Changes in response rates and reinforcement thresholds for intracranial self-stimulation during morphine withdrawal

doi:10.1016/0091-3057(86)90121-8

Pharmacology Biochemistry and Behavior

Volume 25, Issue 6, December 1986, Pages 1263-1269

https://doi.org/10.1016/0091-3057(86)90121-8 Get rights and content

Abstract

Rats were implanted with stimulating electrodes in the medial forebrain bundle-lateral hypothalamus and were trained in an auto-titration brain self-stimulation paradigm. When response rates ad reinforcement thresholds were stable, the animals were implanted with subcutaneous osmotic minipumps (Alzet, 2ML1) which continually delivered morphine (1.2 mg/kg/hr as the base, n = 16) or saline (10.0 μl/hr, n = 11). After one week the pumps were removed, and the animals were again tested in the auto-titration paradigm following the daily administration of either saline (spontaneous withdrawal) or 1.0 mg/kg naloxone (precipitated withdrawal). During the eight-day withdrawal phase there was a decrease in the rate of lever-pressing for the morphine dependent animals and this was greatest on the first day. The magnitude of the decrease was greater in the precipitated withdrawal group than in the spontaneous withdrawal group and an increase in the reinforcement threshold occured only with precipitated withdrawal. Animals in both groups lost weight when measured each morning, but the precipitated group showed greater weight loss during the day. In addition, animals in the precipitated withdrawal group had diarrhea and showed a higher incidence of withdrawal signs than both the non-dependent (control) and spontaneous withdrawal groups. These experiments provide a detailed account of opiate withdrawal following the continuous subcutaneous infusion of a small dose morphine for one week.

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Chronic opioid exposure leads to hedonic deficits and enhanced vulnerability to addiction, which are observed and even strengthen after a period of abstinence, but the underlying circuit mechanisms are poorly understood. In this study, using both molecular and behavioral approaches, we tested the hypothesis that neurons expressing mu opioid receptors (MORs) in the dorsal raphe nucleus (DRN) are involved in addiction vulnerability associated with morphine abstinence.
MOR-Cre mice were exposed to chronic morphine and then went through spontaneous withdrawal for 4 weeks, a well-established mouse model of morphine abstinence. We studied DRN-MOR neurons of abstinent mice using 1) viral translating ribosome affinity for transcriptome profiling, 2) fiber photometry to measure neuronal activity, and 3) an opto-intracranial self-stimulation paradigm applied to DRN-MOR neurons to assess responses related to addiction vulnerability including persistence to respond, motivation to obtain the stimulation, self-stimulation despite punishment, and cue-induced reinstatement.
DRN-MOR neurons of abstinent animals showed a downregulation of genes involved in ion conductance and MOR-mediated signaling, as well as altered responding to acute morphine. Opto-intracranial self-stimulation data showed that abstinent animals executed more impulsive-like and persistent responses during acquisition and scored higher on addiction-like criteria.
Our data suggest that protracted abstinence to chronic morphine leads to reduced MOR function in DRN-MOR neurons and abnormal self-stimulation of these neurons. We propose that DRN-MOR neurons have partially lost their reward-facilitating properties, which in turn may lead to increased propensity to perform addiction-related behaviors.
Advances in the characterization of negative affect caused by acute and protracted opioid withdrawal using animal models
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Opioid use disorder (OUD) is a chronic brain disease which originates from long-term neuroadaptations that develop after repeated opioid consumption and withdrawal episodes. These neuroadaptations lead among other things to the development of a negative affect, which includes loss of motivation for natural rewards, higher anxiety, social deficits, heightened stress reactivity, an inability to identify and describe emotions, physical and/or emotional pain, malaise, dysphoria, sleep disorders and chronic irritability. The urge for relief from this negative affect is one of major causes of relapse, and thus represents a critical challenge for treatment and relapse prevention. Animal models of negative affect induced by opioid withdrawal have recapitulated the development of a negative emotional state with signs such as anhedonia, increased anxiety responses, increased despair-like behaviour and deficits in social interaction. This research has been critical to determine neurocircuitry adaptations during chronic opioid administration or upon withdrawal. In this review, we summarize the recent literature of rodent models of (i) acute withdrawal, (ii) protracted abstinence from passive administration of opioids, (iii) withdrawal or protracted abstinence from opioid self-administration. Finally, we describe neurocircuitry involved in acute withdrawal and protracted abstinence.
This article is part of the Special Issue on “Opioid-induced changes in addiction and pain circuits”.
Determinants of opioid abuse potential: Insights using intracranial self-stimulation
2019, Peptides
Citation Excerpt :
However, drugs with the second profile of effects during repeated treatment (i.e. tolerance to initial ICSS depression without emergence of ICSS facilitation) may or may not function as effective reinforcers in drug self-administration studies and/or maintain some level of abuse in humans [26–29]. Regimens of repeated morphine treatment that increase expression of ICSS facilitation by subsequent morphine doses can also produce signs of physical dependence if subsequent morphine doses are withheld (i.e. spontaneous withdrawal) or if an antagonist is administered (i.e. precipitated withdrawal) [30–34]. For example, Fig. 3 shows ICSS frequency-rate curves collected before, during, or after repeated treatment with saline or different morphine doses [31].
Intracranial self-stimulation (ICSS) is one procedure that can be used for preclinical abuse potential assessment. In ICSS procedures, subjects with microelectrodes implanted into a brain-reward region are trained to press an operant response lever for pulses of electrical brain stimulation, and drugs are evaluated for their effectiveness to increase or “facilitate” ICSS responding (an abuse-related effect) or to depress ICSS responding (an abuse-limiting effect). ICSS has been used for decades to evaluate determinants of opioid abuse potential, and this article reviews pharmacological and biological determinants of opioid abuse potential as revealed by ICSS studies in rodents. One of the most important observations from ICSS studies is that abused mu opioid receptor (MOR) agonists like morphine often fail to produce abuse-related ICSS facilitation in opioid-naïve subjects, but several days of repeated opioid exposure is sufficient for opioid-induced facilitation to emerge. Future studies with ICSS could help (a) to clarify mechanisms that increase MOR agonist abuse potential during early opioid exposure or during chronic exposure leading to dependence, (b) to evaluate novel opioids either developed as candidate analgesics with reduced abuse potential or identified as designer opioids being synthesized and distributed for illicit use, and (c) to test candidate pharmacotherapies for treatment of opioid abuse in non-dependent and dependent subjects.
Ultrasonic Vocalizations Capture Opposing Affective States During Drug Self-Administration: Revisiting the Opponent-Process Model of Addiction
2018, Handbook of Behavioral Neuroscience
Illicit drug use remains a pervasive problem despite decades of research documenting its harmful effects. This chapter discusses how positive and negative drives work together to escalate the transition to addiction. We detail the invaluable contributions of animal models that have improved the ways in which we think about and treat addiction. We discuss how rat ultrasonic vocalizations (USVs) provide a powerful analog to self-reports given by addicts. We review the conceptual framework of the opponent-process model of addiction and discuss how USVs provide new insight as to the time points when positive and negative affective states manifest throughout addiction. We review evidence that links drug-evoked USVs to specific neuronal structures, transmitter systems and circuits. We conclude by discussing the value of utilizing noninvasive and ethologically relevant USVs in studying substance use disorders as well as how the amassed data provide new insight into relationships between affect and addiction.
Differential effects of endocannabinoid catabolic inhibitors on morphine withdrawal in mice
2015, Drug and Alcohol Dependence
Citation Excerpt :
The CPA paradigm represents one among many assays sensitive to opioid withdrawal, and may reflect an aversive state. For example, opioid withdrawal elevates reward thresholds in intracranial self-stimulation, which may indicate an anhedonia-like effect (Altarifi and Negus, 2011; Kenny et al., 2006; Liu and Schulteis, 2004; Schaefer and Michael, 1983, 1986). Furthermore, opioid withdrawal produces anxiogenic effects in rats in the elevated plus maze (Schulteis et al., 1998b; Zhang and Schulteis, 2008).
Inhibition of endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and/or monoacylglycerol lipase (MAGL) reduces somatic morphine withdrawal signs, but its effects on aversive aspects of withdrawal are unknown. The present study investigated whether Δ⁹-tetrahydrocannabinol (THC), the MAGL inhibitor JZL184, the FAAH inhibitor PF-3845, or the dual FAAH/MAGL inhibitor SA-57 would reduce acquisition of morphine withdrawal-induced conditioned place avoidance (CPA) and jumping.
Mice were implanted with placebo or 75 mg morphine pellets, 48 h later injected with naloxone or saline and placed in the conditioning apparatus, and assessed for CPA at 72 h. Subjects were also observed for jumping behavior following naloxone challenge.
Naloxone (0.056 mg/kg) produced robust CPA in morphine-pelleted, but not placebo-pelleted, mice. Morphine pretreatment prevented the occurrence of withdrawal CPA and withdrawal jumping, while clonidine (an α2 adrenergic receptor agonist) only blocked withdrawal CPA. THC, JZL184, and SA-57 significantly reduced the percentage of mice that jumped during the conditioning session, but did not affect acquisition of withdrawal CPA. PF-3845 did not reduce morphine withdrawal CPA or jumping. Finally, neither THC nor the endocannabinoid catabolic enzyme inhibitors in non-dependent mice elicited a conditioned place preference or aversion.
These findings suggest that inhibiting endocannabinoid catabolic enzymes reduces somatic morphine withdrawal signs, but not aversive aspects as inferred in the CPA paradigm. The observation that non-dependent mice administered inhibitors of endocannabinoid degradation did not display place preferences is consistent with the idea that that endocannabinoid catabolic enzymes might be targeted therapeutically, with reduced risk of abuse.
Withdrawal from acute morphine dependence is accompanied by increased anxiety-like behavior in the elevated plus maze
2008, Pharmacology Biochemistry and Behavior
Pretreatment with a single moderate dose of morphine (e.g. 5.6-10 mg/kg) 4-24 hr prior to challenge with an opioid antagonist such as naloxone results in reliable expression of behaviors that resemble aversive or emotional consequences of withdrawal from chronic opioid exposure, including suppression of operant responding, elevations in brain reward thresholds, and conditioned place aversion. Repeated daily or weekly treatment with these same morphine doses results in a progressive increase in naloxone potency to elicit these withdrawal signs. The current study sought to determine whether increased anxiety-like behavior during withdrawal from chronic opioid dependence is also seen after acute morphine exposure, and progresses with repeated intermittent treatment. Male Wistar rats were handled and injected with either vehicle or morphine for 4 consecutive days. Three injection regimens were employed: Morphine Naive (4 vehicle injections), Acute Morphine (3 vehicle injections, 4th injection 5.6 or 10 mg/kg morphine), or Repeat Morphine (all 4 injections with 5.6 or 10 mg/kg morphine). Acute pretreatment with 5.6 mg/kg or 10 mg/kg morphine resulted in time-dependent increases in exploration of the open arms of the plus maze in naloxone-naive rats when tested at 2, 4 or 8 hr after the final pretreatment injection, with the effects at the higher dose appearing later (4 hr) than after the lower dose (2 hr). This pattern of results, in combination with a separate study which confirmed a significant anxiolytic-like effect of a low dose of morphine (0.56 mg/kg) administered 15 min prior to test, suggested that low residual morphine levels remaining in plasma at 2-4 hr after 5.6 and 10 mg/kg morphine may be sufficient to elicit anxiolytic-like effects. Repeat treatment with either dose of morphine resulted in a further increase in the magnitude and duration of this anxiolytic-like effect. These effects had dissipated by 8 hr post-morphine, and therefore precipitation of withdrawal by one of several doses of naloxone (0.10-3.3 mg/kg) was assessed in separate cohorts of rats 8 hr after the final pretreatment under Morphine Naïve, Acute Morphine, or Repeat Morphine conditions. Naloxone resulted in a significant dose-dependent expression of anxiety-like behavior with no effects on general activity after Acute Morphine pretreatment at either 5.6 or 10 mg/kg morphine. A further significant shift in naloxone potency was observed after Repeat Morphine pretreatment at the 10 mg/kg but not the 5.6 mg/kg dose. Thus, anxiety-like behavior is a prominent feature of the negative emotional consequences of naloxone-precipitated withdrawal from acute opioid dependence.

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Changes in response rates and reinforcement thresholds for intracranial self-stimulation during morphine withdrawal

Abstract

Biochem Pharmacol

Physiol Behav

Physiol Behav

Pharmacol Biochem Behav

Changes in operant behavior as an index of a withdrawal state from morphine in rats

Psychon Sci

Production of tolerance and physical dependence in the rat by simple administration of morphine in drinking water

Br J Pharmacol

Modification of morphine withdrawal by drugs interacting with humoral mechanisms: Some contradictions and their interpretation

Nature

A comparison of the effects of naloxone upon body weight loss and suppression of fixed-ratio operant behavior in morphine dependant rats

J Pharmacol Exp Ther

Morphine dependence and self-stimulation: Attenuation of withdrawal-induced weight loss

Res Commun Chem Pathol Pharmacol

An implanted reservoir of morphine solution for rapid induction of physical dependence in rats

Br J Pharmacol

Morphine withdrawal in the rat: Assessment by quantitation of diarrhea and modification by ethanol

Pharmacology

An intraventricular infusion model for inducing morphine dependence in rats: Quantitative assessment of precipitated withdrawal

Behav Neurosci

Morphine and intracranial self-stimulation in the hypothalamus and dorsal brainstem: Differential effects of dose, time and site

Int J Neurosci