Gastrointestinal Helminths in Amietia sp. (Anura: Pyxicephalidae) from the Albertine Rift of Central Africa.

Fourteen Amietia sp. (Pyxicephalidae), from the Albertine Rift of Democratic Republic of the Congo were examined for helminths. Five species of Nematoda were found: Amphibiophilus chabaudi, Aplectana praeputialis, Falcaustra congoensis, Foleyellides duboisi and Orneoascaris chrysanthemoides. Amphibiophilus chabaudi was the most numerous nematode (n = 40) with the highest prevalence (57 %). Five new host records are reported.

A Contribution to the Nematode Fauna of Two Agamid Lizards from Afghanistan.

Information on the recent herpetological and related parasitological collections are very rarely available for Afghanistan. We examined two species of the family Agamidae, Laudakia nuristanica and Paralaudakia caucasia for the presence of the intestinal helminth fauna. Overall, we examined 13 specimens of these lizards and found three species of helminths (Abbreviata achari, Thelandros masaae, T. taylori) in a single specimen of L. nuristanica and four species (A. achari, T. baylisi, T. taylori, P. kasauli) in three specimens of P. caucasia. Here in, we present the first report on the helminth fauna from L. nuristanica, record a new helminth host for P. caucasia and three new country records for the helminth fauna of Afghanistan.

Nalorphine: increased sensitivity of monkeys formerly dependent on morphine.

Three rhesus monkeys Macaca mulatta, formerly dependent on morphine, had increased sensitivity to nalorphine's effect of suppressing operant responding for food, as compared with two monkeys with no history of morphine exposure. Within the dose range employed, nalorphine injections produced emesis, salivation, and hyperirritability in formerly morphine-dependent monkeys but not in controls.

Morphine: conditioned increases in self-administration in rhesus monkeys.

Operant responding in three monkeys was maintained by intravenous presentations of morphine. Nalorphine produced reliable increases in morphine-reinforced responding. With successive daily nalorphine injections there was a decreased latency of self-administration responding for morphine, and substituted saline injections produced conditioned increases in morphine-reinforced responding.

Persistent behavior at high rates maintained by intravenous self-administration of nicotine.

Squirrel monkeys pressed a level at high rates under a second-order schedule of reinforcement in which level pressing produced a brief visual stimulus that was occasionally contiguous with an intravenous injection of nicotine. The rate of lever pressing could be markedly reduced either by substituting saline for nicotine injections or by blocking the effects of nicotine with mecamylamine. The rate of level pressing could be reduced by eliminating the brief visual stimulus. These results show that nicotine can function as an effective reinforcer under a second-order schedule of drug self-administration and that an environmental stimulus associated with nicotine intake can contribute to the maintenance of persistent drug-seeking behavior.

Cocaine receptors on dopamine transporters are related to self-administration of cocaine.

Although cocaine binds to several sites in the brain, the biochemical receptor mechanism or mechanisms associated with its dependence producing properties are unknown. It is shown here that the potencies of cocaine-like drugs in self-administration studies correlate with their potencies in inhibiting [3H]mazindol binding to the dopamine transporters in the rat striatum, but not with their potencies in binding to a large number of other presynaptic and postsynaptic binding sites. Thus, the cocaine receptor related to substance abuse is proposed to be the one associated with dopamine uptake inhibition.

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry implications for drug addiction, sleep and pain.

Adenosine A2A receptors localized in the dorsal striatum are considered as a new target for the development of antiparkinsonian drugs. Co-administration of A2A receptor antagonists has shown a significant improvement of the effects of l-DOPA. The present review emphasizes the possible application of A2A receptor antagonists in pathological conditions other than parkinsonism, including drug addiction, sleep disorders and pain. In addition to the dorsal striatum, the ventral striatum (nucleus accumbens) contains a high density of A2A receptors, which presynaptically and postsynaptically regulate glutamatergic transmission in the cortical glutamatergic projections to the nucleus accumbens. It is currently believed that molecular adaptations of the cortico-accumbens glutamatergic synapses are involved in compulsive drug seeking and relapse. Here we review recent experimental evidence suggesting that A2A antagonists could become new therapeutic agents for drug addiction. Morphological and functional studies have identified lower levels of A2A receptors in brain areas other than the striatum, such as the ventrolateral preoptic area of the hypothalamus, where adenosine plays an important role in sleep regulation. Although initially believed to be mostly dependent on A1 receptors, here we review recent studies that demonstrate that the somnogenic effects of adenosine are largely mediated by hypothalamic A2A receptors. A2A)receptor antagonists could therefore be considered as a possible treatment for narcolepsy and other sleep-related disorders. Finally, nociception is another adenosine-regulated neural function previously thought to mostly involve A1 receptors. Although there is some conflicting literature on the effects of agonists and antagonists, which may partly be due to the lack of selectivity of available drugs, the studies in A2A receptor knockout mice suggest that A2A receptor antagonists might have some therapeutic potential in pain states, in particular where high intensity stimuli are prevalent.

The endocannabinoid system in brain reward processes.

Food, drugs and brain stimulation can serve as strong rewarding stimuli and are all believed to activate common brain circuits that evolved in mammals to favour fitness and survival. For decades, endogenous dopaminergic and opioid systems have been considered the most important systems in mediating brain reward processes. Recent evidence suggests that the endogenous cannabinoid (endocannabinoid) system also has an important role in signalling of rewarding events. First, CB(1) receptors are found in brain areas involved in reward processes, such as the dopaminergic mesolimbic system. Second, activation of CB(1) receptors by plant-derived, synthetic or endogenous CB(1) receptor agonists stimulates dopaminergic neurotransmission, produces rewarding effects and increases rewarding effects of abused drugs and food. Third, pharmacological or genetic blockade of CB(1) receptors prevents activation of dopaminergic neurotransmission by several addictive drugs and reduces rewarding effects of food and these drugs. Fourth, brain levels of the endocannabinoids anandamide and 2-arachidonoylglycerol are altered by activation of reward processes. However, the intrinsic activity of the endocannabinoid system does not appear to play a facilitatory role in brain stimulation reward and some evidence suggests it may even oppose it. The influence of the endocannabinoid system on brain reward processes may depend on the degree of activation of the different brain areas involved and might represent a mechanism for fine-tuning dopaminergic activity. Although involvement of the various components of the endocannabinoid system may differ depending on the type of rewarding event investigated, this system appears to play a major role in modulating reward processes.

Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys.

Many attempts to obtain reliable self-administration behavior by laboratory animals with delta-9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, have been unsuccessful. Because self-administration behavior has been demonstrated in laboratory animals for almost all other psychoactive drugs abused by humans, as well as for nicotine, the psychoactive ingredient in tobacco, these studies would seem to indicate that marijuana has less potential for abuse. Here we show persistent intravenous self-administration behavior by monkeys for doses of THC lower than doses used in previous studies, but comparable to doses in marijuana smoke inhaled by humans.

A new species of Parapharyngodon (Nematoda: Pharyngodonidae) and other helminths in Typhlosaurus lineatus (Squamata: Scincidae), from southern Africa.

Parapharyngodon baueri n. sp. (Nematoda: Pharyngodonidae) from the large intestine of the legless skink, Typhlosaurus lineatus, is described and illustrated. Parapharyngodon baueri is the 42nd species assigned to the genus and differs from other species in the genus by possessing four pairs of caudal papillae, no cloacal lip adornment, and a sharply pointed spicule of 79-98 microm. The cestode, Oochoristica truncata, the nematode, Thubunaea fitzsimonsi, third-stage nematode larvae and acanthocephalan cystacanths were also present.

Helminths in Mesaspis monticola (Squamata: Anguidae) from Costa Rica, with the description of a new species of Entomelas (Nematoda: Rhabdiasidae) and a new species of Skrjabinodon (Nematoda: Pharyngodonidae).

Entomelas duellmani n. sp. (Rhabditida: Rhabdiasidae) from the lungs and Skrjabinodon cortagoensis n. sp. (Oxyurida: Pharyngodonidae) from the intestines of Mesaspis monticola (Sauria: Anguidae) are described and illustrated. E. duellmani is the sixth species assigned to the genus and is the third species described from the Western Hemisphere. It is easily separated from other neotropical species in the genus by pre-equatorial position of its vulva. Skrjabinodon cartagoensis is the 24th species assigned to the genus and differs from other neotropical species in the genus by female tail morphology.

Genetic approaches to the analysis of addiction processes.

Recent studies have shown that large genetic differences exist in the extent to which animals will work to obtain drugs abused by humans. These findings suggest that there may be human populations with elevated risk for developing drug addictions. Frank George and Steven Goldberg describe the behavioral genetic and self-administration methods used in these studies of addiction processes, review the findings obtained in genetic studies of drug addiction, and present hypotheses that can be explored in the attempt to better understand and prevent drug addiction.

The use of pharmacogenetic techniques in drug abuse research.

Pharmacogenetics, the study of genetic factors underlying individual differences in response to drugs, has proven useful for demonstrating that there are large genetic differences in response to a number of abused drugs. Pharmacogenetics also provides a number of useful tools for studying mechanisms underlying the effects of drugs. This review discusses pharmacogenetic techniques with potential utility for drug abuse research and provides examples of their use in studies of the effects of acute and chronic nicotine, cocaine and opiate administration. The importance of using genetically standardized animal models in behavioral and pharmacological research is also discussed.

Cannabinoid abuse and addiction: Clinical and preclinical findings.

Cannabinoid abuse disorders represent a widespread public health issue, but there are no approved medications for their treatment. This review describes efforts to understand the mechanisms of cannabinoid abuse and its adverse effects, to identify molecular targets for pharmacotherapy, and to evaluate potential treatments in human volunteers and animal models of cannabinoid reward, withdrawal, and relapse.

Intravenous self-administration studies with l-deprenyl (selegiline) in monkeys.

l-Deprenyl and its stereoisomer d-deprenyl did not maintain intravenous self-administration behavior in rhesus monkeys. In contrast, l-methamphetamine, the major metabolite of l-deprenyl, as well as the baseline drug, cocaine, maintained high rates of intravenous self-administration behavior. Treatment with l-deprenyl doses up to 1.0 mg/kg before self-administration sessions failed to alter self-administration of either cocaine or l-methamphetamine. Thus l-deprenyl did not appear to have cocaine- or methamphetamine-like reinforcing properties in monkeys and was ineffective in altering established patterns of psychomotor-stimulant self-administration behavior. These results support clinical findings that despite long-term use of l-deprenyl for the treatment of Parkinson's disease by large numbers of patients, no instances of abuse have been documented. l-Deprenyl has recently been suggested as a potential medication for the treatment of various types of drug abuse, including cocaine abuse, but its failure to produce selective effects in decreasing cocaine or methamphetamine self-administration behavior in the present experiments makes such an application seem unlikely.

Exposure to delta-9-tetrahydrocannabinol (THC) increases subsequent heroin taking but not heroin's reinforcing efficacy: a self-administration study in rats.

One concern about the widespread use of cannabis is that exposure to its active ingredient, delta-9-tetrahydrocannabinol (THC), might increase future reinforcing effects of other abused drugs such as heroin. In this study, we investigated the effects of pre-exposure to THC on subsequent intravenous self-administration of heroin by Sprague-Dawley rats. In one group of rats, we studied (1) acquisition of heroin self-administration behavior using a continuous-reinforcement (fixed-ratio (FR) 1) schedule, (2) heroin dose-response relationships using an FR1/variable-dose schedule, and (3) reinforcing efficacy of heroin using a progressive-ratio schedule. The number of rats pre-exposed to THC that subsequently learned to self-administer 50 microg/kg injections of heroin within 10 daily sessions did not differ from vehicle-pretreated controls. In contrast, rats pre-exposed to THC subsequently self-administered significantly more heroin injections per session and showed significantly shorter post-injection pauses over a range of heroin doses (12.5-100 microg/kg/injection) using the variable-dose schedule. Interestingly, the maximum effort rats would exert to receive an injection of the different doses of heroin under the progressive-ratio schedule was not altered by THC pre-exposure. In a second group of rats, we varied the 'price' of heroin (responses required/dose), by manipulating FR response requirements at different doses of heroin across sessions, to calculate demand and response output curves. Again, consumption was significantly higher in the THC-treated rats at the lowest prices of heroin (FR1/100 microg/kg and FR1/50 microg/kg) but there were no differences in the reinforcing efficacy of heroin between THC- and vehicle-pretreated rats. Altogether, these results demonstrate that pre-exposure to THC alters some pharmacological effects of heroin that determine frequency of heroin taking, but offer no support for the hypothesis that pre-exposure to THC alters heroin's efficacy as a reinforcer.

Effects of H1-receptor antagonists on responding punished by histamine injection or electric shock presentation in squirrel monkeys.

Squirrel monkeys were trained to press a key under a two-component schedule of food presentation. In the presence of either green or red stimulus lights, the 30th response produced a food pellet (fixed-ratio schedule). During the red stimulus lights (punishment component), the first response of each fixed ratio produced either an IV injection of histamine (100.0 micrograms/kg/inj) or a brief electric shock (3.0 mA). Responding was selectively suppressed in either punishment component. Presession IM administration of chlorpheniramine (0.1 and 0.3 mg/kg), diphenhydramine (1.0 and 3.0 mg/kg), or pyrilamine (0.1 and 0.3 mg/kg) increased rates of responding punished by histamine but not those punished by electric shock. Presession administration of promethazine (0.1-3.0 mg/kg) or tripelennamine (0.1 and 0.3 mg/kg) also increased rates of responding punished by histamine in all subjects and response rates punished by electric shock in one of three subjects. Chlordiazepoxide (3.0-56.0 mg/kg) increased rates of responding punished by either histamine or electric shock. These results suggest that the punishing effects of histamine injection are mediated by H1 receptors and that H1-receptor antagonists increase rates of responding suppressed by punishment only under limited conditions including those in which histamine is the punishing stimulus.

Monoamine uptake inhibitors alter cocaine pharmacokinetics.

The time course of change in plasma levels of cocaine and its major metabolite benzoylecgonine following 3 mg/kg IV cocaine and the pharmacokinetic interaction between cocaine and several monoamine uptake inhibitors were investigated in conscious rats implanted with arterial and venous cannulae. The IV bolus administration of 3 mg/kg cocaine resulted in plasma levels of 1276 +/- 53 ng/ml cocaine at 0.5 min following its injection and the levels then rapidly declined to 768 +/- 110 ng/ml by 2 min. Thereafter, the decline of plasma cocaine levels was relatively slow. Plasma benzoylecgonine levels were similar at 0.5 and 2 min following cocaine injection but increased gradually over the next 25 min. Pretreatment with the norepinephrine-selective uptake inhibitors desipramine and nisoxetine, the serotonin-selective uptake inhibitor fluoxetine or the dopamine-selective uptake inhibitor GBR 12909 all enhanced plasma levels of cocaine after a 3 mg/kg IV bolus injection at 0.5, but not at 5 min after injection. The enhancement of plasma cocaine levels by GBR 12909 was of greater magnitude than that produced by desipramine, nisoxetine or fluoxetine. These agents, with the exception of the high dose (10 mg/kg) of GBR 12909, did not significantly alter plasma levels of benzoylecgonine measured at either 0.5 or 5 min following cocaine injection. These results indicate that monoamine uptake inhibitors can alter or interfere with the pharmacokinetics of cocaine and that this interaction is not due to a change in the biotransformation of cocaine. It is suggested that the central monoamine uptake sites serving as rapid distribution sites for cocaine may play a role in this pharmacokinetic interaction.

Dopaminergic involvement in the discriminative-stimulus effects of methamphetamine in rats.

RATIONALE: Dopamine plays a major role in the behavioral effects of methamphetamine. OBJECTIVE: In the present experiments, the effects of different dopaminergic agonists, antagonists, and uptake inhibitors were evaluated in rats discriminating methamphetamine from saline. METHODS: In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine, i.p., from saline under a fixed-ratio schedule of food delivery, the ability of various dopaminergic agonists and uptake inhibitors to substitute for methamphetamine was evaluated. Subsequently, the ability of various dopaminergic antagonists to block the discriminative-stimulus effects of the training dose of methamphetamine was tested. RESULTS: The dopamine-uptake inhibitors cocaine (10.0 mg/kg), nomifensine (3.0 mg/kg), GBR-12909 (18.0 mg/kg), and bupropion (30.0 mg/kg) fully substituted for the 1.0 mg/kg training dose of methamphetamine. Chloro-APB (SKF-82958), a full agonist at D1 dopamine receptors, produced about 85% methamphetamine-appropriate responding, but the dose required (0.18 mg/kg) markedly decreased rates of responding. Chloro-PB (SKF-81297), another agonist at D1 receptors with a lower intrinsic activity than Chloro-APB, produced only partial generalization (maximum about 55%) at a dose of 1.0 mg/kg. Full substitution for the training dose of methamphetamine was observed with 0.03 mg/kg of the D2 agonist NPA and 0.56 mg/kg of the D3/D2 agonist 7-OH-DPAT. Both NPA and 7-OH-DPAT markedly decreased rates of responding at these doses. The D1 antagonist SCH-23390 (0.056 mg/kg), the D2 antagonist spiperone (0.18 mg/kg), and the mixed D1, D2 antagonist cis-flupenthixol (0.56 mg/kg) all completely blocked the discriminative-stimulus actions of the training dose of methamphetamine. CONCLUSIONS: The present findings in rats support previous research findings in other species indicating a major role of dopamine in the discriminative-stimulus effects of methamphetamine. These findings further indicate involvement of dopamine uptake sites as well as D1 and D2 receptors.

Noradrenergic modulation of the discriminative-stimulus effects of methamphetamine in rats.

RATIONALE: Neurochemical and clinical studies indicate involvement of noradrenergic (NE) neurotransmitter system in the actions of methamphetamine. OBJECTIVE: The present study investigated NE involvement in the discriminative-stimulus effects of methamphetamine. METHODS: In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine, IP, from saline under a fixed-ratio schedule of food presentation, effects of various NE agonists, antagonists and uptake inhibitors were tested. RESULTS: Desipramine (3.0-18.0 mg/kg) and nisoxetine (5.6-30.0 mg/kg), two selective NE-uptake inhibitors, did not significantly generalize to methamphetamine when administered alone, but 5.6 mg/kg desipramine and 10.0 mg/kg nisoxetine significantly shifted the methamphetamine dose-response curve to the left. The beta NE agonist, isoproterenol (0.56-3.0 mg/kg), and antagonist, propranolol (1.0-18.0 mg/kg), neither generalized to methamphetamine when given alone nor altered the discriminative-stimulus effects of methamphetamine when administered in combination. The alpha- NE agonist methoxamine (1.0-5.6 mg/kg) failed to generalize to the methamphetamine training stimulus. When given in combination with methamphetamine, the alpha-1 NE antagonist, prazosin (1.0 mg/kg), shifted the methamphetamine dose-response curve somewhat to the right and partially blocked the discriminative-stimulus effects of the 1.0 mg/kg training dose of methamphetamine, but these changes were not significant or dose-related, with further increases in prazosin dose (1.8-10.0 mg/kg) either producing similar or smaller changes. The alpha-2 NE agonist, clonidine, partially generalized to methamphetamine at doses of 0.1-0.18 mg/kg and increased drug-appropriate responding at lower doses of methamphetamine, but it partially blocked the discriminative-stimulus effects of higher 0.56-1.0 mg/kg doses of methamphetamine over the same dose range. The alpha-2 NE antagonist, yohimbine, also partially generalized to methamphetamine and blocked the discriminative-stimulus effects of the 1.0 mg/kg training dose of methamphetamine at doses of 5.6-10.0 mg/kg. A lower 3.0 mg/kg dose of yohimbine increased methamphetamine-appropriate responding when given together with low 0.1-0.3 mg/kg doses of methamphetamine. CONCLUSIONS: The present data suggest that the NE system plays a modulatory role in the discriminative-stimulus effects of methamphetamine. These effects appear to be mediated through NE uptake sites and alpha-2 receptors, with limited involvement of alpha- receptors and beta receptors.