Pre-exposure of adolescent mice to morphine results in stronger sensitization and reinstatement of conditioned place preference than pre-exposure to hydrocodone.

BACKGROUND: Opioids are commonly prescribed to treat moderate-to-severe pain. However, their use can trigger the development of opioid use disorder. A major problem in treating opioid use disorder remains the high rate of relapse. AIM: The purpose of this study was to determine whether there are differences among opioids in their ability to trigger relapse after pre-exposure during adolescence. METHODS: On postnatal day 33, mice were examined for the acute locomotor response to saline, morphine, or hydrocodone (5 mg/kg). They were administered with the corresponding opioid or saline during postnatal days 34-38 (20 mg/kg) and 40-44 (40 mg/kg). On postnatal day 45, they were recorded for the development of locomotor sensitization (5 mg/kg). Starting on postnatal day 55, mice were examined for the acquisition (1, 5, 10, 20, and 40 mg/kg), extinction, and drug-induced reinstatement (1, 2.5, and 5 mg/kg) of conditioned place preference. RESULTS: There were no significant differences in the acute locomotor response to morphine and hydrocodone. Morphine induced significantly stronger locomotor sensitization as compared to hydrocodone. Pre-exposure to morphine, but not hydrocodone, sensitized the acquisition of conditioned place preference. There were no significant differences in extinction rates. Mice pre-exposed to morphine reinstate conditioned place preference after priming with a 1 mg/kg dose. In contrast, higher priming doses were required for reinstatement in all other experimental groups. CONCLUSIONS: Adolescent mice administered with morphine develop greater sensitization to its effects and subsequently reinstate conditioned place preference more readily than mice administered with hydrocodone. This suggests higher risk for relapse after pre-exposure to morphine during adolescence as compared to hydrocodone.

Response to opioids is dependent on sociability levels.

Social environment influences the trajectory of developing opioid use disorder (OUD). Thus, the present study tested the hypothesis that sociability levels will affect the responses to opioids. Mice were tested for their baseline sociability, anxiety levels, pain sensitivities, and their acute locomotor response to 5 mg/kg opioids. Then, they were administered repeatedly with saline, hydrocodone, or morphine (20 mg/kg for 5 days, and then 40 mg/kg for 5 days). Subsequently, they were examined for the expression of locomotor sensitization and retested for the effects of opioids on their sociability, anxiety levels, and pain sensitivity. On the basis of their baseline sociability level, mice were divided into socially avoiding and socially exploring. Socially avoiding and socially exploring mice did not differ in their baseline weight and anxiety sensitivities. Socially avoiding mice had slightly higher baseline heat sensitivity than those in socially exploring mice. Repeated administration of opioids had differential effects in socially avoiding and socially exploring mice. In both social groups, repeated morphine administration had overall stronger effects compared with hydrocodone. Morphine-treated socially exploring mice developed greater locomotor sensitization than those in morphine-treated socially avoiding mice. Morphine-treated socially avoiding mice, but not socially exploring mice, spent more time in the center zone of the open-field test and in the light zone of light/dark boxes, and developed heat hyperalgesia. This study suggests that socially exploring animals are more sensitive to the sensitizing effects of opioids. In contrast, opioids have greater effects on the stress and pain systems of socially avoiding animals. Thus, the underlying mechanisms for developing OUD might differ in individuals with various sociability levels.

The role of the vasopressin system and dopamine D1 receptors in the effects of social housing condition on morphine reward.

BACKGROUND: The association with opioid-abusing individuals or even the perception of opioid abuse by peers are risk factors for the initiation and escalation of abuse. Similarly, we demonstrated that morphine-treated animals housed with only morphine-treated animals (referred to as morphine only) acquire morphine conditioned place-preference (CPP) more readily than morphine-treated animals housed with drug-naïve animals (referred to as morphine cage-mates). However, the molecular mechanisms underlying these effects are still elusive. METHODS: Mice received repeated morphine or saline while housed as saline only, morphine only, or cage-mates. Then, they were examined for the expression levels of D1 dopamine receptor (D1DR), D2 dopamine receptor (D2DR), dopamine transporter (DAT), oxytocin, and Arginine-vasopressin (AVP) in the striatum using qPCR. Additionally, we examined the effects of the AVP-V1b receptor antagonist, SSR149415, on the acquisition of morphine conditioned place-preference (CPP). RESULTS: Increased striatal expression of D1DR and AVP was observed in morphine only animals, but not morphine cage-mates. No significant effects were observed on the striatal expression of D2DR, DAT, or oxytocin. Antagonizing the AVP-V1b receptors decreased the acquisition of morphine CPP in the morphine only mice, but did not alter the acquisition of morphine CPP in the morphine cage-mate mice. CONCLUSIONS: Housing with drug-naïve animals protects against the increase in striatal expression of D1DR and AVP elicited by morphine exposure. Moreover, our studies suggest that the protective effect of housing with drug-naïve animals on the acquisition of morphine reward might be, at least partially, mediated by AVP.

The GHR-R antagonist JMV 2959 neither induces malaise nor alters the malaise property of LiCl in the adult male rat.

The orexigenic peptide ghrelin (GHR) interacts with ghrelin receptors (GHR-Rs) to modulate brain reinforcement and feeding circuits. Pharmacological inactivation of GHR-Rs via administration of the drug JMV 2959 attenuates the rewarding/reinforcing effects of several drugs of abuse including alcohol, morphine, amphetamine and nicotine. One view of these results is that inactivation of GHR-Rs taps into brain reinforcement/feeding circuits acted upon by drugs of abuse. An alternate explanation is that JMV 2959 may induce malaise, which in turn may limit reinforcement as well as food ingestion. This is a variable of interest given that nicotine alone can induce malaise which may be enhanced by JMV 2959. In the present study, we assessed the capacity of JMV 2959 to produce malaise using a conditioned taste aversion (CTA) task. Adult male rats were allowed to consume a 0.1% sodium saccharin solution and then injected IP with either vehicle, 0.4mg/kg nicotine, 3mg/kg JMV 2959, a combination of 0.4mg/kg nicotine and 3mg/kg JMV 2959, or 32mg/kg lithium chloride (a positive control known to support induction of CTA). Lithium chloride produced a robust avoidance of the saccharin solution in subsequent 2 bottle (water and saccharin) tests, whereas JMV 2959 alone did not induce CTA. The combination of JMV 2959 and nicotine induced a moderate degree of CTA that was similar to that produced by nicotine alone. These results suggest that JMV 2959 is unlikely to limit either reinforcement or food ingestion via induction of malaise.

Inhibiting social support from massage-like stroking increases morphine dependence.

Our previous studies showed that altering solely the drug experience of the cage mates with which rodents are housed affects the development of morphine dependence. In this study, we used designer receptors exclusively activated by designer drugs to artificially increase or decrease the activity of peripheral dorsal root ganglia sensory neurons expressing the G-protein-coupled receptor MRGPRB4. This is because sensory MRGPRB4-expressing neurons were shown to specifically detect the sensation of massage-like stroking resulting from social grooming, which is an important affiliative social behavior in the rodent. Blocking the sensation of social grooming in morphine-treated mice housed with drug-naive mice (i.e. morphine cage mates) significantly increased the display of jumping behavior in morphine-withdrawn animals. Activating the sensation of social grooming in morphine-treated animals housed solely with other morphine-treated animals (i.e. morphine only) did not significantly alter the display of jumping behavior in morphine-withdrawn animals. Repetitive jumping behaviors have been shown to correlate with morphine dependence. Thus, this study showed a role of social grooming in the protective effect of being housed with drug-naive mice on the development of morphine dependence. It further confirms a role of social support in the development of substance use problems.

Hydrocodone, but Neither Morphine nor Oxycodone, Is Effective in Suppressing Burn-Induced Mechanical Allodynia in the Uninjured Foot Contralateral to the Burn.

Opioids are commonly used to treat severe, burn-induced pain. However, there is a lack of rodent studies that examine the differential effects of various opioids on burn pain. We recently demonstrated that hydrocodone was superior to other opioids in suppressing the development of burn-induced mechanical allodynia in the burned limb. This study monitored the development of mechanical allodynia and compared the abilities of morphine, oxycodone, and hydrocodone to reduce burn-induced mechanical allodynia in the limb contralateral to the burn. Mice were examined for their baseline pain sensitivity thresholds using the von Frey filaments test. Then, they were subjected to burn or sham injury and treated orally with morphine, oxycodone, hydrocodone (20 or 40 mg/kg), or saline twice daily throughout the study. They were retested on days 4, 7, 11, 14, 21, and 28 postburn. Hyperalgesia was developed in the contralateral, uninjured foot beginning 21 days after the burn injury. Hydrocodone was effective in suppressing the development of burn-induced mechanical allodynia. In contrast, morphine and oxycodone had only minimal effects on the development of burn-induced mechanical allodynia. The abnormal pain sensitivities that develop as a result of burn injuries are very difficult to treat and remain a significant public health problem. More rodent studies are required to improve our understanding of the differences among the currently available opioid analgesics in order to optimize the care provided to burn victims as well as those suffering from other pain modalities.

Hydrocodone is More Effective than Morphine or Oxycodone in Suppressing the Development of Burn-Induced Mechanical Allodynia.

BACKGROUND: Pain is the most frequent complaint of burn-injured patients. Opioids are commonly used in the course of treatment. However, there is a lack of rodent studies that examine the differential effects of various opioids on burn pain. OBJECTIVE: This study compared the ability of morphine, oxycodone, and hydrocodone to suppress the development of burn-induced mechanical allodynia and reduce pain sensitivity. METHODS: Mice were examined for their baseline pain sensitivity thresholds using the von Frey Filaments test. Then, they were subjected to burn or sham injury and treated orally with morphine, oxycodone, hydrocodone (20 or 40 mg/kg), or saline twice daily throughout the study. They were retested on days 4, 7, 11, 14, 21, and 28 postburn. RESULTS: In the sham animals, morphine produced significant opioid-induced hyperalgesia (OIH). Development of OIH was minimal for hydrocodone and was not observed for oxycodone. Secondary mechanical allodynia was observed beginning four days after the burn injury and intensified with time. All opioids produced comparable antinociceptive effects. Hydrocodone was effective in suppressing the development of burn-induced mechanical allodynia and fully treated the burn-induced increase in pain sensitivity. In contrast, morphine and oxycodone had only minimal effects on the development of burn-induced mechanical allodynia and only partially treated the burn-induced increase in pain sensitivity. CONCLUSIONS: This study demonstrated that hydrocodone is effective in suppressing the development of burn-induced mechanical allodynia, while both morphine and oxycodone had minimal effects. These findings underscore the need for additional studies on the differences among various opioids using clinically relevant pain models.

Burn injury decreases the antinociceptive effects of opioids.

Burn victim patients are frequently prescribed opioids at doses that are significantly higher than standard analgesic dosing guidelines, and, even despite an escalation in opioid dosing, many continue to experience pain. Thus, the aim of this study was to determine the effect of burn injury on opioid antinociception. Mice were examined for their baseline pain sensitivity thresholds using the von Frey filaments test. Then, they were subjected to burn or sham injury to the dorsal surface of the hindpaw and treated orally with morphine, oxycodone, hydrocodone (20 or 40 mg/kg), or saline twice daily throughout the study. They were retested on days 4, 7, 11, 14, 21, and 28 following the burn injury. The antinociceptive effects of the various drugs were analyzed by computing the daily difference between pain sensitivity threshold scores (in g) before and after treatment. This study showed that burn injury decreases opioid antinociception potency. A marked reduction was observed in the antinociceptive effectiveness of all opioids, and for both doses, in the burn-injured versus the sham animals. These results suggest that burn trauma limits the ability of opioids to be effective in reducing pain.

High-fat diet meal patterns during and after continuous nicotine treatment in male rats.

Smoking to control body weight is an obstacle to smoking cessation, particularly in western cultures where diets are often rich in calories derived from fat sources. The purpose of this study was to investigate the effects of continuous nicotine administration on meal patterns in rats fed a high-fat diet. Male rats were housed in cages designed to continuously monitor food intake and implanted with minipumps to deliver approximately 1.00 mg/kg/day of nicotine or saline. Meal patterns and body weights were assessed for 2 weeks of treatment and 1 week posttreatment. When compared with controls, rats with continuous nicotine treatment exhibited a decrease in the average meal duration(s) during the first week of treatment and a modest, yet sustained reduction in daily number of meals over the 14-day treatment period. Nicotine-induced decreases in body weight gain were observed throughout the 2 weeks of treatment. No differences in meal patterns or body weight gain were seen for 1 week following cessation of treatment. Results from this study suggest that while continuous nicotine treatment decreases daily food intake, meal durations, meal numbers, and weight gain, cessation of this treatment does not result in significant compensatory increases. Understanding the effects of nicotine on feeding patterns and weight gain may allow for improvements in treatment protocols aimed at addressing the factors that contribute to tobacco use. (PsycINFO Database Record

Fluoxetine disrupts motivation and GABAergic signaling in adolescent female hamsters.

Initial antidepressant treatment can paradoxically worsen symptoms in depressed adolescents by undetermined mechanisms. Interestingly, antidepressants modulate GABAA receptors, which mediate paradoxical effects of other therapeutic drugs, particularly in females. Although the neuroanatomic site of action for this paradox is unknown, elevated GABAA receptor signaling in the nucleus accumbens can disrupt motivation. We assessed fluoxetine's effects on motivated behaviors in pubescent female hamsters - anhedonia in the reward investigational preference (RIP) test as well as anxiety in the anxiety-related feeding/exploration conflict (AFEC) test. We also assessed accumbal signaling by RT-PCR and electrophysiology. Fluoxetine initially worsened motivated behaviors at puberty, relative to adulthood. It also failed to improve these behaviors as pubescent hamsters transitioned into adulthood. Low accumbal mRNA levels of multiple GABAA receptor subunits and GABA-synthesizing enzyme, GAD67, assessed by RT-PCR, suggested low GABAergic tone at puberty. Nonetheless, rapid fluoxetine-induced reductions of α5GABAA receptor and BDNF mRNA levels at puberty were consistent with age-related differences in GABAergic responses to fluoxetine and disruption of the motivational state. Whole-cell patch clamping of accumbal slices also suggested low GABAergic tone by the low amplitude of miniature inhibitory postsynaptic currents (mIPSCs) at puberty. It also confirmed age-related differences in GABAergic responses to fluoxetine. Specifically, fluoxetine potentiated mIPSC amplitude and frequency at puberty, but attenuated the amplitude during adulthood. These results implicate GABAergic tone and GABAA receptor plasticity in adverse motivational responses and resistance to fluoxetine during adolescence.

Differential Effects of Oxycodone, Hydrocodone, and Morphine on Activation Levels of Signaling Molecules.

BACKGROUND: Opioids alter the responses of D2-like dopamine receptors (D2DRs), known to be involved in the pathology of addiction and other mental illnesses. Importantly, our recent results demonstrated that various opioids differentially modulate the behavioral responses of D2DRs. OBJECTIVE: To examine the effect of various opioids on striatal activation levels of Akt and ERK1/2, as well as the signaling responses of D2DRs following opioid exposure. METHODS: Mice were pre-treated with 20 mg/kg morphine, hydrocodone, oxycodone, or saline for 6 days. Twenty-four hours later, mice were injected with vehicle or a D2/D3 receptor agonist, quinpirole. Thirty minutes later, dorsal striatum was collected and analyzed using Western blot. RESULTS: In morphine-pretreated animals, baseline Akt activation level was unchanged, but was reduced in response to quinpirole. In contrast, baseline Akt activation levels were reduced in mice pretreated with hydrocodone and oxycodone, but were unchanged in response to quinpirole. In mice pretreated with all opioids, baseline ERK2 activation levels were unchanged and increased in response to quinpirole. However, quinpirole-induced ERK2 activation was significantly higher than drug naïve animals only in the morphine-pretreated mice. CONCLUSIONS: Various opioids differentially modulate the baseline activation levels of signaling molecules, which in turn results in ligand-selective effects on the responses to a D2/D3 dopamine receptor agonist. This demonstrates a complex interplay between opioid receptors and D2DRs, and supports the notion that various opioids carry differential risks to the dopamine reward system. This information should be considered when prescribing opioid pain medication, to balance effectiveness with minimal risk.

Sex differences in motivational responses to dietary fat in Syrian hamsters.

Women are more likely than men to exhibit motivational disorders (e.g., anhedonia and anxiety) with limited treatment options, and to overconsume high-fat "comfort foods" to improve motivational disruptions. Unfortunately, neurobiological underpinnings for sex differences in motivational disruptions and their responses to dietary fat are poorly understood. To help bridge these fundamental knowledge gaps, we assessed behavioral and neurobiological responses to dietary fat in a hamster model of female-biased motivational lability. Relative to social housing, social separation reduced hedonic drive in a new behavioral assay, the reward investigational preference (RIP) test. Fluoxetine or desipramine treatment for 21, but not 7, days improved RIP test performance. Pharmacologic specificity in this test was shown by non-responsiveness to diazepam, tracazolate, propranolol, or naltrexone. In the anxiety-related feeding/exploration conflict (AFEC) test, social separation worsened latency to eat highly palatable food under anxiogenic conditions, but not in home cages. Social separation also reduced weight gain, food intake, and adiposity while elevating energy expenditure, assessed by caloric efficiency and indirect calorimetry. Furthermore, chronic high-fat feeding improved anhedonic and anxious responses to separation, particularly in females. In the motivation-influencing nucleus accumbens, females, but not males, exhibited a separation-induced anxiety-related decrease in Creb1 mRNA levels and an anhedonia-related decrease in ΔFosb mRNA levels. Consistent with its antidepressant- and anxiolytic-like effects on behavior, high-fat feeding elevated accumbal Creb1 and ΔFosb mRNA levels in females only. Another accumbal reward marker, Tlr4 mRNA, was elevated in females by high-fat feeding. These results show that social separation of hamsters provides a novel model of sex-dependent comorbid anhedonia, anxiety, and anorexia, and implicate accumbal CREB, ΔFosB, and TLR4. Moreover, the results validate a new assay for chronic antidepressant efficacy.

Differential effects of oxycodone, hydrocodone, and morphine on the responses of D2/D3 dopamine receptors.

Oxycodone and hydrocodone are opioids which are widely used for pain management and are also commonly misused and abused. The exposure to opioid analgesics has been associated with altered responses of D2-like dopamine receptors (D2DRs). Our recent results suggest that various opioids will differentially modulate the responses of D2DRs. The D2DRs are known to be involved in the pathology of addiction and other mental illnesses, indicating the need to improve our understanding of the effects of opioid analgesics on the responses of the D2DRs. Thus, in this study, we first established equianalgesic oral doses of oxycodone, hydrocodone, and morphine using the tail withdrawal assay. Then, mice were orally administered (gavage) with the various opioids or saline once daily for 6 days. Twenty-four hours later, the mice were tested for their locomotor response to quinpirole, a D2/D3 dopamine receptor agonist. Mice pretreated with oxycodone showed significantly greater locomotor supersensitivity to quinpirole than did morphine-pretreated mice, while hydrocodone-pretreated mice showed sensitivity in between that of mice treated with morphine and oxycodone. This finding suggests that various opioids differentially modulate the responses of D2DRs. It provides further evidence supporting of the notion that various opioids carry differential risks to the dopamine reward system.

Social housing conditions influence morphine dependence and the extinction of morphine place preference in adolescent mice.

BACKGROUND: Adolescent opioid abuse is on the rise, and current treatments are not effective in reducing rates of relapse. Our previous studies demonstrated that social housing conditions alter the acquisition rate of morphine conditioned place preference (CPP) in adolescent mice. Specifically, the acquisition rate of morphine CPP is slower in morphine-treated animals housed with drug-naïve animals. Thus, here we tested the effect of social housing conditions on the development of morphine dependence and the extinction rate of an acquired morphine CPP. METHODS: Adolescent male mice were group-housed in one of two housing conditions. They were injected for 6 days (PND 28-33) with 20 mg/kg morphine. Morphine only mice are animals where all four mice in the cage received morphine. Morphine cage-mate mice are morphine-injected animals housed with drug-naïve animals. Mice were individually tested for spontaneous withdrawal signs by quantifying jumping behavior 4, 8, 24, and 48 h after the final morphine injection. Then, mice were conditioned to acquire morphine CPP and were tested for the rate of extinction. RESULTS: Morphine cage-mates express less jumping behavior during morphine withdrawal as compared to morphine only mice. As expected, morphine cage-mate animals acquired morphine CPP more slowly than the morphine only animals. Additionally, morphine cage-mates extinguished morphine CPP more readily than morphine only mice. CONCLUSIONS: Social housing conditions modulate morphine dependence and the extinction rate of morphine CPP. Extinction testing is relevant to human addiction because rehabilitations like extinction therapy may be used to aid human addicts in maintaining abstinence from drug use.

Ghrelin and ghrelin receptor modulation of psychostimulant action.

Ghrelin (GHR) is an orexigenic gut peptide that modulates multiple homeostatic functions including gastric emptying, anxiety, stress, memory, feeding, and reinforcement. GHR is known to bind and activate growth-hormone secretagogue receptors (termed GHR-Rs). Of interest to our laboratory has been the assessment of the impact of GHR modulation of the locomotor activation and reward/reinforcement properties of psychostimulants such as cocaine and nicotine. Systemic GHR infusions augment cocaine stimulated locomotion and conditioned place preference (CPP) in rats, as does food restriction (FR) which elevates plasma ghrelin levels. Ghrelin enhancement of psychostimulant function may occur owing to a direct action on mesolimbic dopamine function or may reflect an indirect action of ghrelin on glucocorticoid pathways. Genomic or pharmacological ablation of GHR-Rs attenuates the acute locomotor-enhancing effects of nicotine, cocaine, amphetamine and alcohol and blunts the CPP induced by food, alcohol, amphetamine and cocaine in mice. The stimulant nicotine can induce CPP and like amphetamine and cocaine, repeated administration of nicotine induces locomotor sensitization in rats. Inactivation of ghrelin circuit function in rats by injection of a ghrelin receptor antagonist (e.g., JMV 2959) diminishes the development of nicotine-induced locomotor sensitization. These results suggest a key permissive role for GHR-R activity for the induction of locomotor sensitization to nicotine. Our finding that GHR-R null rats exhibit diminished patterns of responding for intracranial self-stimulation complements an emerging literature implicating central GHR circuits in drug reward/reinforcement. Finally, antagonism of GHR-Rs may represent a smoking cessation modality that not only blocks nicotine-induced reward but that also may limit weight gain after smoking cessation.

Differential effects of methadone and buprenorphine on the response of D2/D3 dopamine receptors in adolescent mice.

BACKGROUND: There is a lack of studies that examine the effects of opioid maintenance drugs on the developing adolescent brain, limiting the ability of physicians to conduct a science-based risk assessment on the appropriateness of these treatments for that age group. Our recent observations indicate higher potential risks in repeated exposure to morphine during adolescence, specifically to the D2/D3 dopamine receptors' signaling. Disturbances in dopaminergic signaling could have broader implications for long-term mental health. Thus, this study examined whether buprenorphine and methadone differentially alter the responses of the D2/D3 dopamine receptors in adolescents. METHODS: Adolescent mice were orally administered buprenorphine (0.1-0.4 mg/kg), methadone (25-100 mg/kg), or saline once daily for 6 days. Two hours or three days later, the mice were tested for their locomotor response to 10 mg/kg quinpirole, a D2/D3 dopamine receptor agonist. RESULTS: Buprenorphine-treated adolescent mice did not significantly differ from control drug-naïve animals in their response to quinpirole. However, an enhanced response was observed in methadone-treated adolescent animals. This enhanced locomotion was significantly higher two hours following the final dose of methadone, as compared to three days afterwards. CONCLUSIONS: This study suggests that exposure to various opioids carries differential probabilities of altering the highly sensitive neurochemistry of adolescent brains. Methadone exposure disturbs the D2-like receptor's response, indicating a potential risk in administering methadone to adolescents (either for the treatment of opioid dependency/abuse or for pain management). In contrast, buprenorphine appears to have a significantly lower effect on the behavioral sensitivity of D2/D3 dopamine receptors in adolescents.

Social influences on morphine conditioned place preference in adolescent mice.

Social/peer influences are among the strongest predictors of adolescent drug use. However, this important subject does not get much attention in pre-clinical studies. We recently observed that exposure to different social partners modulates morphine locomotor sensitization. Sensitivity to the hyper-locomotor response of drugs of abuse is a predictor of sensitivity to other drug-induced behaviors. Thus, this study examined how exposure to different social partners affected the rewarding properties of morphine. All animals were group-housed four per cage in one of two conditions referred to as 'only' and 'cage-mates'. In the mixed treatment condition, morphine- and saline-treated mice were housed together. These groups are referred to as 'morphine cage-mates' and 'saline cage-mates', respectively. In the separated treatment conditions, all mice in the cage received morphine (i.e. 'morphine only') or saline (i.e. 'saline only'), and cages were visually separated from each other. All animals were subsequently individually tested for the acquisition of morphine conditioned place preference (CPP) following one conditioning session with 10, 20 or 40 mg/kg morphine or saline. As expected, one conditioning session established morphine CPP in the morphine only animals, but not in the saline only animals. Notably, morphine CPP was not acquired by the morphine cage-mate animals. Additionally, 40 mg/kg morphine was sufficient to establish morphine CPP in the saline cage-mate animals. These results indicate that social environment has an effect on the rewarding properties of morphine. It suggests that exposure to different peers can alter the abuse potential of opioids and potentially other illicit drugs.

Initial characterization of mice null for Lphn3, a gene implicated in ADHD and addiction.

The LPHN3 gene has been associated with both attention deficit-hyperactivity disorder (ADHD) and addiction, suggesting that it may play a role in the etiology of these disorders. Unfortunately, almost nothing is known about the normal functions of this gene, which has hampered understanding of its potential pathogenic role. To begin to characterize such normal functions, we utilized a gene-trap embryonic stem cell line to generate mice mutant for the Lphn3 gene. We evaluated differential gene expression in whole mouse brain between mutant and wild type male littermates at postnatal day 0 using TaqMan gene expression assays. Most notably, we found changes in dopamine and serotonin receptors and transporters (Dat1, Drd4, 5Htt, 5Ht2a), changes in neurotransmitter metabolism genes (Th, Gad1), as well as changes in neural developmental genes (Nurr, Ncam). When mice were examined at 4-6 weeks of age, null mutants showed increased levels of dopamine and serotonin in the dorsal striatum. Finally, null mutant mice had a hyperactive phenotype in the open field test, independent of sex, and were more sensitive to the locomotor stimulant effects of cocaine. Considered together, these results suggest that Lphn3 plays a role in development and/or regulation of monoamine signaling. Given the central role for monoamines in ADHD and addiction, it seems likely that the influence of LPHN3 genotype on these disorders is mediated through alterations in monoamine signaling.

Morphine alters the locomotor responses to a D2/D3 dopamine receptor agonist differentially in adolescent and adult mice.

The D2-like dopamine receptors mediate the emotional/aversive state during morphine withdrawal. Given age-dependent differences in the affective responses to withdrawal, this study examined whether the response to dopamine receptor agonists is altered differentially across ages following morphine administration. Adolescent and adult mice were injected with morphine (twice daily, 10-40 mg/kg, s.c.) or saline for 6 days. Subsequently, they were examined for their locomotor response to quinpirole, a D2/D3 receptor agonist, and SKF 38393, a D1 receptor agonist. Quinpirole dose-dependently reduced locomotion in drug-naïve animals. Initial suppression was also observed in morphine-treated animals, but was followed by enhanced locomotion. Notably, this enhanced locomotion was markedly greater in adolescents than adults. Quinpirole-induced hypo-locomotion is thought to be mediated by the presynaptic D2Short receptors, whereas its activating effect is mediated by postsynaptic D2Long/D3 receptors. This suggests that following morphine administration, the postsynaptic, but not the presynaptic, dopaminergic signaling is differentially modulated across ages. This locomotor supersensitivity was not observed for SKF 38393, a D1 dopamine receptor agonist. The D2/D3 receptors are involved in the pathophysiology of many mental illnesses. Thus, this study offers a potential explanation for the increased psychiatric disorder co-morbidities when drug use begins during adolescence.

Analgesia or addiction?: implications for morphine use after spinal cord injury.

Opioid analgesics are among the most effective agents for treatment of moderate to severe pain. However, the use of morphine after a spinal cord injury (SCI) can potentiate the development of paradoxical pain symptoms, and continuous administration can lead to dependence, tolerance, and addiction. Although some studies suggest that the addictive potential of morphine decreases when it is used to treat neuropathic pain, this has not been studied in a SCI model. Accordingly, the present studies investigated the addictive potential of morphine in a rodent model of SCI using conditioned place preference (CPP) and intravenous self-administration paradigms. A contusion injury significantly increased the expression of a CPP relative to sham and intact controls in the acute phase of injury. However, contused animals self-administered significantly less morphine than sham and intact controls, but this was dose-dependent; at a high concentration, injured rats exhibited an increase in drug-reinforced responses over time. Exposure to a high concentration of morphine impeded weight gain and locomotor recovery. We suggest that the increased preference observed in injured rats reflects a motivational effect linked in part to the drug's anti-nociceptive effect. Further, although injured rats exhibited a suppression of opiate self-administration, when given access to a high concentration, addictive-like behavior emerged and was associated with poor recovery.