Paolo Nencini

Khat consumption: a pharmacological review

The present review deals with the considerable body of evidence gathered in the last ten years on the clinical and experimental pharmacology of Khat. Khat effects are generally agreed to be of amphetamine-like type. In particular, Khat ingestion, like amphetamine ingestion, produces sympathetic activation, anorexia, euphoria, increased intellectual efficiency and alertness. These effects are mainly mediated by phenylalkylamines, such as cathinone and cathine, because the pharmacological actions of these agents and those produced by amphetamine almost overlap. In infra-human species cathinone is an effective positive reinforcer (i.e., it maintains self-administration). However, it would be inappropriate to infer from cathinone and cathine effects assessed in animals a high potential of abuse for Khat in humans; apart from other reasons the bulk volume of Khat leaves, limits the ingestion of high quantities of the active principles. Accordingly, in habitual consumers Khat dependence is probably mild, because craving and tolerance to the sympathomimetic and neuroendocrine effects of Khat are present, but there is no definite abstinence syndrome. Therefore, in our opinion, policies restricting the use of Khat should be adopted with caution, lest they simply change the pattern of drug abuse and increase the spread of more dangerous drugs.

Social isolation selectively reduces hippocampal brain-derived neurotrophic factor without altering plasma corticosterone

It is well known that housing conditions may alter several physiological and behavioral parameters. In this study, we have investigated whether a prolonged period of partial social isolation can modify central brain-derived neurotrophic (BDNF) concentrations. Male Sprague-Dawley rats were singly housed for 8 weeks before hippocampi, prefrontal cortices and striata were collected for BDNF determination. Compared to rats housed two per cage, isolated rats showed a significant reduction on BDNF protein concentrations in the hippocampus while no changes were observed in the other brain regions examined. Moreover, housing condition had no effect on basal plasma corticosterone. On the basis of the proposed etiological participation of reduced central BDNF concentrations in affective disorders, our results would candidate social isolation as a model for the study of antidepressant treatments.

Ambience and Drug Choice: Cocaine- and Heroin-Taking as a Function of Environmental Context in Humans and Rats

BACKGROUND We have recently observed an unforeseen dissociation in the effect of environmental context on heroin versus cocaine self-administration in rats. Rats housed in the self-administration chambers (Residents) took more heroin than rats that were transferred to the self-administration chambers only for the test sessions (Nonresidents). The contrary was found for cocaine. The twofold aim of the present study was to investigate: 1) drug choice as a function of ambience in rats given access to both cocaine and heroin, and 2) ambience of choice for cocaine- versus heroin-taking in human addicts. METHODS Resident and Nonresident rats with double-lumen intrajugular catheters were trained to self-administer cocaine (400 microg/kg/infusion) and heroin (25 microg/kg/infusion) on alternate days and then given the opportunity to choose between the two drugs during seven daily sessions. In the human study, we asked heroin and cocaine abusers where they preferred to take these drugs. RESULTS Approximately 46.7% of Resident rats exhibited a preference for heroin over cocaine; 33.3% preferred cocaine, and 20% expressed no preference. In contrast, only 8.3% of Nonresident rats preferred heroin, whereas 66.7% preferred cocaine, and 25% expressed no preference. In the human study, 73% of co-abusers reported that they used heroin exclusively or mostly at home (22% used it outside the home), whereas only 25% reported using cocaine at home (67% took it outside their homes). CONCLUSIONS Environmental context plays an important role in drug choice in both humans and rats self-administering heroin and cocaine.

Subjective effects of khat chewing in humans.

The subjective effects of Khat (Catha edulis) chewing were studied in 14 male somali, habitual khat users, by means of the Addiction Research Center Inventory (ARCI) questionnaire and of visual analogue scales concerning mood and appetite. Results show that euphoria, improved intellectual efficiency and alertness were associated with khat consumption in 10 subjects. In contrast, the remaining 4 subjects experienced only dysphoria and mild sedation. These latter effects were present in all the subjects in the post-chewing period. In spite of these subjective differences, blood pressure and pulse rate increased in all the volunteers studied. As a whole, these results are consistent with the presumed amphetamine-like action of khat, but suggest also a major role of environmental factors in the expression of these actions.

Khat Chewing from the Pharmacological Point of View: An Update

Khat chewing is deeply rooted in the every day life of people living in the Horn of Africa and in South Arabia, where Catha edulis is endemic. Considered little more than an exotic habit producing just mild pharmacological effects, systematic investigations on its active principles have instead lead to the isolation and chemical characterization of cathinone, a compound structurally related to amphetamine. Three decades of intense experimental and clinical research on khat have depicted a consistently clear picture of its pharmacological and toxicological effects.

The role of opiate mechanisms in the development of tolerance to the anorectic effects of amphetamines

To study the role played by opiate mechanisms in the tolerance to the anorectic effects of amphetamines, the influence of chronic treatment with d,1-amphetamine (AMPH) on the effects of the selective kappa opiate agonist U50488H (U50), of morphine (MORPH) and of diazepam (DZP) on food and water intake was evaluated in rats. Since diuresis is selectively enhanced by kappa agonists, its sensitivity to chronic AMPH was also evaluated. On the first day of AMPH treatment the feeding response to U50 was depressed. On day 9, when tolerance to the anorectic effects of AMPH had developed, this response was enhanced and prolonged. U50-mediated diuresis was not increased in the AMPH group. AMPH however produced diuresis by itself and this effect may be responsible for the increased water intake that developed during chronic treatment. The administration of MORPH (on day 17), but not of DZP (on day 13), produced a similar pattern of response. Interruption of AMPH treatment brought about a slow normalization of response to U50, that appeared to be completed after 17 days. An increase in feeding response to U50 was also obtained after 14 days of cathinone administration, confirming the amphetamine-like properties of this drug. In order to evaluate the possibility that preventing sensitization of opiate mechanisms could also prevent tolerance to anorectic effects of AMPH, we chronically administered MORPH in combination with AMPH, obtaining a further reduction of feeding and an apparent slowing in tolerance development. However, such a reduction was also obtained acutely, although MORPH alone produced feeding stimulation. We suggest that opiates may both activate and inhibit feeding and that AMPH inhibits the activatory branch and works synergically with the inhibitory branch. The prolonged inhibition of the activatory branch causes its compensatory hypertrophy resulting in hypersensitivity to exogenous opiates.

Modulatory effect of environmental context and drug history on heroin-induced psychomotor activity and fos protein expression in the rat brain

The goal of the present study was to investigate the role of environmental context and drug history in modulating the effects of heroin on locomotor activity and Fos protein expression in the neocortex and striatal complex of the rat. It was found that (1) repeated i.p. administrations of a relatively low dose of heroin (1 mg/kg, i.p.) induced psychomotor sensitization only when the treatment was administered in a relatively ‘novel’ environment (ie, a unique test environment distinct from the home cage) but not when the same treatment was administered in the home cage; (2) environmental novelty facilitated heroin-induced Fos expression in the caudate, particularly in its most caudal regions; (3) environmental context also modulated heroin-induced Fos expression in the nucleus accumbens and in the neocortex; (4) repeated exposures to heroin dramatically altered its effects on Fos expression in the caudate and in the neocortex; and (5) Fos protein levels in the postero-dorsal caudate, in the shell of the nucleus accumbens, and in the barrel field cortex predicted most of the variance in heroin-induced activity scores, as shown by multiple regression analysis. The present report demonstrates that environment and drug history powerfully interact in shaping the neurobehavioral response to heroin, as previously shown for amphetamine and cocaine. Thus, a full understanding of the mechanisms responsible for the neurobehavioral adaptations produced by addictive drugs will also require taking into due consideration the environment in which drugs are experienced.

Amphetamine reinstates polydipsia induced by chronic exposure to quinpirole, a dopaminergic D2 agonist, in rats

The hypothesis that the combined activation of D1 and D2 dopaminergic receptors is instrumental in inducing amphetamine (AMPH)-mediated hyperdipsia was tested in rats. The D1 agonist SKF-38393 (SKF) and the D2 agonist quinpirole (QNP) were i.p. injected, alone or in combination, to male rats for 10 days. After 2 days of wash-out, a single dose of AMPH (3 mg/kg) was administered. Intake of water and food and diuresis were daily measured at 2, 5 and 24 h. In two further experiments the higher dose of QNP (0.56 mg/kg) was given with two different doses of the D1 antagonist SCH-23390 (SCH), or, respectively, of the peripheral D2 antagonist domperidone (DMP). In a fourth experiment, the possibility that QNP, given alone or in combination with SKF, produces an AMPH-like internal state was evaluated by using a drug-discrimination paradigm. Results show that chronic administration of QNP produced a significant increase of 24 h water intake that was reinstated by AMPH. This QNP effect was only partially prevented by DMP, suggesting a main central mechanism of action. By itself D1 receptor manipulation did not affect water intake, but influenced QNP polydipsia that, accordingly, was enhanced by the lower dose of SKF (0.3 mg/kg) and inhibited by the lower dose of SCH (0.01 mg/kg). In rats trained to discriminate AMPH from solvent, QNP partially generalized for the AMPH stimulus, an effect that was potentiated by SKF. In conclusion, a D1-modulated sensitization of D2 dopaminergic mechanisms is probably involved in AMPH-induced hyperdipsia.

High levels of morphine-6-glucuronide in street heroin addicts

RationaleIn the body, heroin is rapidly transformed to 6-acetylmorphine (6-AM) and then to morphine, that in turn is mainly metabolized to morphine-3-glucuronide (M3G) and, at lesser extent, to morphine-6-glucuronide (M6G). Unlike M3G, M6G is a potent opioid agonist. Intravenous heroin abusers (IHU) are exposed to a wide array of drugs and contaminants that might affect glucuronidation.ObjectivesWe assessed plasma and urine concentrations of M3G and M6G in four groups of subjects: the first two included long-term IHU either exposed to street heroin (n=8) or receiving a single IV injection of morphine (n=4), while the other two groups included non-IHU patients receiving acute IV (n=8) or chronic oral (n=6) administrations of morphine.MethodsAfter solid phase extraction plasma and urine concentrations of morphine metabolites were determined by HPLC analyses.ResultsM3G accounted for the greater part of morphine glucuronides detected in body fluids of non-IHU patients treated with morphine. This pattern of metabolism remained stable across 15 days of oral administration of incremental doses of morphine. In contrast, the two groups of IHU (street heroin taking or morphine-treated subjects) showed a reduction of blood and urine M3G concentrations in favor of M6G. Consequently, M6G/M3G ratio was significantly higher in the two IHU groups in comparison with the non-IHU groups.ConclusionsChronic exposure to street heroin causes a relative increase in concentrations of the active metabolite, M6G. Since the pattern of M6G action seems closer to heroin than to morphine, the increased synthesis of M6G observed in IHU may prolong the narrow window of heroin effects.

Quinpirole- and amphetamine-induced hyperdipsia: influence of fluid palatability and behavioral cost.

Daily administration of moderate doses of amphetamine or of the dopaminergic D2 agonist quinpirole is associated with the development of excessive, non-regulatory drinking. Here we compared the influence of manipulating fluid palatability and behavioral cost on the development of this drinking augmentation. Experiment 1 was based on the phenomenon of contrafreeloading (CFL): animals work for a resource even though the same resource is freely available. The effects of 15 daily injections of amphetamine (1.0 and 1.7 mg/kg i.p. ) or quinpirole (0.1 and 0.56 mg/kg i.p.) were evaluated in mildly water-deprived rats. For the first 6 days the rats obtained water by lever pressing (FR3) only; over the following 9 days water was also freely available (CFL). Initially, 0.56 mg/kg quinpirole reduced lever pressing for water. A complete recover of responding was then obtained, and was followed by a progressive increment in the amount water obtained by lever pressing during the CFL phase (from 10 to 50%). Amphetamine did not affect percent CFL, but at the highest dose (1.7 mg/kg) reduced total water intake during the last 3 days of treatment. In experiment 2 the rats had free access to two bottles, one of which contained tap water, and the other contained either an ethanol (6%) or a sucrose (5%) solution. After habituation to this regimen, the rats received 10 daily i.p. injections of vehicle, amphetamine (1.0 or 3 mg/kg), or quinpirole (0.1 or 0.56 mg/kg). Quinpirole 0.56 mg/kg enhanced daily fluid intake under both sucrose and ethanol conditions, but selectively reduced ethanol preference. The higher amphetamine dose reduced fluid intake and sucrose preference. In conclusion, chronic exposure to a dopaminergic D2 agonist, but not to amphetamine, produced an increment of drinking that was resistant to manipulation of either palatability or the behavioral cost of the fluid.