects of THC (5 mg/kg, i.p.). Conclusions: These studies further confirm that the effects of repeated vapor exposure to THC in adolescence last into early to middle adulthood, including decreased volitional consumption of nicotine. Effects of repeated nicotine in adolescence were comparatively minor.
MeSH term(s)	Rats ; Animals ; Female ; Dronabinol/pharmacology ; Nicotine/pharmacology ; Rats, Sprague-Dawley ; Heroin ; Cannabis ; Electronic Nicotine Delivery Systems
Chemical Substances	Dronabinol (7J8897W37S) ; Nicotine (6M3C89ZY6R) ; Heroin (70D95007SX)
Language	English
Publishing date	2024-01-29
Publishing country	Germany
Document type	Journal Article
ZDB-ID	130601-7
ISSN	1432-2072 ; 0033-3158
ISSN (online)	1432-2072
ISSN	0033-3158
DOI	10.1007/s00213-024-06545-5
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Article: Adult consequences of repeated nicotine and Δ

Gutierrez, Arnold / Creehan, Kevin M / Grant, Yanabel / Taffe, Michael A

bioRxiv : the preprint server for biology

2023

Abstract: The use of Electronic Drug Delivery Systems (EDDS, "e-cigarettes") to ingest nicotine and ... ...

Abstract	The use of Electronic Drug Delivery Systems (EDDS, "e-cigarettes") to ingest nicotine and Δ
Language	English
Publishing date	2023-09-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.08.556932
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Article ; Online: The long-term effects of repeated heroin vapor inhalation during adolescence on measures of nociception and anxiety-like behavior in adult Wistar rats.

Gutierrez, Arnold / Harvey, Eric L / Creehan, Kevin M / Taffe, Michael A

Psychopharmacology

2022 Volume 239, Issue 12, Page(s) 3939–3952

Abstract: Rationale: Adolescents represent a vulnerable group due to increased experimentation with illicit substances that is often associated with the adolescent period, and because adolescent drug use can result in long-term effects that differ from those ... ...

Abstract	Rationale: Adolescents represent a vulnerable group due to increased experimentation with illicit substances that is often associated with the adolescent period, and because adolescent drug use can result in long-term effects that differ from those caused by drug use initiated during adulthood. Objectives: The purpose of the present study was to determine the effects of repeated heroin vapor inhalation during adolescence on measures of nociception, and anxiety-like behavior during adulthood in female and male Wistar rats. Methods: Rats were exposed twice daily to 30 min of heroin vapor from post-natal day (PND) 36 to PND 45. At 12 weeks of age, baseline thermal nociception was assessed across a range of temperatures with a warm-water tail-withdrawal assay. Anxiety-like behavior was assessed in an elevated plus-maze (EPM) and activity was measured in an open-field arena. Starting at 23 weeks of age, baseline thermal nociception was re-assessed, nociception was determined after acute heroin or naloxone injection, and anxiety-like behavior was redetermined in the EPM. Results: Adolescent heroin inhalation altered baseline thermal nociception in female rats at 12 weeks of age and in both female and male rats at ~ 23 weeks. Heroin-treated animals exhibited anxiety-like behavior when tested in the elevated plus-maze, showed blunted heroin-induced analgesia, but exhibited no effect on naloxone-induced hyperalgesia. Conclusions: The present study demonstrates that heroin vapor inhalation during adolescence produces behavioral and physiological consequences in rats that persist well into adulthood.
MeSH term(s)	Rats ; Animals ; Male ; Female ; Rats, Wistar ; Heroin/pharmacology ; Nociception ; Anxiety ; Naloxone/pharmacology
Chemical Substances	Heroin (70D95007SX) ; Naloxone (36B82AMQ7N)
Language	English
Publishing date	2022-10-26
Publishing country	Germany
Document type	Journal Article
ZDB-ID	130601-7
ISSN	1432-2072 ; 0033-3158
ISSN (online)	1432-2072
ISSN	0033-3158
DOI	10.1007/s00213-022-06267-6
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Article: Oxycodone Self-Administration in Female Rats is Enhanced by ∆

Nguyen, Jacques D / Grant, Yanabel / Yang, Celine / Gutierrez, Arnold / Taffe, Michael A

bioRxiv : the preprint server for biology

2023

Abstract: Epidemiological evidence suggests that the legalization of cannabis may reduce opioid-related harms. Preclinical evidence of neuropharmacological interactions of endogenous cannabinoid and opioid systems prompts further investigation of cannabinoids as ... ...

Abstract	Epidemiological evidence suggests that the legalization of cannabis may reduce opioid-related harms. Preclinical evidence of neuropharmacological interactions of endogenous cannabinoid and opioid systems prompts further investigation of cannabinoids as potential therapeutics for the non-medical use of opioids. In these studies female rats, previously trained to self-administer oxycodone (0.15 mg/kg/infusion) intravenously in 6 h sessions, were allowed to self-administer oxycodone after exposure to cannabidiol (CBD) and Δ
Language	English
Publishing date	2023-10-31
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.26.564282
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Article ; Online: Adult consequences of repeated nicotine vapor inhalation in adolescent rats.

Gutierrez, Arnold / Nguyen, Jacques D / Creehan, Kevin M / Grant, Yanabel / Taffe, Michael A

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco

2023

Abstract: Introduction: There has been a resurgence in nicotine inhalation in adolescents due to the popularity and availability of Electronic Nicotine Delivery Systems (ENDS). Almost five times as many US high-school seniors inhale nicotine vapor daily compared ... ...

Abstract	Introduction: There has been a resurgence in nicotine inhalation in adolescents due to the popularity and availability of Electronic Nicotine Delivery Systems (ENDS). Almost five times as many US high-school seniors inhale nicotine vapor daily compared with those who smoke tobacco. This study was conducted to determine the impact of repeated adolescent vapor inhalation of nicotine on behavior in adulthood. Methods: Male and female Sprague-Dawley rats were exposed to 30-minute sessions of ENDS vapor inhalation, twice daily, from Post-Natal Day (PND) 31 to PND 40. Conditions included vapor from the propylene glycol (PG) vehicle or nicotine (30 mg/mL in the PG). Animals were assessed for effects of nicotine on open field (PND 74-105) and wheel activity (PND 126-180) and for volitional exposure to nicotine vapor (PND 285-395). Plasma nicotine and cotinine were assessed in separate groups of male and female Wistar and Sprague-Dawley rats after a single nicotine inhalation session. Results: Group mean plasma nicotine ranged from 39 to 59 ng/mL post-session with minimal strain differences detected. Adolescent nicotine exposure enhanced sensitivity to the locomotor stimulating effects of nicotine (0.1-0.8 mg/kg, s.c.) in an open field in female rats, but didn't change effects of nicotine on wheel activity. Female rats exposed to nicotine (30 mg/mL) vapor as adolescents responded more vigorously than PG exposed females for nicotine vapor in a FR5 challenge. Conclusions: Repeated adolescent nicotine vapor inhalation leads to enhanced liability for volitional exposure to nicotine vapor in adulthood in female rats, but minimal change in spontaneous locomotor behavior. Implications: These results show that adolescent vaping of nicotine can lead to lasting sensitization to the effects of nicotine in adulthood, including volitional responding for nicotine vapor. Demonstration of this in a controlled animal model establishes causality in a manner not possible from longitudinal evidence in human populations. These findings further highlight the importance of decreasing adolescent nicotine exposure by e-cigarettes to reduce consumption in adulthood.
Language	English
Publishing date	2023-11-08
Publishing country	England
Document type	Journal Article
ZDB-ID	1452315-2
ISSN	1469-994X ; 1462-2203
ISSN (online)	1469-994X
ISSN	1462-2203
DOI	10.1093/ntr/ntad211
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Article ; Online: A vapor exposure method for delivering heroin alters nociception, body temperature and spontaneous activity in female and male rats.

Gutierrez, Arnold / Creehan, Kevin M / Taffe, Michael A

Journal of neuroscience methods

2020 Volume 348, Page(s) 108993

Abstract: Background: The ongoing crisis related to non-medical use of opioids makes it of continued importance to understand the risk factors for opioid addiction, the behavioral and neurobiological consequences of opioid exposure and to seek potential avenues ... ...

Abstract	Background: The ongoing crisis related to non-medical use of opioids makes it of continued importance to understand the risk factors for opioid addiction, the behavioral and neurobiological consequences of opioid exposure and to seek potential avenues for therapy. Pre-clinical rodent models have been critical to advancing understanding of opioid consequences for decades, but have been mostly limited to drug delivery by injection or by oral dosing. Inhalation, a significant route for many human users, has not been as well-established. Method: We adapted an e-cigarette based exposure system, previously shown efficacious for delivery of other drugs to rats, to deliver heroin vapor. Effectsin vivo were assessed in male and female Sprague-Dawley rats using a warm-water assay for anti-nociception and an implanted radiotelemetry system for evaluating changes in body temperature and spontaneous activity rate. Results: Inhalation of vapor created by heroin 100 mg/mL in the propylene glycol (PG) vehicle significantly slowed tail-withdrawal from a 52 °C water bath, bi-phasically altered activity, and increased temperature in male and female rats. Inhalation of heroin 50 mg/mL for 15 min produced significant effects, as the lower bound on efficacy, whereas inhalation of heroin 100 mg/mL for 30 min produced robust effects across all endpoints and groups. Conclusions: This work shows that e-cigarette devices deliver psychoactive doses of heroin to rats, using concentrations of ∼50-100 mg/mL and inhalation durations of 15-30 min. This technique may be useful to assess the health consequences of inhaled heroin and other opioid drugs.
MeSH term(s)	Analgesics, Opioid/pharmacology ; Animals ; Body Temperature ; Electronic Nicotine Delivery Systems ; Female ; Heroin/toxicity ; Male ; Nociception ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Temperature
Chemical Substances	Analgesics, Opioid ; Heroin (70D95007SX)
Language	English
Publishing date	2020-10-30
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	282721-9
ISSN	1872-678X ; 0165-0270
ISSN (online)	1872-678X
ISSN	0165-0270
DOI	10.1016/j.jneumeth.2020.108993
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Article ; Online: Behavioral effects of ethanol in the Red Swamp Crayfish (Procambarus clarkii).

Gutierrez, Arnold / Creehan, Kevin M / de Guglielmo, Giordano / Roberts, Amanda J / Taffe, Michael A

Journal of the experimental analysis of behavior

2022 Volume 117, Issue 3, Page(s) 472–492

Abstract: Alcohol abuse remains one of the primary preventable sources of mortality in the United States. Model species can be used to evaluate behavioral and other biological changes associated with alcohol and to identify novel treatments. This report describes ... ...

Abstract	Alcohol abuse remains one of the primary preventable sources of mortality in the United States. Model species can be used to evaluate behavioral and other biological changes associated with alcohol and to identify novel treatments. This report describes methods for evaluating the behavioral effects of ethanol (EtOH) in crayfish. Crayfish (Procambarus clarkii) were immersed in ethanol concentrations ranging from 0.1 to 1.0 molar, for 10-30 min. Studies evaluated hemolymph alcohol concentration, locomotion in an open field and anxiety-like behavior using a Light/Dark transfer approach. EtOH immersion produced dose-dependent increases in hemolymph EtOH (up to 249 mg/dL) and reductions in open field locomotion that depended on EtOH concentration or exposure duration. Untreated crayfish exhibit avoidance of the open parts of the locomotor arena and a preference for a covered portion. Acute EtOH immersion decreased time spent in the covered portion of the Light/Dark arena, consistent with a decrease in anxiety-like behavior. Daily EtOH immersion for 5 days did not alter locomotor responses, however, activity was increased 3 days after the repeated EtOH regimen. Overall, this study shows that this inexpensive, easily maintained species can be used for behavioral pharmacological experiments designed to assess the acute and repeated effects of EtOH.
MeSH term(s)	Animals ; Anxiety ; Astacoidea/physiology ; Ethanol/pharmacology ; Locomotion
Chemical Substances	Ethanol (3K9958V90M)
Language	English
Publishing date	2022-03-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	219405-3
ISSN	1938-3711 ; 0022-5002
ISSN (online)	1938-3711
ISSN	0022-5002
DOI	10.1002/jeab.746
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Article ; Online: Female rats self-administer heroin by vapor inhalation.

Gutierrez, Arnold / Nguyen, Jacques D / Creehan, Kevin M / Taffe, Michael A

Pharmacology, biochemistry, and behavior

2020 Volume 199, Page(s) 173061

Abstract: Over the last two decades the United States has experienced a significant increase in the medical and non-medical use of opioid drugs, resulting in record numbers of opioid-related overdoses and deaths. There was an initial increase in non-medical use of ...

Abstract	Over the last two decades the United States has experienced a significant increase in the medical and non-medical use of opioid drugs, resulting in record numbers of opioid-related overdoses and deaths. There was an initial increase in non-medical use of prescription opioids around 2002, followed later by increased heroin use and then most recently fentanyl. Inhalation is a common route of administration for opioids, with a documented history spanning back to Mediterranean antiquity and up through modern use with e-cigarette devices. Unfortunately, preclinical studies using inhalation as the route of administration remain relatively few. This study was conducted to determine the efficacy of e-cigarette vapor inhalation of heroin in rats. Non-contingent exposure to heroin or methadone vapor produced anti-nociceptive efficacy in male and female rats. Female rats were trained to self-administer heroin vapor; the most-preferring half of the distribution obtained more vapor reinforcers when the concentration of heroin was reduced in the vapor vehicle and when pre-treated with the opioid receptor antagonist naloxone. The anti-nociceptive effect of heroin self-administered by vapor was identical in magnitude to that produced by intravenous self-administration. Finally, anxiety-like behavior increased 24-48 h after last heroin vapor access, consistent with withdrawal signs observed after intravenous self-administration. In sum, these studies show that rewarding and anti-nociceptive effects of heroin are produced in rats by vapor inhalation using e-cigarette technology. Importantly, self-administration models by this route can be deployed to determine health effects of inhaled heroin or other opioids.
MeSH term(s)	Administration, Inhalation ; Animals ; Behavior, Animal/drug effects ; Electronic Nicotine Delivery Systems ; Female ; Heroin/administration & dosage ; Heroin/pharmacology ; Male ; Methadone/administration & dosage ; Methadone/pharmacology ; Narcotics/administration & dosage ; Narcotics/pharmacology ; Rats ; Rats, Wistar ; Self Administration
Chemical Substances	Narcotics ; Heroin (70D95007SX) ; Methadone (UC6VBE7V1Z)
Language	English
Publishing date	2020-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	191042-5
ISSN	1873-5177 ; 0091-3057
ISSN (online)	1873-5177
ISSN	0091-3057
DOI	10.1016/j.pbb.2020.173061
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