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The motor response to vasopressin, a neuropeptide promoting the reabsorption of water, was isometrically investigated in vitro in human renal calyces and pelvis in relation to possible modulation of urinary flow by these tubular structures. Kidneys were obtained from nine male patients who underwent nephrectomy for either renal or ureteral cancer. Minor calyces and pelvis were carefully removed. Strips (10 mm x 3 mm) were cut from infundibular region of minor calyces and from renal pelvis and placed in 10 ml organ bath for isometric tension recordings. Calyceal and pelvic smooth muscle strips exhibited spontaneous phasic contractions which occurred with regular frequency and amplitude. Vasopressin induced a dose-dependent [10(-10) to 10(-6) M] enhancement of basal tone (P <0.01) and a decrease of spontaneous contractions on isolated strips from minor calyces and pelvis. The effect of vasopressin was inhibited by prior administration of D(CH2)5Tyr(Me)2-Arg8-Vasopressin antagonist [10(-7) M]. The excitatory response to vasopressin was Tetrodotoxin [TTX]-resistant and was not affected by pre-treatment with phentolamine [10(-5) M], atropine [10(-5) M], and hexamethonium [10(-5) M]. After incubation of the specimens in Ca2+-free medium containing EGTA [0.5 mM] or after treatment with nifedipine [10(-5) M], both spontaneous and vasopressin-induced contractions [10(-10) to 10(-6) M] were completely inhibited in all specimens. Our results can be interpreted to imply that the tonic contractions induced by vasopressin facilitate the reabsorption of water by increasing the hydraulic resistance of the tubular structures below collecting ducts.

The effects of the cannabinoid receptor agonist Win 55,212-2 and of the competitive cannabinoid receptor antagonist SR 141716A on the electrically-evoked peristalsis of isolated distal colon of mouse were studied. Intraluminal pressure, longitudinal displacement, ejected fluid volume and changes in morphology of external intestinal wall were simultaneously recorded in the pre-drug period and in presence of Win 55,212-2 alone or in combination with SR 141716A. In the pre-drug period (control), peristaltic activity was characterised by regular, monophasic waves and the intraluminal content propelled towards anterograde (oro-aboral) direction with a propulsion velocity of 1.25 +/- 0.1 mm x s(-1). Pressure and shortening waves showed a peak amplitude of 2.44 +/- 0.32 kPa and 1.8 +/- 0.72 mm, respectively. The mean amount of fluid volume ejected during each contraction was 80 +/- 12.6 microl. The addition of Win 55,212-2 [10(-7)-10(-4) M] to the organ bath determined a dose-related attenuation of peristaltic activity consequent to the decrease of circular and longitudinal muscle strength. The decrease of contractile activity was followed by dose-dependent decrease of the amount of fluid ejected during peristalsis. The effects of Win 55,212-2 [10(-7)-10(-5) M] were prevented by SR 141716A, indicating the presence of cannabinoid CB1 receptors in the mouse distal colon. SR 141716A alone enhanced both tonic and phasic motor activities in the colonic longitudinal smooth muscle, suggesting that CB1 receptor antagonists could act either through antagonising the effect of endogenous CB1 receptor agonist or by an agonist effect on these receptors. The present results further support the hypothesis that cannabinoids perform a neuromodulatory role in various tracts of gastrointestinal system and first demonstrate their action also in the distal colon of rodents.

The present paper briefly reviews the most relevant experimental data on the reducing effect of some medicinal herbs on voluntary alcohol intake in animal models of alcoholism. Pueraria lobata, Tabernanthe iboga, Panax ginseng, Salvia miltiorrhiza and Hypericum perforatum proved to be effective in decreasing alcohol consumption. Reduction of alcohol absorption from the gastrointestinal system appears to be a common feature among most of the above plants. These data suggest that medicinal plants may constitute novel and effective pharmacotherapies for alcoholism.

Clinical trials carried out to compare methadone and buprenorphine in the treatment of opioid dependence have generally employed an alcoholic solution of buprenorphine, which has a bioavailability superior to that of the tablets. Since the product available for large scale use is in tablet form, one intended to verify the efficacy of this formulation. In a multicentre randomised controlled double blind study, 72 opioid dependent patients were assigned to treatment with buprenorphine (8 mg/day) or methadone (60 mg/day) for a period of 6 months. The two compounds did not show any significant difference with regard to urinalyses: the average percentage of analyses proving negative was 60.4% for patients assigned to buprenorphine, and 65.5% for those assigned to methadone. With regard to retention, a non-significant trend in favour of methadone was observed. Patients completing the trial improved significantly in terms of psychosocial adjustment and global functioning, as ascertained by the DSM-IV-GAF and symptom checklist-90 (SCL-90) scales, and this was independent of the treatment group. Finally, in the case of buprenorphine, patients who dropped out differed significantly from those who stayed, in terms of a higher level of psychopathological symptoms, and a lower level of psychosocial functioning. The results of the study further support the utility of buprenorphine for the treatment of opioid dependence.

Cannabinoids produce analgesia, hypomotility, catalepsy, cognitive deficits and positive reinforcement. Moreover, Delta(9)-tetrahydrocannabinol (9-THC) and synthetic cannabinoids stimulate dopaminergic neurons and increase dopamine release in different brain areas. In order to clarify the role of endogenously released dopamine in the hypothermic response to cannabinoids, the effect of D(1) and D(2) dopamine receptor agonists and antagonists on Delta(9)-THC-induced hypothermia was studied in rats. Delta(9)-THC (2.5 and 5 mg/kg intraperitoneally [IP]) decreased body temperature in a dose-related manner. This effect was antagonized not only as expected by the CB(1) cannabinoid receptor antagonist SR 141716A (0.5 mg/kg, IP) but also, unexpectedly, by the dopaminergic D(2) receptor antagonists S(-)-sulpiride (5 and 10 mg/kg, IP) and S(-)-raclopride (1 and 3 mg/kg, IP). Conversely, the hypothermic effect of Delta(9)-tetrahydrocannabinol was potentiated by the D(2) dopamine receptor agonists (-)-quinpirole (0.025 and 0.500 mg/kg, SC) and (+)-bromocriptine (0.5 and 1 mg/kg, IP). In contrast, the Delta(9)-THC-induced hypothermic effect was not modified by either by the D(1) dopamine agonist SKF 38393 (10 mg/kg SC) or by the D(1) dopamine antagonist SCH 23390 (0.5 mg/kg SC). These results suggest that the D(2) dopamine receptors have a permissive role in the hypothermic action of cannabinoids.

The present study examined the involvement of GABA(A) and GABA(B) receptors in the discriminative stimulus effects of gamma-hydroxybutyric acid (GHB). Rats were trained to discriminate either 300 or 700 mg/kg GHB IG from water using a T-maze, food-reinforced drug-discrimination procedure. The direct GABA(B) agonist, baclofen, substituted completely for both training doses of GHB; its potency to substitute for GHB increased moderately as the training dose of GHB was increased. The positive GABA(A) modulator, diazepam, substituted partially for 300 mg/kg GHB, but failed to elicit GHB-appropriate responding in rats trained with the higher GHB dose. Finally, the GABA(B) antagonist, CGP 35348, completely blocked the discriminative stimulus effects of the high training dose of GHB, but only partially antagonized the effects of the low training dose. These results suggest that (a) GHB produces a compound stimulus, and (b) both GABA(B)- and GABA(A)-mediated cues are prominent components of this compound stimulus; the contribution of each component, however, appears to vary as the training dose of GHB is increased.

Gamma-hydroxybutyric acid (GHB) is a drug recently utilized for alcoholism management. It has been shown that GHB has anabolic effects since it can increase growth hormone (GH) release in healthy subjects. At present, there are no studies investigating body composition in alcoholics during long-term GHB treatment. In this study body composition and GH secretion in alcohol dependent subjects was evaluated during addiction and at different time of GHB administration and alcohol abstinence. A total of 45 male alcohol dependent patients (mean age 39.7+/-9.8 yrs, mean height: 171+/-6.8 cm, body mass index--BMI--22.1+/-1.6 kg/m(-2)) were consecutively enrolled. Body composition was assessed by anthropometry, bioimpedance analysis and tritiated water method. A 7-day food diary was collected. Plasma GH levels were determined by radioimmunoassay. A 6-month total abstinence was obtained in 22 patients, by means of psychological support counseling and self-help groups in 9 subjects and also by 50 mg/kg/day of GHB in 13 subjects. At 1, 2, 3 and 6 months of abstinence, the biochemical assessment and metabolic variables were re-examined. Fat-free mass (FFM) and basal GH secretion were similar at the different times of follow-up in both groups of patients. GHB treated patients and those receiving psychological support alone showed similar values in FFM and GH. Both groups of patients did not differ in FFM and plasma GH level from healthy controls at any of the times evaluated. Waist-to-hip ratio did not differ between patient groups, while higher values were shown in alcoholics with respect to control subjects. The present study shows that long-term administration of GHB did not affect muscular mass and did not determine an increase of GH release in chronic alcoholics. This findings could be due to an impairment of the hypothalamic-limbic system and of GABAergic neurotransmission in alcoholics' brain.

GABA, the predominant inhibitory neurotransmitter present in the mammalian CNS, is also found in the periphery. GABA actions are mediated by the ionotropic GABA(A)/GABA(C) receptors, as well as the metabotropic GABA(B) receptor. The rat GABA(B) receptor has recently been cloned and two cDNA clones have been isolated encoding two isoforms of the receptor, GABA(B)R1a and R1b. Northern blot analysis revealed the presence of both transcripts in the rat brain using specific cDNA probes for GABA(B)R1a and R1b, respectively. However, Northern blot analysis, hybridized with a probe containing a sequence common to both isoforms, revealed specific RNAs in the rat brain and in testis, but not in other peripheral tissues. In the present study, by using the more sensitive reverse transcriptase-polymerase chain reaction with a specific set of primers for each isoform and Southern blot analysis, we found that both isoforms of the GABA(B) receptor are expressed not only throughout the brain but also in all peripheral organs examined, including heart, spleen, lung, liver, small intestine, large intestine, kidney, stomach, adrenal, testis, ovary and urinary bladder. The peripheral distribution of GABA(B)R1 mRNAs supports the notion of a physiological role for GABA in the control of a wide range of peripheral organs.

Gamma-hydroxybutyric acid (GHB) has recently been introduced in clinical practice for alcoholism management, due to its utility in inducing abstinence from alcohol. In the present study we investigated the usefulness of greater dosage fractioning of GHB in non-responder alcoholics to the usual three administrations per day. A total of 154 alcoholics were admitted to the study and were treated with GHB (50 mg/Kg orally administered three times per day) for 8 weeks (phase 1); the patients who continued to drink alcohol in phase 1 were administered the same dose of GHB divided into six times per day for another 8 weeks (phase 2). Of the 154 patients, 115 completed phase 1; 78 (67.8%) of these began and maintained abstinence (group A) while 37 subjects (32.2%) continued to drink alcohol (group B) showing a craving significantly higher than group A at the end of phase 1 (P < 0.001); in these patients the major fractioning of the drug in phase 2 caused a significant reduction in craving (P < 0.005) and 26 (70.2%) began and maintained abstinence. Moreover no significant differences in final craving score between group A and B was observed. Within the limits of an open study, our data show that non-responder subjects to the conventional fractioning of GHB seem to benefit from the greater fractioning of the drug and seem to indicate the need for a slow-release form of GHB with a prolonged action.

The reinforcing effects of gamma-hydroxybutyric acid (GHB) were studied by means of intravenous self-administration in drug-naive mice. GHB self-administration was concentration-dependent (0.01-0.5 mg/kg/inj.) according to a bell-shaped curve. Pretreatment with the specific GHB receptor antagonist NCS-382 at a dose of 12.5 mg/kg i.p. completely antagonized the reinforcing effects of GHB. These data suggest that GHB is able to induce reinforcing effects in mice and support the hypothesis of an abuse liability of this drug.

Gamma-hydroxybutyric acid (GHB) is an endogenous compound present in mammalian brain suggested as a putative neurotransmitter, which has been shown to affect several aspects of dependence from various classes of drugs of abuse. In the present study, two sets of experiments were performed to investigate the effects of acute pretreatment with GHB on intravenous cocaine self-administration in rats. In the first experiment GHB was administered intragastrically at the doses of 175, 350, and 700 mg/kg to Long-Evans rats trained to self-administer cocaine using nose-poke as operandum. In the second experiment, GHB was administered intraperitoneally at the doses of 100, 200, and 400 mg/kg to Wistar rats trained to self-administer cocaine intravenously using lever-pressing as operandum. In both experiments acute pretreatment with GHB significantly and dose dependently reduced cocaine self-administration. The effectiveness of GHB was similar in both experiments, indicating that the effect of GHB on cocaine self-administration is independent of animal strain. route of administration, and type of operant response required. These results indicate that GHB reduces cocaine-seeking behavior in rats, modulating the acute reinforcing effect of cocaine. The clinical effectiveness of GHB in dependence from various classes of abused drugs warrants further studies to evaluate the possibility that GHB might represent a useful therapeutic agent for cocaine addiction in humans.

The effect of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight was assessed in adult, non-obese Wistar rats. The daily administration of SR 141716 (2.5 and 10 mg/kg; i.p.) reduced dose-dependently both food intake and body weight. Tolerance to the anorectic effect developed within 5 days; in contrast, body weight in SR 141716-treated rats remained markedly below that of vehicle-treated rats throughout the entire treatment period (14 days). The results suggest that brain cannabinoid receptors are involved in the regulation of appetite and body weight.

The purpose of this study was to investigate the influence of the severity of concomitant psychiatric symptomatology on some selected measures of methadone maintenance treatment efficacy in a comprehensive methadone maintenance treatment program (MMTP). The cohort studied included 267 patients who entered a maintenance program in the years 1991-92. Two groups of patients differing in the severity of psychiatric symptomatology were obtained on the bases of the referral to the psychiatrist and the ascertainment of a current disorder. These two groups were compared for retention in treatment, urine tests positive for morphine while in treatment and methadone dose during an observation period of 2 years. The outcome of the study suggests that on these outcome parameters, patients on MMTP who are more psychiatrically ill can perform as well as the other patients.

Patients on methadone maintenance were forewarned that a law prohibiting take-home dosages was to be enforced within 6 months. At the end of the 6-month period preceding the enforcement of the law the effect of the anticipated suppression of the take-home privilege was studied on a cohort of 211 methadone-maintained patients on take-home dosages. The outcome of the treatment of these patients was compared to that of a control group of 220 patients at the end of a 6-month period prior to the announcement of the new law. The outcome of the study suggests that the restrictive regulation is counterproductive for retaining patients in treatment.

The effect of dihydropyridine calcium channel antagonist isradipine (PN 200-110) on morphine reinforcement has been investigated using i.v. self-administration test in rats. Rats were given the opportunity to self-administer a solution of morphine (1 mg/ml, i.v.) in a 1 hr limited access paradigm (FR = 1). Within 5-7 days rats had learned to self-administer approximately 1 mg of morphine in 1 hr as evidenced by a plateau of responding. The administration of isradipine (1.2, 2.5 and 5.0 mg/kg s.c.) 90 min before the morphine self-administration session, induced dose-dependent increase in the number of morphine self-infusions with respect to basal values. This response pattern was very similar to the one observed when morphine solution was substituted by saline in trained rats not treated with isradipine. The results indicate that isradipine inhibits partially the reinforcing properties of morphine in self-administration test.

The effect of isradipine, a dihydropyridine calcium antagonist, on intravenous self-administration of nicotine in naive mice has been investigated. When nicotine injections were made contingent upon nose-poke response by naive mice, they increased their rate of nose poking with respect to animals receiving contingent saline injections or yoked control animals receiving noncontingent nicotine injections. Pretreatment of mice with mecamylamine (2.4 mg/kg) inhibited self-administration of nicotine contingent upon a nose-poke response. The same effect was observed with isradipine (0.5-1.0 mg/kg) in a dose-related manner and stereospecifically. These data suggest that isradipine suppresses the reinforcing properties of nicotine and might be useful for treatment of nicotine abuse.

The selective NK3 tachykinin agonist senktide evokes in rodents 5-HT mediated behaviors, including 5-HT2 receptor-mediated wet dog shakes (WDS) and head shakes (HS). It was observed previously that genetically selected Sardinian alcohol-preferring (sP) rats show a small number of WDS and HS following intracerebroventricular (ICV) injection of senktide. The present study was aimed at confirming these observations and at providing information on the reasons accounting for the anomalous response of sP rats. Senktide (500-2000 ng/rat, ICV) produced a much lower number of WDS and HS in sP rats than in nonselected Wistar (nsW) rats. Both behaviors were suppressed by the 5-HT2 antagonist ritanserin (1 mg/kg, subcutaneously), confirming that 5-HT2 receptors mediate the response. HS induced by the ICV injection of 5-HT agonists endowed with marked activity at 5-HT2 receptors, such as quipazine (1500-6000 ng/rat) or DOI (500-3500 ng/rat), were much less pronounced in sP rats than in nsW rats. Moreover, WDS following peripheral injection of 5-hydroxytryptophan, 25-100 mg/kg, and carbidopa, 12.5 mg/kg, were less intense in sP and in ethanol-naive sP rats than in nsW and in Sardinian alcohol-nonpreferring rats. These findings suggest that sP rats have an inherent different regulation of central 5-HT2 mechanisms.

The model of sleep deprivation in rats by the platform method has been extensively studied in our laboratory as a possible animal model of mania. At the end of the period of sleep deprivation, the rat does not fall asleep as soon as it is returned to its home cage, but shows a period of wakefulness of about 30 min, during which the animal presents a cohort of symptoms that appear to mimic those present in idiopathic mania. In particular, during this period the animal displays insomnia, a high degree of hyperactivity, irritability, aggressiveness, hypersexuality and stereotypy. Haloperidol (0.2 mg/kg) was effective in reducing latency to sleep, while L-sulpiride was much weaker (< 50 mg/kg). The dopamine D1 receptor antagonist SCH 23390 exhibited an extremely high potency and efficacy in reducing sleep latency, a significant effect being observed with 3 micrograms/kg. The administration of the specific D1 receptor agonist SKF 38393 markedly prolonged the period of insomnia with the correlated behavioral syndrome. When lithium was added to the diet and consumed during the sleep deprivation period in adequate amounts to produce serum lithium levels of 0.7-1.0 mEq/l, sleep latency and locomotor activity were significantly reduced. The administration of naloxone (1-10 mg/kg) reduced the latency to sleep in a dose-related manner. By contrast, morphine (1 and 5 mg/kg, i.p.), beta-endorphin and [D-Ala2,D-Leu5]enkephalin (i.c.v., 2 and 1 micrograms, respectively) markedly prolonged the insomnia. The model not only represents a confirmation in the rat that sleep loss often precedes and may trigger a manic episode in man, but suggests that an opioid-dopamine interaction may play a pathogenetic role in mania.

The effect of isradipine and nimodipine, two dihydropyridine calcium antagonists, on intravenous self-administration of cocaine and morphine in naive mice has been investigated. When morphine or cocaine injections were made contingent upon nose-poke response by naive mice, they increased their rate of nose-poking with respect to animals receiving contingent saline injections or yoked control animals, receiving noncontingent cocaine or morphine injections. Pretreatment of mice with isradipine (1.0-3.0 mg/kg, SC) or nimodipine (5-20 mg/kg, SC) inhibited in a dose-related manner self-administration both of cocaine and morphine contingent upon a nose-poke response. The ED50 of isradipine against cocaine and morphine self-administration was 1.7 and 2.1 mg/kg, respectively. The relative values for nimodipine were 14.5 and 11.4 mg/kg, respectively. These data suggest that nimodipine and, especially, isradipine suppress the reinforcing properties of morphine and cocaine and may be an effective pharmacotherapy for treatment of cocaine and heroin abuse.

Chronic treatment with imipramine increased the locomotor response to quinpirole, a selective D2 receptor agonist. This effect was blocked by minute doses of prazosin (0.1-1 mg/kg), a selective alpha 1 receptor blocker, in a dose-dependent manner. Conversely, in control rats the locomotor response to quinpirole was enhanced by the stimulation of alpha 1 receptors with the selective agonist St 587. The results suggest that alpha 1 receptor stimulation plays a permissive role in the supersensitivity of D2 receptors following chronic treatment with imipramine.

The intravenous administration of cocaine (0.5-8 mg/kg) produced a dose-related inhibition of the firing rate of substantia nigra (A9) dopaminergic (DA) neurons. Pretreatment with the calcium antagonist flunarizine (5 mg/kg i.v.) prevented cocaine-induced effects but failed to antagonize the inhibition of firing induced by a low dose of apomorphine (10 micrograms/kg i.v.). This finding rules out the possibility that flunarizine antagonism of cocaine effect might depend on DA autoreceptors blockade by flunarizine. It is suggested that flunarizine, by blocking calcium influx into DA neurons, prevents DA release from dendrites, thereby counteracting the main mechanism by which cocaine inhibits dopaminergic neuronal activity.

The effect of the intracerebroventricular (ICV) administration of omega-conotoxin GVIA on penile erection and yawning induced by oxytocin or by the dopaminergic agonist apomorphine was studied in male rats. The peptide toxin, 1-10 ng given ICV 5 min before oxytocin (30 ng ICV) or apomorphine (80 micrograms/kg SC), but not its carboxymethylated (CM) derivative, prevented the above behavioral responses in a dose-dependent manner. Similarly, omega-conotoxin (5 ng) unilaterally injected in the paraventricular nucleus of the hypothalamus (PVN) prevented penile erection and yawning induced by the microinjection of oxytocin (10 ng) or apomorphine (50 ng) in the PVN. omega-Conotoxin injected in the PVN, but not in the preoptic area, prevented also penile erection and yawning induced by systemic apomorphine (80 micrograms/kg SC). ICV omega-conotoxin was unable to prevent stereotypy induced by apomorphine (500 micrograms/kg SC). The present results provide further evidence that calcium plays a major role in the expression of penile erection and yawning and that apomorphine and oxytocin induce these behavioral responses by mobilizing calcium through omega-conotoxin-sensitive (N-type) calcium channels.

The effect of verapamil, flunarizine, nimodipine, nicardipine, and nifedipine, calcium channel inhibitors, and of indomethacin and aspirin, inhibitors of prostaglandin synthesis, on penile erection and yawning induced by oxytocin was studied in male rats. All calcium channel inhibitors given intraperitoneally (IP) 60 min before the intracerebroventricular (ICV) injection of oxytocin (30 ng) prevented in a dose-dependent manner oxytocin effect. Nimodipine and nicardipine were the most effective being active at doses between 5 and 20 mg/kg, while the others were active at doses higher than 15 mg/kg. Prevention of oxytocin effect was also seen after ICV injection of the above compounds. Unlike calcium channel inhibitors, indomethacin given either IP (10 and 50 mg/kg) or ICV (50 micrograms), or aspirin (100 mg/kg IP) were ineffective. Microinjection of calcium, but not of prostaglandin E2 and prostaglandin F2 alpha in the paraventricular nucleus of the hypothalamus, the brain area most sensitive for the induction of the above behavioral responses by oxytocin, induced a symptomatology similar to that induced by oxytocin. The present results suggest that calcium might be the second messenger which mediates the expression of penile erection and yawning induced by oxytocin.

The effect of the intracerebroventricular (ICV) injection of the oxytocin antagonist d(CH2)5Tyr(Me)-Orn8-vasotocin on the stimulation of copulatory behavior induced by the dopamine (DA) agonist apomorphine was studied in male rats. Apomorphine (80 micrograms/kg SC) given 5 min before mating tests decreased intromission frequency and ejaculation latency in experienced male rats. Such effects were abolished and reversed by pretreatment with 50 and 1000 ng of the oxytocin antagonist given ICV 5 min before apomorphine. The peptide per se markedly increased intromission and ejaculation latency and abolished ejaculation in control rats. The results suggest that brain oxytocin is implicated in the expression of sexual behavior, and apomorphine might improve male copulatory behavior by releasing oxytocin in brain.

The intracerebroventricular administration of ACTH1-24 (3-5 micrograms/rat) produced a behavioural syndrome characterized by recurrent episodes of penile erection and yawning in rats. Hypophysectomy prevented ACTH1-24-induced yawning and penile erection. These results suggest that pituitary has a "trophic" action not only on peripheral target organs but also on structures in brain controlling specific behavioural responses.

A small dose of apomorphine (25 or 50 micrograms/kg, SC) induced repeated episodes of yawning, penile erection, genital grooming and a decrease in locomotor activity in rats. Hypophysectomy almost completely abolished yawning, penile erection and genital abolished yawning, penile erection and genital grooming but failed to modify the hypomotility induced by apomorphine. These results suggest that pituitary hormones are directly or indirectly involved in the apomorphine-induced yawning, penile erection and genital grooming but not in the sedative response to this drug.

Following treatment with dopamine (DA) receptor agonists, such as apomorphine, N-n-propyl-norapomorphine, lisuride and 3-(3-hydroxyphenyl)-N-n-propyl-piperidine (3-PPP) (50, 2.5, 400 and 5000 micrograms/kg, respectively), male rats attain ejaculation with receptive females sooner and after fewer penile intromissions than controls. Since doses of DA agonists needed to produce "premature ejaculation" are within the low dose range needed to stimulate DA autoreceptors, it is suggested that "premature ejaculation" in rats results from inhibition of DA neurotransmission. This hypothesis is supported by the finding that 6 hr after haloperidol (1 mg/kg), rats achieve ejaculation after fewer intromissions than normal.

The effect of ethanol, either administered by gavage or voluntarily ingested, on brain dopamine (DA) metabolism was studied in alcohol-preferring and alcohol non-preferring rats. In alcohol non-preferring rats ethanol administration (2 g/kg) increased 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and reduced DA levels in the caudate nucleus and olfactory tubercle but was ineffective in the medial prefrontal cortex. In alcohol-preferring rats ethanol effect was greater than in non-preferring animals and ethanol influenced DA metabolism also in the medial prefrontal cortex. The effect of voluntary ethanol ingestion was studied in alcohol-preferring rats trained to consume their daily fluid intake within 2 hrs. Voluntary ingestion of ethanol (3.1 +/- 0.7 g/kg in 1 hr) increased DA metabolites and reduced DA levels in the caudate nucleus, olfactory tubercle and medial prefrontal cortex. The results suggest that voluntary ethanol ingestion increases the release of DA from nigro-striatal and meso-limbic DA neurons.

Apomorphine in combination with a peripheral dopamine receptor blocker (domeperidone) was administered to four parkinsonian patients in a double-blind placebo-controlled study. The therapeutic efficacy of apomorphine was not reduced by domperidone, while nausea, drowsiness, sedation, and arterial hypotension were prevented. Combination of domperidone with dopamine agonists may result in more effective treatment of Parkinson's disease.

Male healthy subjects, fasting 12 hours, ingested increasing amounts of a mixture containing a fixed proportion of seven essential amino acids (L-isoleucine 11.5%, L-leucine 18.0%, L-lysine 13.1%, L-methionine 18.0%, L-phenylalanine 18.0%, L-threonine 8.2%, L-valine 13.1%) and lacking tryptophan. The diets produced a rapid fall in plasma tryptophan which was proportional to the total amount of the amino acids ingested. Following the highest dose administered (36.6 g) plasma tryptophan fell to a minimum of about 35% the initial level and remained markedly reduced at 6 hours after treatment. The mechanism of this decrease and its potential clinical relevance are discussed.

The intracerebroventricular (ICV) injection of oxytocin at doses between 5 and 100 ng induced repeated episodes of penile erection and yawning, while at doses between 100 ng and 10 micrograms it induced motor disturbances often culminating in barrel rotation in rats. The intensity of motor disturbances was inversely correlated to the number of yawning and penile erection episodes. Pretreatment with the dopaminergic agonist apomorphine (80 and 240 micrograms/kg SC) failed to modify the incidence of motor disturbance induced by high doses of oxytocin, but markedly reduced the intensity of the symptomatology in a dose-dependent manner. The present results suggest that high doses of oxytocin induce motor disturbances which mask penile erection and yawning, and that brain dopaminergic systems have a protective role against this symptomatology.