Effects of dopaminergic drugs on innate pheromone-mediated reward in female mice: A new case of dopamine-independent "liking."

Male sexual pheromones are innately rewarding to adult female mice, but the role of dopamine in this natural reward is unknown. The authors have tackled this issue by assessing the effects of intraperitoneal injections of dopamine D? (SCH 23390, 0.02- 0.05mg/kg) and D? (sulpiride, 20.00 mg/kg) antagonists, a dopamine releasing agent (amphetamine, 0.50 -2.00 mg/kg), and D? (SKF 38393, 10.00 -20.00 mg/kg) and D? (quinpirole, 0.20 -1.00 mg/kg) agonists on the chemoinvestigation displayed by female mice in male- versus female-soiled bedding 2-choice tests. Dopamine antagonists and quinpirole failed to affect the unconditioned preference displayed by females towards male chemosignals, whereas both amphetamine and SKF 38393 abolished it. Finally, D? and D? antagonists did not block the induction of operant place conditioning by male chemosignals. As the female mice were tested in their first encounter with male sexual pheromones, their behavior can only be influenced by the "liking" component of reward. Therefore, the results suggest that dopamine mediates neither the hedonic properties of male sexual pheromones nor the acquisition of conditioned place preference. However, dopamine acting on D1 receptors might inhibit female mice attraction towards male chemosignals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Naloxone blocks place preference conditioning after paced mating in female rats.

Sexual behavior in male rats induces a positive affect as evaluated by conditioned place preference (CPP). In addition, when females control or "pace" the rate of sexual interaction, a clear CPP is also observed. The reward state induced by mating in male rats is blocked by the injection of the opioid antagonist naloxone. In the present experiment, a dose of 4 mg/kg of naloxone completely blocked the CPP induced in females by paced mating. It appears that a common opioid system is involved in the positive affect induced by sexual behavior in both male and female rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of the fatty acid compositions in intraepithelial and infiltrating lesions of the cervix: part II, free fatty acid profiles

Clinical studies report a low incidence of intestinal side effects with transdermally administered fentanyl (TTS-fentanyl) in comparison with oral morphine. To support these clinical data, analgesic and intestinal effects of both opioids were compared in rats. After subcutaneous injection, analgesia in the tail withdrawal reaction test was obtained at a peak effect dose of 0.032 mg/kg with fentanyl and 8.0 mg/kg with morphine. This analgesic dose exceeded the ED50 for inhibition of castor oil-induced diarrhea only slightly (1.1 x) in the case of fentanyl (0.028 mg/kg) but markedly (36 x) in the case of morphine (0.22 mg/kg). To reverse completely the antidiarrheal effect of equivalent analgesic doses of the opioids (their ED50S for analgesia lasting 2 hours), much more naloxone was required in the case of morphine (5.4 mg/kg) than in the case of fentanyl (0.19 mg/kg). After oral administration, the difference between both opioids was less pronounced. Analgesia was obtained at 0.85 mg/kg with fentanyl and 32 mg/kg with morphine. This analgesic dose only slightly (1.7 x) exceeded the antidiarrheal dose in the case of fentanyl (0.49 mg/kg) but significantly (6.2 x) in the case of morphine (5.2 mg/ kg). To reverse completely the antidiarrheal effect of equivalent analgesic oral doses of the opioids (their ED50S for analgesia lasting 2 hours), more naloxone was required in the case of morphine (11 mg/kg) than in the case of fentanyl (2.0 mg/kg). Rapid penetration of fentanyl into the brain is thought to be responsible for small dissociation between the analgesic and intestinal effect of this lipophilic opioid. The present data provide preclinical evidence to support the relatively low incidence of intestinal side effects observed clinically with the use of TTS-fentanyl in comparison with orally administered morphine.     

Discriminative stimulus effects of opioids in pigeons trained to discriminate fentanyl, bremazocine and water: evidence of pharmacological selectivity

The purpose of the present investigation was to examine the discriminative stimulus effects of opioids with activity at mu and kappa opioid receptors, in pigeons trained to discriminate the mu opioid fentanyl, the kappa opioid bremazocine and water in a three-choice discrimination task. The apparent pkB values obtained for naloxone as an antagonist of the stimulus effects of fentanyl were higher than those obtained against the bremazocine stimulus. The mu opioids morphine and l-methadone substituted for the fentanyl stimulus, the kappa opioids U50,488 and U69,593 substituted for the bremazocine stimulus, and the non-opioid pentobarbital failed to substitute for either the fentanyl or bremazocine stimulus. A series of opioids with activity at both the mu and kappa opioid receptor sites, including nalorphine, butorphanol, buprenorphine, nalbuphine, ethylketocyclazocine, (-)-ketocyclazocine, (-)-n-allylnormetazocine (NANM) and levallorphan, produced high levels of substitution for the fentanyl stimulus without producing appreciable levels of substitution for the bremazocine stimulus. At doses that did not substitute for the fentanyl stimulus, (-)-NANM, levallorphan, nalorphine and nalbuphine partially antagonized the bremazocine stimulus (i.e. produced responding on the water key). Butorphanol and buprenorphine also antagonized the bremazocine stimulus, although this effect was evidenced only at doses that substituted for the fentanyl stimulus. In contrast, even when tested up to doses that markedly decreased rates of responding, ethylketocyclazocine and (-)-ketocyclazocine failed to antagonize the bremazocine stimulus. The present findings indicate that in this three-choice task the fentanyl-like substitution patterns produced by opioids with activity at both the mu and kappa opioid receptors are similar to those reported in pigeons trained to discriminate either fentanyl or bremazocine from saline (i.e. two-choice tasks). In this task, however, the level of kappa antagonist activity evidenced by these opioids was considerably less than that obtained in pigeons trained to discriminate bremazocine from saline.     

Opioid Craving and Seeking Behavior in Physically Dependent Volunteers: Effects of Acute Withdrawal and Drug Reinforcement Opportunity.

This study examined whether acute opioid withdrawal and drug reinforcement opportunity increase opioid craving and seeking behavior. The author used a 3 × 2 within-subject randomized crossover design to assess craving and operant behavioral effects of 3 pretreatments (naloxone 0.1 mg/70 kg, fentanyl 0.75 mg/70 kg, or saline iv) and drug or money reinforcement opportunity in 8 methadone-maintained volunteers. Each pretreatment was paired with response-contingent (15 × fixed-ratio 100) delivery of drug (fentanyl 1.5 mg/70 kg iv) and money (rated equivalent of fentanyl) in different sessions. Naloxone significantly increased opioid craving, withdrawal signs, and symptoms, but not operant behavior, relative to saline and fentanyl pretreatment. However, drug versus money reinforcement opportunity did not significantly increase opioid craving or seeking behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Activation of POMC neurons during general arousal but not sexual behavior in male rats.

Exogenous opioids influence male rat sexual behavior, suggesting that endogenous opioid peptides are released during mating. Supporting this hypothesis, the authors recently showed that mating induced activation of mu opioid receptors. However, it is unknown which ligand(s) is acting on these receptors during mating. The current set of experiments tested the hypothesis that beta-endorphin-producing neurons, that is, proopiomelanocortin (POMC) neurons, are activated during sexual behavior. Mating-induced activation of POMC neurons was investigated during either the dark phase or the light phase, following different components of male rat sexual behavior or following control manipulations that resulted in general arousal. Results show activation of POMC neurons in the mediobasal hypothalamus following general arousal but not specifically related to sexual behavior per se. In addition, mating did not activate the subpopulation of POMC neurons that project to the medial preoptic nucleus. These results suggest that it is unlikely that POMC neurons contribute to the action of endogenous opioids in the brain area during sexual behavior but instead may contribute to the change in arousal state essential for the expression of sexual behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reinforcing properties of ejaculation in the male rat: Role of opioids and dopamine.

Ejaculation-induced reward in the male rat was evaluated by the conditioned place-preference paradigm. It was supposed that ejaculation induces a reward state such that it can be conditioned to environmental stimuli. Males were allowed to ejaculate once and were then immediately transferred to a place-preference cage. One ejaculation produced place preference. Naloxone (16 mg/kg) not only blocked this place preference but also induced a place aversion. Naloxone by itself had no effect on place preference. It is suggested that release of endogenous opioids renders ejaculation rewarding. Pimozide, in a dose of 1 mg/kg, had no effect on ejaculation-induced reward. Dopamine thus seems to be of slight importance for that effect of copulation. Perhaps compulsive sexual activity obeys the same mechanisms as compulsive drug use in opiate addicts. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lead toxicosis in a captive bottlenose dolphin (Tursiops truncatus) consequent to ingestion of air gun pellets

Male rats of the Wistar strain were selected as good copulators (displaying at least 1 ejaculation in each of three consecutive tests for male sexual behavior) and sexually sluggish animals (displaying no ejaculations in each of three consecutive tests). The administration of low doses (1 and 2.5 mg/kg, i.p.) of kainic acid in sexually sluggish rats induced an enhancement of some parameters of copulatory behavior. In particular, significant reductions in latency to the first mount and intromission and increases in frequency of mounts and intromissions were observed. In contrast, the drug failed to exert any effect in good copulators. At the dose of 5 mg/kg (i.p.) kainic acid exerted an inhibitory effect on sexual behavior parameters both in good copulators and in sluggish rats. A persistent increase in latency to the first mount, intromission and ejaculation, and reduction in frequency of mounts, intromissions and ejaculation both in good copulators and in sluggish rats were observed 20 days after kainic acid treatment at the higher dose. No persistent effect of kainic acid 1 and 2.5 mg/kg was observed 20 days after treatment. These results suggest that kainic acid may affect in a dose-dependent manner several copulatory parameters of male sexual behavior repertoire. The bimodal effects could be explained considering a possible interaction of kainic acid with different neurotransmissions or receptor subtypes.     

Establishment of a preference by the newborn lamb for its mother: The role of opioids.

Mother-young relationships in sheep are characterized by individual recognition and a rapidly developing exclusive bond. The authors examined the role of opioids in establishment of the lamb's preference for its mother. Newborn lambs received the opioid receptor antagonist naltrexone (0.0, 1.5, or 3.0 mg/kg ip), and lambs were tested at 24 hr and 48 hr of age. At 24 hr, controls spent significantly more time near the mother than near an alien ewe; no significant difference was obtained for the naltrexone-treated groups. The effect of naltrexone persisted at 48 hr. No other significant behavioral difference was observed. Results support the hypothesis that opioids mediate the establishment of mother preference and the view that positive affect associated with social attachment and maternal care may be modulated by opioids. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sexual reinforcement is blocked by infusion of naloxone into the medial preoptic area.

Determined whether infusions of naloxone into specific brain sites can block sexual reinforcement as evaluated with the conditioned place preference procedure. Methylnaloxonium (5 μg/cannula) was infused bilaterally either into the medial preoptic area (MPOA) or into the nucleus accumbens (NAC) of sexually experienced male rats. The MPOA was chosen because it is important for sexual behavior, and several opioid peptides have been shown to modify sexual behavior when infused there. The NAC appears to be a critical structure for drug-induced reward. Methylnaloxonium blocked place preference produced by ejaculation after infusion into the MPOA without affecting sexual behavior. Infusion of the antagonist into the NAC did not reduce the reinforcing properties of ejaculation. Data suggest that the MPOA may be a site where sexual reward is produced. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The significance of dopamine, versus other catecholamines, for L-dopa induced facilitation of sexual behavior in the castrated male rat

The effects of a wide dose range of L-DOPA on male rat sexual behavior were investigated. The animals were castrated as adults and supplied with small amounts of testosterone propionate. It was found that doses of L-DOPA up to 2.5 mg/kg facilitated, while higher doses inhibited, sexual behavior in animals pretreated with pargyline, 20 mg/kg, + MK486, 50 mg/kg. The effects of L-DOPA on sexual behavior were not restricted to the copulatory act, but included elements preceding the copulatory act as well. Most of the facilitatory effects of L-DOPA 2.5 mg/kg were prevented by the dopamine receptor blocker pimozide; 0.10 mg/kg. It is concluded that dopamine is the catecholamine of major importance in mediating the L-DOPA induced facilitation of sexual behavior in the castrated male rat. However, some elements of the copulatory act appear to be modified by noradrenaline and/or adrenaline as well.     

Sex difference and testosterone modulation of pheromone-induced NeuronalFos in the Ferret's main olfactory bulb and hypothalamus

A carnivore, the ferret possesses a vomeronasal organ--accessory olfactory bulb (VNO-AOB) projection to the hypothalamus; however, little is known about its function. Pheromones in soiled bedding from estrous female ferrets or an artificial peppermint odor significantly augmented nuclear Fos protein immunoreactivity (Fos-IR), a marker of neural activation, in several main olfactory bulb (MOB) sites but not in the AOB of gonadectomized male and females. Testosterone propionate (TP) significantly augmented the MOB's neuronal Fos responses to estrous females' pheromones, but not to peppermint. Estrous odors, but not peppermint, also augmented neuronal Fos-IR in the medial preoptic area (mPOA) of female, but not male, subjects. Pheromones in soiled bedding from breeding male ferrets significantly augmented neuronal Fos-IR in the MOB and in the medial amygdala of gonadectomized, TP-treated male and female subjects. Again, male pheromones failed to influence neuronal Fos-IR in the AOB of either sex, and only females showed significant increases in neuronal Fos-IR in the lateral aspect of the ventromedial nucleus and mPOA. These results point to an essential role among higher mammals of the main olfactory epithelium-MOB projection to the hypothalamus in detecting and processing pheromones. Gonadectomized ferrets showed significant increases in sniffing behavior when placed on either female or male bedding. This occurred regardless of whether they had received TP or oil vehicle, suggesting that testosterone's facilitation of neuronal Fos responses to estrous females' odors in the MOB of both sexes cannot be attributed to increased scent gathering. Androgen receptor-IR was present in the MOB granule cell layer of male and female ferrets, raising the possibility that testosterone acts directly on these cells to augment their responsiveness to pheromones.     

Intake of high-fat food is selectively enhanced by mu opioid receptor stimulation within the nucleus accumbens

The present study was designed to further investigate the nature of feeding induced by opioid stimulation of the nucleus accumbens through an examination of the effects of intra-accumbens (ACB) opioids on macronutrient selection. In 3-hr tests of free-feeding (satiated) rats, intra-ACB administration of the mu receptor agonist D-Ala2,N,Me-Phe4, Gly-ol5-enkephalin (DAMGO; 0, 0.025, 0.25 and 2.5 micrograms bilaterally) markedly enhanced the intake of fat or carbohydrate when the diets were presented individually (although the effect on fat intake was much greater in magnitude). Intra-ACB injections of DAMGO, however, produced potent preferential stimulatory effects on fat ingestion with no effect on carbohydrate ingestion when both fat and carbohydrate diets were present simultaneously. Moreover, this selective stimulation of fat intake was independent of base-line diet preference and could be blocked by systemic injection of naltrexone (5 mg/kg). We also examined the effect of 24-hr food deprivation on the pattern of macronutrient intake in rats with access to both carbohydrate and fat. In contrast to the DAMGO-induced selective enhancement of fat intake, food deprivation significantly increased the intake of both diets to the same extent; however, in this case, only the stimulated fat intake was blocked by systemic naltrexone. Intra-ACB administration of DAMGO in hungry rats produced an effect similar to that observed in free-feeding rats; preference was strongly shifted to fat intake. Similarly, the opioid antagonist naltrexone (20 micrograms) infused directly into ACB preferentially decreased fat intake in hungry rats. These findings suggest that endogenous opioids within the ventral striatum may participate in the mechanisms governing preferences for highly palatable foods, especially those rich in fat.     

Sexual behavior regulated (paced) by the female induces conditioned place preference.

The possibility that female-paced coital behavior induces a reward state of sufficient intensity and duration to induce conditioning was evaluated by the conditioned-place-preference paradigm. Ovariectomized female rats, treated with estradiol benzoate and progesterone, regulated (paced) their coital interactions with a stud male through a 2-compartment chamber in which only the female could freely move from one compartment to the other. The females that paced their coital interactions showed a clear place preference. In contrast, no change in preference was observed in the females that could not pace their coital contacts. The change in preference in the females that paced their coital interactions was similar to that produced by an injection of morphine (1 mg/kg). These results suggest that coital interactions in females can induce a reward state when the females can control the pace of the sexual interaction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Opioids and rate of positively reinforced behavior: II. Antagonism by β-funaltrexamine.

Lever pressing by rats (Rattus norvegicus) was maintained under a fixed-ratio 20 schedule of food presentation. Response rate-decreasing effects of the opioid compounds fentanyl, U50,488, butorphanol, and nalorphine were examined alone and in combination with the irreversible, μ-selective opioid antagonist β-funaltrexamine (β-FNA) antagonized the rate-decreasingly effects of both fentanyl and butorphanol. β-FNA was more potent and the duration of antagonism was greater, against butorphanol than against fentanyl. β-FNA also antagonized the effects of the higher nalorphine doses: however, lower doses of nalorphine, which were without effect alone, decreased response rates in the presence of β-FNA. The dose–effect curve for U50,488 was shifted leftward in the presence of β-FNA. These data suggest that, β-FNA may be useful in assessing μ-receptor activity related to the effects of opioids on rate of operant behavior and the efficacy with which opioids produce these effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Glutamate receptor-mediated hyperexcitability after ethanol exposure in isolated neonatal rat spinal cord

The influence of maternal opioid receptor blockade (50 mg/kg naltrexone, NTX) or saline (controls) throughout pregnancy on nociception and brain opioid receptor characteristics of rat offspring were examined; all animals were crossfostered to untreated mothers at birth. At 21 and 30 days, NTX-exposed pups weighed 8.2-24.3% more than controls, but both NTX and control groups were of similar body weights at 48, 60, and 80 days. Rats in the NTX and control groups displayed comparable baseline reactions to the hotplate. Morphine challenge tests and nociceptive measures revealed that NTX-subjected offspring examined at 21, 30, 48, and 60 days did not react to dosages that invoked 42-132% decreases from baseline levels in controls. Animals exposed prenatally to NTX were analgesic when injected with the opioid butorphanol or the nonopioid xylazine. The binding affinity (Kd) and capacity (Bmax) of delta and kappa opioid receptors were similar in NTX and control groups at 21 and 80 days. However, the Bmax, but not the Kd, of mu opioid receptors was subnormal in NTX offspring by about 20% in contrast to control rats at 21 and 80 days. The results imply that the interactions of some endogenous opioids with opioid receptors during development are determinants of certain aspects of pain sensitivity as well as the density of particular opioid receptors in the postnatal period.     

Analgesic potency of mu and kappa opioids after systemic administration in amphibians

The relative analgesic potency of 11 opioid agents was assessed by using the acetic acid test in amphibians. Systemic administration of the mu agonists, fentanyl, levorphanol, methadone, morphine, meperidine and codeine; the partial mu agonist, buprenorphine; and the kappa agonists nalorphine, bremazocine, U50488 and CI-977 was made by s.c. injection into the dorsal lymph sac of the Northern grass frog, Rana pipiens. All agents produced a dose-dependent and long-lasting analgesia which persisted for at least 4 hr. The analgesic effects of single doses of each agent were significantly blocked or reduced by pretreatment with naltrexone. Systemic opioids produced log dose-response curves which yielded ED50 values ranging from 1.4 nmol/g for fentanyl to 320.9 nmol/g for nalorphine. Comparison of ED50 values gave a rank order of analgesic potency = fentanyl > CI-977 > levorphanol > U50488 > methadone > bremazocine > morphine > buprenorphine > meperidine > codeine > nalorphine. The relative analgesic potency of mu opioids in amphibians was significantly correlated with relative analgesic potency of these same agents obtained on the mouse writhing and hot plate tests. These data suggest that the amphibian model may serve as an adjunct or alternative model for the testing of opioid agents. Furthermore, given the inactivity of kappa opioids on rodent hot plate and tail-flick tests, the acetic acid test in amphibians may be especially well-suited for the assessment of opioid analgesia after administration of kappa-selective opioids.     

Comparative clinical pharmacology of short-acting mu opioids in drug abusers

The clinical pharmacology of fentanyl and alfentanil was examined in opioid-experienced volunteers with agonist and antagonist sensitivity measures. Two studies used within-subject, placebo-controlled, crossover designs. In study 1, fentanyl (0.125, 0.25 mg/70 kg i.v.) was followed at 0, 20, 60 and 180 min by naloxone (10 mg/70 kg i.m.). Agonist effects during 180-min and 0-min (control; simultaneous fentanyl-naloxone i.v. infusion) challenge sessions were compared. Fentanyl rapidly constricted pupils, depressed respiration and produced subjective "high" and opiate symptoms lasting 60 to 120 min, depending on the measure. Naloxone precipitated withdrawal symptoms of comparable intensity at each challenge point. In study 2, fentanyl (0.125, 0.25 mg/70 kg i.v.), alfentanil (1, 2 mg/70 kg i.v.) and saline were followed at 1 and 6 hr by naloxone (10 mg/70 kg i.m.). Agonist effects were examined during 6-hr challenge sessions. The two drugs produced a comparable range of effects with similar peak magnitude for 0.125 mg/70 kg fentanyl and 1 mg/70 kg alfentanil and for 0.25 mg/70 kg fentanyl and 2 mg/70 kg alfentanil. Alfentanil's duration of action was brief ( < 60 min). Withdrawal was precipitated at 6 hr only after 0.25 mg/70 kg fentanyl. These findings support typical mu opioid characteristics (pleasurable subjective effects, physical dependence) for both drugs, differential duration of action (fentanyl > alfentanil) and peak effects consistent with a 1:8 (fentanyl/alfentanil) potency ratio.     

Opioids and sexual behavior of male rats: Involvement of the medial preoptic area.

Local infusion of β-endorphin (β-END) into the medial preoptic area (MPOA) dose-dependently impaired the gating of the copulatory response and the execution of the sexual performance of sexually experienced, intact male rats. Local naloxone treatment prevented the impairment of the sexual response by β-END, but failed to facilitate unimpaired copulation. Local infusion into the MPOA of equimolar doses of α-endorphin, dynorphin-A-(1-17) or met-enkephalin were less effective than β-END. It is suggested that endogenous opioid systems in the MPOA are normally quiescent, and increased activity may be related to disrupted or inhibited male sexual behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Steady-state methadone effect on generalized arousal in male and female mice.

Methadone is widely used in treatment of short-acting opiate addiction. The on-off effects of opioids have been documented to have profound differences from steady-state opioids. The authors hypothesize that opioids play important roles in either generalized arousal (GA) or aversive state of arousal during opioid withdrawal. Both male and female C57BL6 mice received steady-state methadone (SSM) through osmotic pumps at 10 or 20 mg/kg/day, and GA was measured in voluntary motor activity, sensory responsivity, and contextual fear conditioning. SSM did not have any effect on those GA behaviors in either sex. Females had higher activity and less fear conditioning than males. The effects of SSM on stress-responsive orexin gene expression in the lateral hypothalamus (LH) and medial hypothalamus (MH, including perifornical and dorsomedial areas) were measured after the behavioral tests. Females showed significantly lower basal LH (but not MH) orexin mRNA levels than males. A panel of GA stressors increased LH orexin mRNA levels in females only; these increases were blunted by SSM at 20 mg/kg. In summary, SSM had no effect on GA behaviors. In females, SSM blunted the GA stress-induced LH orexin gene expression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)