Drake Morgan

Social dominance in monkeys: Dopamine D2 receptors and cocaine self-administration

Disruption of the dopaminergic system has been implicated in the etiology of many pathological conditions, including drug addiction. Here we used positron emission tomography (PET) imaging to study brain dopaminergic function in individually housed and in socially housed cynomolgus macaques (n = 20). Whereas the monkeys did not differ during individual housing, social housing increased the amount or availability of dopamine D2 receptors in dominant monkeys and produced no change in subordinate monkeys. These neurobiological changes had an important behavioral influence as demonstrated by the finding that cocaine functioned as a reinforcer in subordinate but not dominant monkeys. These data demonstrate that alterations in an organisms environment can produce profound biological changes that have important behavioral associations, including vulnerability to cocaine addiction.

Effects of positive allosteric modulators of the GABAB receptor on cocaine self-administration in rats

RationalePrevious studies have strongly implicated a role for GABAB receptors in modulating the reinforcing effects of cocaine.ObjectiveThe purpose of the present study was to examine the efficacy of two novel positive allosteric modulators of the GABAB receptor, CGP7930 and GS39783, to decrease cocaine self-administration in rats responding under various schedules of reinforcement.MethodsRats were trained to self-administer cocaine under progressive ratio (PR), fixed ratio (FR) and discrete trials (DT) schedules of reinforcement, and the ability of CGP7930 and GS39783 to decrease cocaine-maintained responding was examined.ResultsOn a PR schedule, CGP7930 markedly decreased break points maintained by 1.5xa0mg/kg per injection cocaine in a dose-dependent manner. GS39783 produced only modest decreases in cocaine-reinforced break points, with only the highest dose decreasing break points relative to baseline. On an FR1 schedule of reinforcement, both drugs decreased responding for a threshold dose of cocaine, but did not alter responding for higher doses of cocaine. In a DT procedure, 1.5xa0mg/kg per injection cocaine was made available during three 10-min trials each hour during 24-h sessions (DT3), engendering a circadian pattern of responding characterized by high numbers of infusions during the dark phase and low numbers of infusions during the light phase. Doses of 30xa0mg/kg CGP7930, 3.0xa0mg/kg GS39783 and 2.5xa0mg/kg baclofen significantly decreased cocaine-maintained responding when administered at the beginning of the dark phase of the cycle. Across all schedules, CGP7930 was more effective at decreasing cocaine self-administration than GS39783, a finding that may be due to differences in bioavailability between the two drugs.ConclusionsThese findings suggest that positive allosteric modulators of the GABAB receptor may hold promise as potential pharmacotherapies for cocaine abuse and dependence.

Sensitization to the reinforcing effects of cocaine following binge-abstinent self-administration

The process of addiction in humans involves a transition from recreational drug use to compulsive drug-taking. To understand or study this behavioral phenomenon from a neurobiological perspective, behavioral models that reflect this process are necessary. Data from typical (restricted access) self-administration procedures demonstrate a stable pattern of responding over time, and thus fail to capture the transitional phases of this process. Here we describe the development of a model that incorporates self-administration-induced changes in the reinforcing efficacy of cocaine, assessed using a progressive ratio schedule of reinforcement to probe the motivational state of the animal. To date we have identified two necessary conditions for the development of this sensitization: extended access to cocaine and a deprivation period. This model, in conjunction with recently developed tools to characterize neurochemical and epigenetic changes, will provide a better understanding of the neurobiological bases of the addiction process.

Predictors of social status in cynomolgus monkeys (Macaca fascicularis) after group formation

The purpose of the present study was to determine whether various behavioral and hormonal markers obtained in individually housed monkeys would be predictive of social rank following group housing. Body weight, serum cortisol and testosterone levels, and locomotor activity in an open‐field apparatus were examined in 20 experimentally naive male cynomolgus monkeys (Macaca fascicularis) while they were individually housed. It was hypothesized that eventual subordinate monkeys would have higher cortisol levels and increased locomotor activity scores. These monkeys were then placed in social groups of four (five pens of four monkeys), and social rank was determined based on outcomes of dyadic agonistic encounters. Body weight correlated significantly with eventual social rank. In general, the heavier the monkey the higher the social rank. Locomotor activity in an open‐field apparatus following administration of a low dose of cocaine (0.01 mg/kg, i.v.), which has been shown to increase CNS dopamine, correlated with eventual social rank such that individually housed monkeys with high levels of locomotion were more likely to become subordinate. Serum cortisol and testosterone levels failed to correlate with eventual social rank. Hypothalamic‐pituitary feedback sensitivity and adrenal responsiveness were examined by measuring cortisol levels after administration of dexamethasone and following ACTH challenge. Cortisol responses in these tests were not associated with eventual social rank. These results suggest that, in addition to body weight, the level of reactivity in a novel environment after administration of a low dose of cocaine is a potential trait marker for social rank. This trait is apparently not associated with hormone levels, but may involve other CNS mechanisms. Am. J. Primatol. 52:115–131, 2000.

Sensitization of the reinforcing effects of self-administered cocaine in rats: effects of dose and intravenous injection speed

Speed of drug onset is assumed to be an important determinant of the abuse liability of a drug. Studies in human and non‐human primates suggest that the subjective and reinforcing effects of cocaine can be influenced by route of administration and/or speed of intravenous injection. Sensitization to the reinforcing effects of cocaine was studied in rats and the effects of various injection durations (i.e. speed of injection) on the development of sensitization was examined using a progressive ratio schedule. In addition, the effects of cocaine dose on sensitization and the effects of injection duration on the acute reinforcing effects of cocaine were examined. The initial study demonstrated that the development of sensitization (i.e. progressive increases in breakpoints) was dose‐dependent. A robust sensitization of the reinforcing effects of cocaine was replicated in animals receiving cocaine at the highest rate (i.e. shortest duration; 5u2003s), but not in animals receiving the same dose over 25 or 50u2003s. Subsequent testing revealed that injection duration did not have profound effects on the acute reinforcing effects of cocaine (assessed by breakpoints or rate of responding on a fixed ratio schedule). These findings are similar to recent studies demonstrating that the development of sensitization, but not the acute responsivity, to cocaines locomotor‐activating effects are influenced by rate of intravenous injection. Taking these findings together, we hypothesize that the process of drug addiction involves both the acute reinforcing effects and the development of sensitization.

Effects of extended-access self-administration and deprivation on breakpoints maintained by cocaine in rats.

RationaleAnimal models that identify the effects of self-administration histories on subsequent patterns, levels of intake, and other aspects of reinforcement will help clarify the controlling variables of human drug use.ObjectiveIdentify the effects of extended-access to cocaine and 1 or 7xa0days of deprivation on cocaine-maintained breakpoints on a progressive ratio (PR) schedule of reinforcement.MethodsMale, Sprague–Dawley rats were trained to self-administer intravenous cocaine (expt 1: 1.5xa0mg/kg per infusion; expt 2: 0.75xa0mg/kg per infusion), and then given various histories of self-administration and deprivation. Breakpoints, the number of infusions self-administered on a PR schedule, were assessed following the deprivation period.ResultsRates of cocaine intake increased when access to cocaine was extended to 6xa0h/day. From day 1 to day 14, daily intake increased from 92 (±2.5) to 101 (±2.8)xa0mg/kg in expt 1, and from 55 (±4) to 78 (±2.2)xa0mg/kg in expt 2. Total intake across this 2-week period was approximately 1260 and 970xa0mg/kg in expts 1 and 2. Breakpoints were not different following this escalation period. The introduction of a 7-day deprivation period failed to alter breakpoints.ConclusionsThere is dissociation between changes in rate of cocaine intake (or consumption) and breakpoints maintained on a PR schedule. Extended-access to cocaine produced increases in rate of intake without altering breakpoints. Depending on the experimental question, extended-access conditions may prove useful for studying changes in certain aspects of reinforcement, such as consumption, but not others, such as the strength of a drug as a reinforcer.

An examination of the interactions between the antinociceptive effects of morphine and various μ-opioids : The role of intrinsic efficacy and stimulus intensity

UNLABELLEDnWe examined the effects of several opioids that vary in intrinsic efficacy at the mu-opioid receptor alone and in combination with morphine in a rat warm water tail withdrawal procedure using 50 degrees C and 52 degrees C water (i.e., low- and high-stimulus intensities). Morphine, levorphanol, dezocine, and buprenorphine produced dose-dependent increases in antinociception using both stimulus intensities. Butorphanol produced maximal levels of antinociception at the low, but not at the high, stimulus intensity, whereas nalbuphine failed to produce antinociception at either stimulus intensity. For cases in which butorphanol and nalbuphine failed to produce antinociception alone, these opioids dose-dependently antagonized the effects of morphine. When levorphanol, dezocine, and buprenorphine were combined with morphine, there was a dose-dependent enhancement of morphines effects. Similar effects were obtained at the low-stimulus intensity when butorphanol was administered with morphine. In most cases, the effects of these combinations could be predicted by summating the effects of the drugs when administered alone. These results indicate that the level of antinociception produced by an opioid is dependent on the intrinsic efficacy of the drug and the stimulus intensity. Furthermore, the level of antinociception produced by the opioid, not necessarily the opioids intrinsic efficacy, determines the type of interaction among opioids.nnnIMPLICATIONSnCompared with high-efficacy opioids, lower efficacy opioids produce lower levels of pain relief, especially in situations of moderate to severe pain. When opioids are given in combination, the effects can only be predicted on the basis of the antinociception obtained when the drugs are administered alone.

Binge self-administration and deprivation produces sensitization to the reinforcing effects of cocaine in rats

RationaleBehavioral procedures that incorporate dynamic changes in drug-maintained behavior are needed to model the development of cocaine addiction in humans.ObjectivesBecause sensitization may occur to some aspects of drug administration during the addiction process, the objective of the present study was to define the critical features of self-administration histories that result in subsequent increases in the reinforcing efficacy of cocaine (measured using the progressive ratio (PR) schedule).MethodsAnimals were trained to self-administer cocaine on a fixed ratio (FR) schedule, baseline performance on a PR schedule was determined, and animals were given various histories of cocaine self-administration and drug deprivation. PR performance was reassessed following this experience.ResultsCocaine self-administration under a discrete-trials procedure (24xa0h/day) for 10 days, followed by a 7-day deprivation period resulted in sensitization to the reinforcing effects of cocaine as assessed by the PR schedule (increases in maximal breakpoints maintained by cocaine with no change in sensitivity at lower doses). Similar levels of daily cocaine intake on a FR schedule (typically completed within 6xa0h) coupled with a deprivation period failed to produce changes in breakpoint. Providing access to cocaine during the “deprivation period” by repeated testing on a PR schedule prevented the sensitization.ConclusionsThese data suggest that these self-administration-induced changes in breakpoint reflect sensitization, and show that a drug-free deprivation period is necessary, but not sufficient, to produce this increase.

Comparison of the reinforcing effects of cocaine and cocaine/heroin combinations under progressive ratio and choice schedules in rats.

The co-use of cocaine and heroin is relatively common, with a growing clinical and preclinical literature dedicated to investigating the factors underlying the phenomenon. Specifically, several studies have compared the reinforcing effects of the coadministration of cocaine and heroin, referred to commonly as ‘speedball’, to either drug alone. The present study assessed whether addition of heroin to a wide range of cocaine doses produces reinforcing effects greater than cocaine alone using both a progressive ratio (PR) schedule and a choice procedure. Patterns of coadministration of cocaine and heroin offered simultaneously were also assessed using double-lumen cannulas. Under the PR schedule, speedball combinations across a range of doses (0.38–3.0 mg/kg/inf cocaine+1.5–48 μg/kg/inf heroin) did not support higher break points than cocaine alone. When cocaine and heroin were made available concurrently (ie on two separate levers), rats self-administered cocaine exclusively. Using a choice procedure, however, a preference was demonstrated for some speedball combinations (eg 0.18 mg/kg/inf cocaine+50 μg/kg/inf heroin; 0.38 mg/kg/inf cocaine+50 μg/kg/inf heroin) over cocaine alone (0.75 mg/kg/inf). So while results obtained using the PR schedule do not support the hypothesis that speedball combinations are more reinforcing than cocaine alone, data from the choice procedure do support this hypothesis. These apparently discrepant results demonstrate that these models are measuring different aspects of drug reinforcement, and suggest that choice procedures in rats provide a useful tool to study speedball self-administration.

Effect of strain and sex on μ opioid receptor-mediated G-protein activation in rat brain

Strain and sex differences in mu opioid-mediated antinociception have been reported in rodents. The present studies evaluated mu opioid receptor-mediated G-protein activation in Lewis and Fischer 344 (F344) male and female rats using agonist-stimulated [35S]GTPgammaS binding. Compared to Lewis rats, F344 rats exhibited a 35% higher level of net DAMGO-stimulated [35S]GTPgammaS binding in striatum. Basal [35S]GTPgammaS binding was approximately 30% lower in thalamus of Lewis than F344 rats. Female Lewis rats also exhibited slightly ( approximately 15%) lower basal [35S]GTPgammaS binding in cingulate cortex relative to F344 rats of either sex. The relative efficacies of the mu partial agonists, morphine and buprenorphine, were also examined. Buprenorphine exhibited approximately 40% lower relative efficacy in the periaqueductal gray in Lewis compared to F344 rats, but no other relative efficacy differences were found between strains or sexes. Moreover, regional differences in the relative efficacy of buprenorphine were also detected in Lewis but not F344 rats. In contrast to these results, the only difference found between sexes was the 13% lower basal [35S]GTPgammaS binding in the cingulate cortex of female compared to male Lewis rats. These results suggest that differences in mu opioid receptor-mediated G-protein activation may contribute to strain differences in opioid antinociception, whereas sex differences may result predominantly from other mechanisms.