Voluntary Morphine Consumption Research Articles

A Novel Morphine Drinking Model of Opioid Dependence in Rats.

An animal model of voluntary oral morphine consumption would allow for a pre-clinical evaluation of new treatments aimed at reducing opioid intake in humans. However, the main limitation of oral morphine consumption in rodents is its bitter taste, which is strongly aversive. Taste aversion is often overcome by the use of adulterants, such as sweeteners, to conceal morphine taste or bitterants in the alternative bottle to equalize aversion. However, the adulterants’ presence is the cause for consumption choice and, upon removal, the preference for morphine is not preserved. Thus, current animal models are not suitable to study treatments aimed at reducing consumption elicited by morphine itself. Since taste preference is a learned behavior, just-weaned rats were trained to accept a bitter taste, adding the bitterant quinine to their drinking water for one week. The latter was followed by allowing the choice of quinine or morphine (0.15 mg/mL) solutions for two weeks. Then, quinine was removed, and the preference for morphine against water was evaluated. Using this paradigm, we show that rats highly preferred the consumption of morphine over water, reaching a voluntary morphine intake of 15 mg/kg/day. Morphine consumption led to significant analgesia and hyperlocomotion, and to a marked deprivation syndrome following the administration of the opioid antagonist naloxone. Voluntary morphine consumption was also shown to generate brain oxidative stress and neuroinflammation, signs associated with opioid dependence development. We present a robust two-bottle choice animal model of oral morphine self-administration for the evaluation of therapeutic interventions for the treatment of morphine dependence.

Chronic Sleep Deprivation Blocks Voluntary Morphine Consumption but Not Conditioned Place Preference in Mice.

The opioid epidemic remains a significant healthcare problem and is attributable to over 100,000 deaths per year. Poor sleep increases sensitivity to pain, impulsivity, inattention, and negative affect, all of which might perpetuate drug use. Opioid users have disrupted sleep during drug use and withdrawal and report poor sleep as a reason for relapse. However, preclinical studies investigating the relationship between sleep loss and substance use and the associated underlying neurobiological mechanisms of potential interactions are lacking. One of the most common forms of sleep loss in modern society is chronic short sleep (CSS) (<7 h/nightly for adults). Here, we used an established model of CSS to investigate the influence of disrupted sleep on opioid reward in male mice. The CSS paradigm did not increase corticosterone levels or depressive-like behavior after a single sleep deprivation session but did increase expression of Iba1, which typically reflects microglial activation, in the hypothalamus after 4 weeks of CSS. Rested control mice developed a morphine preference in a 2-bottle choice test, while mice exposed to CSS did not develop a morphine preference. Both groups demonstrated morphine conditioned place preference (mCPP), but there were no differences in conditioned preference between rested and CSS mice. Taken together, our results show that recovery sleep after chronic sleep disruption lessens voluntary opioid intake, without impacting conditioned reward associated with morphine.

Saffron (Crocus sativus L.) stigma reduces symptoms of morphine-induced dependence and spontaneous withdrawal in rats

ABSTRACT Background: Chronic morphine induces physical and psychological dependence signs. Saffron (Crocus sativus L.) stigma has been shown to have anxiolytic, antidepressant, and antinociceptive properties and to alleviate naloxone-precipitated withdrawal signs. Objectives: Therefore, this study was designed to examine the effects of saffron aqueous extract on the severity of physical-psychological dependence, voluntary morphine consumption, and the cerebrospinal fluid (CSF) serotonin levels following locomotor sensitization in morphine-dependent rats and in rats undergoing morphine withdrawal. Materials: Adult male rats were treated with morphine (10 mg/kg, sc twice daily) for 10 days. Rats received saffron extract (60 mg/kg, ip) daily, during the induction of morphine dependence and/or withdrawal. Then, rats were tested for spontaneous withdrawal signs, anxiety using the elevated plus-maze, depression using sucrose preference test, and voluntary morphine consumption using a two-bottle choice paradigm, and then challenged with morphine (1 mg/kg, ip) to evaluate of locomotor sensitization and CSF serotonin levels. Results: The results showed saffron extract during induction of morphine dependence decreased the severity of withdrawal signs (P = .05), while it had no effect on anxiety and depression-like behaviors. Saffron extract during morphine withdrawal exhibited an increase in the percentage (or ratio) of open/total arm entries (P = .017), higher levels of sucrose preference (P = .0001), a lower morphine preference ratio (P = .02) and also, a decrease in locomotor activity (P = .004) and an increase in the CSF serotonin levels (P = .041) in rats challenged to morphine. Conclusions: Saffron extract may exert a protective effect against morphine-induced behavioral sensitization in rats, probably through increasing serotonin levels.

Environmental Enrichment Ameliorates Psychological Dependence Symptoms and Voluntary Morphine Consumption in Morphine Withdrawn Rats Under Methadone Maintenance Treatment

Introduction:Previous studies have shown that physical and psychological dependence and the vulnerability to relapse are still present during MMT. Thus, this study examined whether Enriched Environment (EE) would attenuate anxiety, depressive, and obsessive-compulsive-like behaviors, as well as voluntary morphine consumption following Methadone Maintenance Treatment (MMT) in morphine withdrawn rats.Methods:The rats were injected bi-daily doses (10 mg/kg, 12-h interval) of morphine for 14 days. Then, the rats were reared in a Standard Environment (SE) or EE for 30 more days during morphine withdrawal, simultaneous with receiving MMT. The rats were tested for anxiety (the Elevated Plus Maze [EPM]) and depression (Sucrose Preference Test [SPT]), Obsessive-Compulsive Disorder (OCD) as grooming behavior, and voluntary morphine consumption using a Two-Bottle Choice (TBC) paradigm.Results:The findings revealed that EE experience in morphine withdrawn rats under MMT significantly increased the EPM open-arm time and higher sucrose preference than SE rats. Also, we found that the EE decreased the self-grooming behavior and morphine preference ratio in morphine withdrawn rats receiving MMT compared to the SE group.Conclusion:We conclude that exposure to EE decreased methadone-induced anxiety, depressive and OCD-like behaviors, and voluntary morphine consumption in morphine withdrawn rats under MMT. Thus, the EE seems to be one of the strategies for reducing MMT-induced behavioral dysfunction and the risk of relapse induced by morphine withdrawal.

Effect of swimming exercise on spatial learning and memory, and voluntary morphine consumption in maternally separated rats in adulthood

Effect of swimming exercise on spatial learning and memory, and voluntary morphine consumption in maternally separated rats in adulthood

Effect of enriched environment during adolescence on spatial learning and memory, and voluntary consumption of morphine in maternally separated rats in adulthood.

This study was designed to examine the effect of environmental enrichment (EE) during adolescence on spatial learning and memory and voluntary morphine consumption in maternally separated (MS) male and female rats in adulthood. Male Wistar rats were allowed to mate with female virgin Wistar rats. Pups were separated from the dams daily for 180min during postnatal days 2-14. All pups were weaned on day 21. The pups of both sexes were reared in a standard (SE) or enriched (EE) environment during postnatal days 21-50. Then, adulthood rats were tested for spatial learning and memory (Morris Water Maze), and voluntary consumption of morphine using a two-bottle choice paradigm (TBC). We found that the MS/SE rats showed longer escape latencies to find the platform on the third (the male) and fourth (the female) days of training than No MS/SE rats. Also, exposure to EE shortened the latency to escape in the male and female MS rats as training progressed than MS/SE rats. Moreover, the No MS/EE and MS/EE male rats spent significantly more time in the target zone compared with the SE control groups in the probe test. We also found that voluntary morphine consumption was higher in the male and female MS/SE than No MS/SE rats, while it was lower in the male and female MS/EE rats. The present results have shown that EE treatment may have potential therapeutic application for the prevention of the development of drug addiction and recovery from cognitive deficits following neonatal MS during adulthood.

Treadmill exercise attenuates the severity of physical dependence, anxiety, depressive-like behavior and voluntary morphine consumption in morphine withdrawn rats receiving methadone maintenance treatment

This study was designed to examine whether treadmill exercise would attenuate the severity of physical dependence, methadone-induced anxiety, depression and voluntary morphine consumption in morphine withdrawn rats receiving methadone maintenance treatment (MMT). The rats were chronically treated with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine for 14 days. The exercising rats receiving MMT were forced to run on a motorized treadmill for 30 days during morphine withdrawal. Then, rats were tested for the severity of morphine dependence, the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that naloxone- precipitated opioid withdrawal signs were decreased in exercising morphine-dependent rats receiving MMT than sedentary rats. Also, the exercising morphine-dependent rats receiving MMT exhibited an increased time on open arms, preference for sucrose and a lower morphine preference ratio than sedentary rats. We conclude that treadmill exercise decreased the severity of physical dependence, anxiety/depressive-like behaviors and also the voluntary morphine consumption in morphine withdrawn rats receiving MMT. Thus, exercise may benefit in the treatment of addicts during MMT.

Maternal swimming exercise during pregnancy attenuates anxiety/depressive-like behaviors and voluntary morphine consumption in the pubertal male and female rat offspring born from morphine dependent mothers.

This study was designed to examine whether maternal swimming exercise during pregnancy would attenuate prenatally morphine-induced anxiety, depression and voluntary consumption of morphine in the pubertal male and female rat offspring. Pregnant rats during the development of morphine dependence were allowed to swim (30-45min/d, 3days per a week) on gestational days 11-18. Then, the pubertal male and female rat offspring were tested for the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that male and female rat offspring born of the swimmer morphine-dependent mothers exhibited an increase in EPM open arm time and entries, higher levels of sucrose preference than their sedentary control mothers. Voluntary consumption of morphine was less in the male and female rat offspring born of the swimmer morphine-dependent mothers as compared with their sedentary control mothers during three periods of the intake of drug. Thus, swimming exercise in pregnant morphine dependent mothers decreased anxiety, depressive-like behavior and also the voluntary morphine consumption in the pubertal male and female offspring, which may prevent prenatally morphine-induced behavioral sensitization in offspring.

Comparison of chronic physical and emotional social defeat stress effects on mesocorticolimbic circuit activation and voluntary consumption of morphine

Chronic social defeat stress (CSDS) is a well-established rodent model of depression that induces persistent social avoidance. CSDS triggers molecular adaptations throughout the mesocorticolimbic reward circuit, including changes in the activity of dopamine neurons in the ventral tegmental area (VTA), that may also influence drug reward. One limitation of traditional, physical CSDS (PS) is that injury complicates the study of opiate drugs like morphine. Thus, we sought to characterize a variation of CSDS, termed emotional CSDS (ES), that eliminates this confound. We assessed the effect of PS and ES on mesocorticolimbic circuit activation, VTA gene expression, and morphine intake. We found that PS and ES similarly induced ΔFosB in the hippocampus, but only PS significantly increased ΔFosB expression in the prefrontal cortex and striatum. In contrast, cFos expression was similarly reduced by both PS and ES. Interestingly, we found that PS and ES similarly increased voluntary morphine consumption immediately following stress, despite differences in the magnitude of the depressive phenotype and striatal ΔFosB expression at this time point. Combined, these data suggest that both stress paradigms may be useful for investigation of stress-induced changes in drug behavior.

Effects of environmental enrichment during abstinence in morphine dependent parents on anxiety, depressive-like behaviors and voluntary morphine consumption in rat offspring

Chronic morphine exposure during puberty increased morphine-induced rewarding effects and sensitization in the next generation. Given the well-known beneficial effects of environmental enrichment on the severity of physical and psychological dependence on morphine, we examined effects of enriched environment during morphine abstinence in morphine dependent parental rats before mating on the anxiety and depressive-like behaviors, and voluntary morphine consumption in their offspring. Paternal and/or maternal rats were injected with bi-daily doses (10mg/kg, 12h intervals) of morphine for 14days followed by rearing in a standard environment (SE) or enriched environment (EE) during 30days of morphine abstinence before mating. The pubertal male and female rat offspring were tested for anxiety (the elevated plus maze- EPM) and depression (sucrose preference test-SPT), and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that EE experience in morphine-dependent both parents result in an increase in the percentage of time spent into open arms/time spent on both arms using EPM in male offspring, higher levels of sucrose preference in female offspring and lower levels of voluntary morphine consumption in male and female offspring. Thus, EE experience in morphine-dependent both parents reduced anxiety, depressive-like behavior and also the voluntary morphine consumption in their offspring during puberty which may prevent the vulnerability of the next generation to drug abuse.

Effect of environmental enrichment on physical and psychological dependence signs and voluntary morphine consumption in morphine-dependent and morphine-withdrawn rats.

This study was designed to examine the effect of environmental enrichment during morphine dependency and withdrawal on the severity of naloxone-precipitated withdrawal signs, anxiety, and depressive-like behaviors and voluntary morphine consumption in morphine-dependent rats. The rats were injected with bi-daily doses (10 mg/kg, 12 h intervals) of morphine for 14 days following rearing in a standard environment (SE) or enriched environment (EE) during the development of morphine dependence and withdrawal. Then, rats were tested for withdrawal signs after naloxone injection, anxiety (the elevated plus maze) and depression-related behavior (sucrose preference test), and voluntary consumption of morphine using a two-bottle choice paradigm, in morphine-dependent and morphine-withdrawn rats. The results showed that EE decreased naloxone-precipitated withdrawal signs, but not anxiety or sucrose preference during dependence on morphine. The EE-withdrawn rats showed an increase in the elevated plus maze open arm time and entries and higher levels of sucrose preference than SE rats. Voluntary consumption of morphine was lower in the EE-withdrawn rats than in the SE groups in the second period of drug intake. Thus, exposure to EE reduced the severity of morphine dependence and voluntary consumption of morphine, alongside reductions in anxiety and depression-related behavior in morphine-withdrawn rats.

The Effect of Ventral Tegmental Area Rictor Knockout on Susceptibility to Chronic Social Defeat Stress and Stress‐induced Changes in Morphine Reward

There is significant co‐morbidity of addiction and depression and this may be due to dysregulation of common brain circuits. For example, similar alterations in signaling in the ventral tegmental area (VTA) have been identified in response to both chronic morphine and chronic social defeat stress (CSDS), a rodent model of depression. We are particularly interested in target of rapamycin complex 2 (TORC2) signaling in the VTA as it has been established to play a critical role in morphine reward and morphine‐induced neuroadaptations. However, whether it plays a similar role in stress‐induced changes in morphine reward, or stress susceptibility itself, is unknown. To address these questions, we used viral and genetic approaches to decrease VTA TORC2 signaling by knocking out the expression of Rictor, a TORC2 component protein necessary for TORC2 function. Floxed‐Rictor mice were either crossed with a TH‐Cre mouse line to eliminate TORC2 signaling in all catecholaminergic neurons or underwent stereotaxic surgery to specifically decrease TORC2 signaling in the VTA via AAV‐Cre infusion. The mice were then subjected to chronic physical or emotional CSDS and their susceptibility to stress was measured using the social interaction (SI) test. Following SI testing, mice underwent a two‐bottle choice assay to assess voluntary morphine preference and consumption. In contrast to previous data that found that decreasing AKT signaling was sufficient to increase susceptibility to stress, we found that decreased VTA TORC2 signaling did not alter stress susceptibility. However, we did observe a difference in morphine consumption, as Rictor knockout mice (both TH‐Cre positive and AAV‐Cre) that underwent stress consumed significantly more morphine than stressed controls (intact TORC2 signaling). Additionally, following stress, Rictor knock‐out mice also exhibited an increase in water and sucrose consumption, suggestive of an overall increase in consummative drive. Importantly, these changes were only evident in mice following stress, suggesting a novel role for VTA TORC2 signaling in stress‐mediated changes in consumption.Support or Funding InformationThis work was supported by NIH T32 GM092715 (SK) and NIDA DA037426 (MMR).

Role of Ventral Tegmental Area TORC2 Signaling in Stress‐Induced Morphine Reward

Drug addiction and depression are co-morbid diseases that may share an underlying etiology, specifically dysfunction of the ventral tegmental area (VTA). Using the chronic social defeat stress (CSDS) paradigm, which has strong face validity as a rodent model of depression, we tested the hypothesis that susceptibility to CSDS would increase morphine reward. We subjected mice to 10 days of CSDS and identified mice susceptible to stress using the social interaction test. We then evaluated morphine reward using conditioned place preference (CPP) and voluntary two-bottle choice assays. We found that susceptibility to stress increased morphine CPP and voluntary morphine consumption. Next, we want to determine the molecular mechanisms underlying this change in morphine reward. We are examining the role of VTA mammalian target of rapamycin complex 2 (TORC2) as it has been shown to play a role in morphine reward in the absence of stress. We are using genetic and viral approaches to alter VTA TORC2 signaling in mice to determine if stress-induced facilitation of morphine reward can be rescued by increasing VTA TORC2 signaling. Our data suggest that stress-induced neuroadaptations affect morphine reward and understanding the molecular mechanisms responsible, such as TORC2, will allow us to identify novel targets for therapeutic intervention in these co-morbid disorders. This work was supported by a PhRMA Foundation Research Starter Grant and NIH T32GM092715.

Swimming reduces the severity of physical and psychological dependence and voluntary morphine consumption in morphine dependent rats

Previous studies have indicated that voluntary exercise decreases the severity of the anxiogenic-like behaviors in both morphine-dependent and withdrawn rats. This study examined the effects of regular swimming exercise during the development of dependency and spontaneous morphine withdrawal on the anxiety-depression profile and voluntary morphine consumption in morphine dependent rats. The rats were chronically treated with bi-daily doses (10mg/kg, at 12h intervals) of morphine over a period of 14 days. The exercising rats were allowed to swim (45min/d, five days per a week, for 14 or 21 days) during the development of morphine dependence and withdrawal. Then, rats were tested for the severity of morphine dependence, the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice paradigm in animal models of craving. The results showed that withdrawal signs were decreased in swimmer morphine dependent rats than sedentary rats (P<0.05). Also, the swimmer morphine-dependent and withdrawn rats exhibited an increase in EPM open arm time and entries (P<0.05), higher levels of sucrose preference (P<0.001) than sedentary rats. Voluntary consumption of oral morphine was less in the swimmer morphine-withdrawn rats than the sedentary groups during four periods of the intake of drug (P<0.01). We conclude that regular swimming exercise reduces the severity of morphine dependence and voluntary morphine consumption with reducing anxiety and depression in morphine-dependent and withdrawn rats. Thus, swimming exercise may be a potential method to ameliorate some of the deleterious behavioral consequences of morphine dependence.

Effects of voluntary exercise on anxiety-like behavior and voluntary morphine consumption in rat pups borne from morphine-dependent mothers during pregnancy

Exposure to morphine during pregnancy produced long-term effects in offspring behaviors. Recent studies have shown that voluntary exercise decreases the severity of anxiety behaviors in both morphine-dependent and withdrawn rats. Thus, the aims of the present study were to examine whether maternal exercise decreases prenatal dependence-induced anxiety and also, voluntary consumption of morphine in animal models of craving in rat pups. Pregnant rats were made dependent by chronic administration of morphine in drinking water simultaneously with access to a running wheel that lasted at least 21 days. Then, anxiety-like behaviors using the elevated plus-maze (EPM) and voluntary consumption of morphine using a two-bottle choice paradigm (TBC) were tested in male rat pups. The results showed that the rat pups borne from exercising morphine-dependent mothers exhibited an increase in EPM open arm time (P<0.0001) and entries (P<0.05) as compared with the sedentary groups. In animal models of craving showed that voluntary consumption of morphine in the rat pups borne from exercising morphine-dependent mothers was less in the second (P<0.032) and third (P<0.014) periods of intake as compared with the sedentary group. This study showed that maternal exercise decreases the severity of the anxiogenic-like behaviors and voluntary consumption of morphine in rat pups.

Role of mu opioid receptor endocytosis in the beneficial and side‐effects of prolonged opioid use

The utility of morphine for chronic pain is hindered by the development of analgesic tolerance and dependence. For decades the field has hypothesized that tolerance is mediated by “desensitization” of opioid receptors. In fact, morphine and its derivatives are unique agonists because they do not promote endocytosis of their target receptor, the mu opioid receptor (MOR) while, paradoxically, the endogenous ligands do. In light of this, we propose that endocytosis and recycling serves a protective role in reducing opioid tolerance and dependence. To examine this hypothesis, we generated a knock‐in mouse that expresses a mutant form of the MOR, RMOR for recycling MOR, that endocytoses and recycles in response to morphine. Mice expressing RMOR show enhanced analgesia and reward to morphine compared to wild type (WT) mice and equivalent analgesia and reward to drugs that drive endocytosis in both genotypes. Importantly, mice expressing RMOR develop reduced tolerance and physical dependence to morphine, and do not transition to compulsive drug seeking even after weeks of voluntary morphine consumption, unlike WT mice. Together, these results suggest that drugs that drive endocytosis of the MOR would retain the beneficial effects of opiates including analgesia and reward, while reducing the liability for the side effects of tolerance, dependence and addiction. Supported by DA019958 and the State of California/UCSF.

Fine Mapping of a Major QTL Influencing Morphine Preference in C57BL/6 and DBA/2 Mice Using Congenic Strains

C57BL/6J (B6) and DBA/2J (D2) mice differ in behaviors related to substance abuse, including voluntary morphine consumption and preference in a two-bottle choice paradigm. Two major quantitative trait loci (QTL) for morphine consumption and preference exist between these strains on chromosomes (Chrs.) 6 and 10 when the two-bottle choice involves morphine in saccharin vs quinine in saccharin. Here, we report the refinement of the Chr. 10 QTL in subcongenic strains of D2.B6-Mop2 congenic mice described previously. With these subcongenic mouse strains, we have divided the introgressed region of Chr. 10 containing the QTL gene(s) into two segments, one between the acromere and Stxbp5 (in D2.B6-Mop2-P1 mice) and the other between marker D10Mit211 and marker D10Mit51 (in D2.B6-Mop2-D1 mice). We find that, similar to B6 mice, the D2.B6-Mop2-P1 congenic mice exhibit a strong preference for morphine over quinine, whereas D2.B6-Mop2-D1 congenic mice avoid morphine (similar to D2 mice). We have also created a line of double congenic mice, B6.D2-Mop2.Qui, which contains both Chr. 10 and Chr. 6 QTL. We find that they are intermediate in their morphine preference scores when compared with B6 and D2 animals. Overall, these data suggest that the gene(s) involved in morphine preference in the morphine-quinine two-bottle choice paradigm are contained within the proximal region of Chr. 10 (which harbors Oprm1) between the acromere and Stxbp5, as well as on distal Chr. 6 between marker D6Mit10 and the telomere.

Effects of Strain, Behavior and Age on the Self-Administration of Ethanol, Nicotine, Cocaine and Morphine by Two Rat Strains

Two genetically different strains, Brown Norway rats (BNR) and Wistar Kyoto rats (WKR), with the latter showing higher emotionality and lower plasma stress catecholamine responses, were compared for their voluntary intake of ethanol, nicotine, cocaine and morphine. Younger BNR self-administered the same amounts of all 4 substances as did the younger WKR suggesting a similar genetic basis for all drugs at this age. Older BNR consumed less ethanol and nicotine but equal amounts of cocaine and morphine as compared to older WKR, and older BNR were more sensitive to the effects of ethanol than WKR suggesting a different genetic basis for different drugs at an older age. Forcing both strains to consume one of the drugs did not affect a subsequent voluntary consumption of ethanol and morphine but reduced nicotine intake in WKR and decreased cocaine intake in both strains suggesting that drug use is determined by individual preferences and not drug exposure per se. The behavioral characteristics of both strains coincide only with the self-administration of ethanol and nicotine supporting a possible genetic linkage between anxiety/stress and ethanol and nicotine use.

Voluntary Consumption of Amphetamine, Cocaine, Ethanol and Morphine by Rats as Influenced by a Preceding Period of Forced Drug Intake and Clozapine

Forced nicotine intake was previously found to decrease a subsequent free choice selection, whereas clozapine (CL) caused a marked increase in its consumption. Here these findings are extended to ethanol, cocaine, morphine and amphetamine. Forced intake of ethanol, cocaine, morphine and amphetamine had no major effect on a subsequent voluntary intake. CL, a dopamine D4 antagonist, increased the voluntary consumption of amphetamine and morphine with no effects on ethanol or cocaine intake. Only for cocaine was it found that low-consuming rats increased but high-consuming rats decreased their voluntary cocaine intake by CL. Thus, forced drug exposure per se does not lead to subsequent enhancement of voluntary intake; CL exerts differential effects on intake of these drugs, and a specific dopaminergic set point may govern the voluntary intake of cocaine by individual rats.

Physical dependence induced by the voluntary consumption of morphine in inbred mice

When given a two-bottle choice between gradually increasing morphine concentrations (in 0.2% saccharin) and plain tap water, C57BL/6J mice consumed almost 90% of their daily fluid intake from the morphine-saccharin bottle, while the DBA/2J strain, in contrast, consumed 13% or less from the morphine-saccharin solution. The C57BL/6J strain consistently consumed mean daily doses of morphine sulfate in excess of 200 mg/kg, which was sufficient to induce an easily discernable withdrawal syndrome upon removal of the morphine solution, either with or without naloxone challenge. Hypothermia, tremor, wet dog shakes, jumping, and diarrhea were prominent withdrawal signs. In separate experiments, the saccharin was removed from the morphine-containing bottle, yet the C57BL/6J mice continued to prefer the morphine solution over tap water. In complete contrast to the above, mice of the DBA/2J strain rejected the morphine-saccharin solution at the lowest concentration employed, and at no time did their mean daily morphine dose exceed 20 mg/kg. Thus, morphine-saccharin preference is strongly genetically determined, and a high degree of physical dependence can result in the morphine-preferring strain. Palatability differences appear not to be the predominant explanation for these differences in morphine-saccharin consumption.