Functional and radiological outcomes after bridging therapy versus direct thrombectomy in stroke patients with unknown onset: Bridging therapy versus direct thrombectomy in unknown onset stroke patients with 10-point ASPECTS.

BACKGROUND AND PURPOSE: The aim was to assess functional and radiological outcomes after bridging therapy (intravenous thrombolysis plus mechanical thrombectomy) versus direct mechanical thrombectomy (MT) in unknown onset stroke patients. METHODS: A cohort study was conducted on prospectively collected data from unknown onset stroke patients who received endovascular procedures at ≤6 h from symptom recognition or awakening time. RESULTS: Of the 349 patients with a 10-point Alberta Stroke Program Early Computed Tomography Score (ASPECTS), 248 received bridging and 101 received direct MT. Of the 134 patients with 6-9-point ASPECTS, 123 received bridging and 111 received direct MT. Each patient treated with bridging was propensity score matched with a patient treated with direct MT for age, sex, study period, pre-stroke disability, stroke severity, type of stroke onset, symptom recognition to groin time (or awakening to groin time), ASPECTS and procedure time. In the two matched groups with 10-point ASPECTS (n = 73 vs. n = 73), bridging was associated with higher rates of excellent outcome (46.6% vs. 28.8%; odds ratio 2.302, 95% confidence interval 1.010-5.244) and successful recanalization (83.6% vs. 63%; odds ratio 3.028, 95% confidence interval 1.369-6.693) compared with direct MT; no significant association was found between bridging and direct MT with regard to rate of symptomatic intracerebral hemorrhage (0% vs. 1.4%). In the two matched groups with 6-9-point ASPECTS (n = 45 vs. n = 45), no significant associations were found between bridging and direct MT with regard to rates of excellent functional outcome (44.4% vs. 31.1%), successful recanalization (73.3% vs. 76.5%) and symptomatic intracerebral hemorrhage (0% vs. 0%). CONCLUSIONS: Bridging at ≤ 6 h of symptom recognition or awakening time was associated with better functional and radiological outcomes in unknown onset stroke patients with 10-point ASPECTS.

Thrombolysis and bridging therapy in patients with acute ischaemic stroke and Covid-19.

BACKGROUND AND PURPOSE: Comorbidity of acute ischaemic stroke with Covid-19 is a challenging condition, potentially influencing the decision of whether to administer intravenous thrombolysis (IVT). We aimed to assess the 1-month outcome in ischaemic stroke patients with Covid-19 infection who received IVT alone or before thrombectomy (bridging therapy). METHODS: As a collaboration initiative promoted by the Italian Stroke Organization, all Italian stroke units (n = 190) were contacted and invited to participate in data collection on stroke patients with Covid-19 who received IVT. RESULTS: Seventy-five invited centers agreed to participate. Thirty patients received IVT alone and 17 received bridging therapy between 21 February 2020 and 30 April 2020 in 20 centers (n = 18, Northern Italy; n = 2, Central Italy). At 1 month, 14 (30.4%) patients died and 20 (62.5%) survivors had a modified Rankin Scale (mRS) score of 3 to 5. At 24 to 36 hours, asymptomatic intracerebral hemorrhage (ICH) was reported in eight (17.4%) patients and symptomatic ICH (sICH) in two (4.3%) patients. Causes of death were severe ischaemic stroke (n = 8), a new ischaemic stroke (n = 2), acute respiratory failure (n = 1), acute renal failure (n = 1), acute myocardial infarction (n = 1), and endocarditis (n = 1). In survivors with a 1-month mRS score of 3 to 5, baseline glucose level was higher, whereas endovascular procedure time in cases of bridging therapy was longer. Baseline National Institutes of Health Stroke Scale glucose and creatinine levels were higher in patients who died. CONCLUSIONS: Intravenous thrombolysis for patients with stroke and Covid-19 was not a rare event in the most affected areas by pandemic, and rates of 1-month unfavorable outcomes were high compared to previous data from the pre-Covid-19 literature. However, risk of sICH was not increased.

Stroke unit care in clinical practice: an observational study in the Florence center of the European Registers of Stroke (EROS) Project.

BACKGROUND: Randomized trials and meta-analyses indicate positive effects of stroke unit (SU) care on survival and dependency of patients with stroke. However, data on the advantages of SU in 'real-world' settings are limited. We prospectively assessed, in a large University Hospital, the effect of SU versus other conventional wards (OCW) care on all-cause mortality, death or dependency, death or institutionalization. METHODS: In a prospective observational study in the European Registers of Stroke Project, patients hospitalized for first-in-a-lifetime stroke were evaluated for demographics, risk factors, clinical presentation, resource use, 3-month and 1-year survival, and functional outcome. RESULTS: Overall, 355 patients (54.1% men, mean age 73.4 ± 14.5 years) were registered, 140 (39.4%) admitted to the SU, and 215 (60.6%) to OCW. OCW patients were older, whilst SU patients had more severe strokes according to NIHSS (P for trend = 0.025). SU patients were significantly more often treated by specialists in stroke medicine, stroke nurses, physiotherapists and speech therapists (all P < 0.001), psychologists (P = 0.025), dietitians (P < 0.001), and social workers (P = 0.003). MRI, carotid, and transcranial Doppler were significantly more often performed in SU patients (all P < 0.001). Intravenous fluids (P = 0.003) and intravenous anticoagulation (P < 0.001) were more often prescribed in SU. Controlling for case-mix, SU significantly reduced 1-year mortality (P = 0.020), death or dependency at 3 months (P = 0.006) and 1 year (P = 0.043), and death or institutionalization at 3 months (P = 0.001) and 1 year (P = 0.009). CONCLUSIONS: We confirmed the benefits of SU care in a clinical setting. Further analyses should define the contribution of individual components of care to stroke outcome.

Cross-national interrater agreement on the clinical diagnostic criteria for dementia. WHO-PRA Age-Associated Dementia Working Group, WHO-Program for Research on Aging, Health of Elderly Program.

We assessed the interobserver agreement on the clinical diagnosis of dementia syndrome and dementia subtypes as part of a cross-national project on the prevalence of dementia. Fourteen clinicians from the participating countries (Canada, Chile, Malta, Nigeria, Spain, and the United States) independently assessed the diagnosis of 51 patients whose clinical information was in standard records written in English. We used the DSM-III-R and ICD-10 criteria for dementia syndrome, the NINCDS-ADRDA criteria for Alzheimer's disease (AD), and the ICD-10 criteria for other dementing diseases, and measured interobserver agreement. We found comparable levels of agreement on the diagnosis of dementia using the DSM-III-R (kappa = 0.67) as well as the ICD-10 criteria (kappa = 0.69). Cognitive impairment without dementia was a major source of disagreement (kappa = 0.10). The kappa values were 0.58 for probable AD, 0.12 for possible AD, and rose to 0.72 when the two categories were merged. The interrater reproducibility of the diagnosis of vascular dementia was 0.66 in terms of kappa index; the diagnoses of other dementing disorders as a whole reached a kappa value of 0.40. This study suggests that clinicians from different cultures and medical traditions can use the DSM-III-R and the ICD-10 criteria for dementia effectively and thus reliably identify dementia cases in cross-national research. The interrater agreement on the diagnosis of dementia might be improved if clear-cut guidelines in the definition of cognitive impairment are provided. To improve the reliability of AD diagnosis in epidemiologic studies, we suggest that the NINCDS-ADRDA "probable" and "possible" categories be merged.

Effects of nimodipine on the discriminative stimulus properties of d-amphetamine in rats.

The discriminative stimulus (DS) properties of d-amphetamine (AMP) are thought to be mediated by enhanced release of catecholamines, which may involve neuronal calcium influx through voltage sensitive channels. The present study examined the influence of nimodipine, a calcium channel blocker, on the DS properties of AMP. Rats (N = 8) were trained to discriminate AMP (0.5 mg/kg, IP) from saline in a two-lever, food-reinforced, drug discrimination paradigm. Nimodipine alone (2.0-5.6 mg/kg, IP) did not substitute for AMP. When given in combination with AMP, 2.0 mg/kg nimodipine increased by less than 2-fold the AMP dose necessary to induce AMP-appropriate responses. Higher doses of nimodipine combined with AMP did not increase the magnitude of this effect. Nimodipine enhanced the effects of AMP on response rate. Haloperidol (0.125 mg/kg) increased by approximately 4-fold, whereas diazepam (0.5 or 1.0 mg/kg) and morphine (5.0 mg/kg) increased by approximately 2-fold the AMP dose necessary to induce AMP-appropriate responses. The interaction with AMP was associated with enhanced reduction of response rate in the tests with diazepam and morphine but not haloperidol. These results suggest that nimodipine attenuates the DS properties of AMP, probably in a non-specific way, due to the ability of nimodipine itself to induce a discriminable internal state.

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.

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.

Modulation of food intake by the kappa opioid U-50,488H: evidence for an effect on satiation.

The main goal of the present study was to test the hypothesis that the prophagic effect of the kappa opioid agonist U-50,488H (U50) is primarily due to an effect on satiation. In Experiment 1, the feeding effects of U50 (2.0 and 4.0 mg/kg, i.p.) was tested in animals with ad libitum access to ground food and to three sucrose solutions (1, 4, and 20%). In Experiment 2, a classical "one-bottle" test was utilized to test for the effect of U50 (4.0 mg/kg, i.p.) on the intake of five different sucrose solutions (1, 4, 16, 32, and 40%) over a 30-min period. Finally, in Experiment 3 we evaluated the effect of U50 (2.0, 4.0, and 6.0 mg/kg, i.p.) on extracellular dopamine (DA) concentration in the nucleus accumbens. In Experiment 1, U50 enhanced the intake of ground food but not of sucrose. In Experiment 2, U50 increased the intake of high concentration sucrose solutions whereas it decreased that of low concentration solutions. In Experiment 3, U50 produced a dose-dependent decrease in DA concentrations in the absence but not in the presence of food. The most likely explanation for the present results is that U50 enhances feeding by activating mechanisms that block satiety and satiation. In contrast, we found little evidence for an effect of U50 on palatability.

(-)-Norpseudoephedrine, a metabolite of cathinone with amphetamine-like stimulus properties, enhances the analgesic and rate decreasing effects of morphine, but inhibits its discriminative properties.

Like psychomotor stimulants, a weak amphetamine-like agent, such as phenylpropanolamine, enhances the analgesic effects of morphine (MOR). Thus, it is possible that full psychomotor stimulant potency is not required to increase the analgesic action of opiates. The validity of this assumption is here tested by studying the ability of (-)-norpseudoephedrine (NPE), an enantiomer of phenylpropanolamine and a metabolite of cathinone, to influence both the analgesic effects of MOR and its discriminative stimulus properties. In mice NPE (5.6-10.0-17.0 mg/kg i.p.) did not prolong the latency to lick or to remove paws from a plate warmed at 54 degrees C. However, it significantly potentiated the analgesic effect of 3.2 mg/kg of MOR. These results were replicated in rats by use of the formalin test, which measures the numbers of hind paw flinches produced by injecting 50 microl of formalin into the dorsal surface of the paw. The higher dose of NPE (17 mg/kg) increased the effect of sub-analgesic doses of MOR (0.56 and 1.0 mg/kg). In rats trained to discriminate between 0.5 mg/kg of amphetamine and solvent in a two-lever operant behavior reinforced by water access. NPE induced a dose-dependent increment of drug lever responding from 0% at 1.0 mg/kg to 100% at 32.0 mg/kg. In contrast, NPE did not generalize for the MOR cue up to the dose of 56.0 mg/kg, which produced a substantial reduction of the response rate. However, when given in combination, NPE attenuated the discriminative effects of MOR and potentiated its inhibitory action on the response rate. These results exclude a direct action of NPE on the mu opiate system. In conclusion, NPE preserves amphetamine-like properties and these properties are probably responsible for the interaction of the drug with the analgesic and discriminative effects of MOR. Therefore, this study contradicts the assumption that the analgesic effects of MOR can be enhanced by a sympathomimetic drug that lacks significant psychostimulant actions.

Chronic systemic administration of amphetamine increases food intake to morphine, but not to U50-488H, microinjected into the ventral tegmental area in rats.

Chronic intermittent administration of amphetamine (AMPH) sensitizes rats to the stimulatory effects on feeding produced by systemic injections of either morphine (MORPH) or the kappa-opiate receptor agonist, U50,488H (U50). Both morphine and the putative kappa-receptor endogenous ligand, dynorphin, have been reported to stimulate feeding when administered into the ventral tegmental area (VTA). To evaluate whether the VTA is the site where AMPH produces sensitization to the feeding effects of opiates, rats were given daily IP injections of either saline or AMPH (3 mg/kg). The amount of powdered food ingested during the 5 h following the injections was measured. After 9 days of AMPH or saline administration, twice weekly tests were begun of the effects of either saline, MORPH (1-10 nmol) or U50 (10 pmol to 10 nmol) injected into the VTA; AMPH administration was continued on intervening days. MORPH produced a statistically significant greater increase in food intake in rats chronically treated with AMPH than in saline treated rats. No statistically significant effects were produced by U50. However, when U50 was administered systemically to the same animals, food intake increased, and the effect was significantly greater in the AMPH-pretreated group. Thus the sensitization to the feeding effects of MORPH and U50 produced by chronic AMPH administration appears to involve different systems; the mesolimbic dopamine system appears to mediate sensitization to the effects of the predominately mu-receptor agonist, MORPH, but not of the kappa-receptor agonist, U50.

Enhancement of morphine-induced analgesia after repeated injections of methylenedioxymethamphetamine.

Repeated administration of methylenedioxymethamphetamine (MDMA) to rats results in long-term depletion of serotonin (5-hydroxytryptamine; 5-HT) in several brain regions. Because of the apparent role of 5-HT in morphine-induced antinociception, the present experiment was designed to determine the effects of repeated MDMA injections on morphine-induced analgesia. Rats (n = 48) received 8 s.c. injections (one every 12 h for 4 days) of MDMA (20 mg/kg) or saline (1.0 ml/kg). Two weeks after the last injection, the groups were divided into 4 subgroups that received either saline, or morphine 2.5, 3.55 or 5.0 mg/kg (s.c.). Nociception was assayed before and after saline or morphine administration by the method of tail immersion in warm water (55 degrees C). The day after analgesia testing, the animals were sacrificed, brains and spinal cords removed and 5-HT, norepinephrine (NE) and dopamine (DA) levels in various brain and spinal cord regions were assayed. The analgesic effect of morphine was enhanced in rats that had received repeated MDMA injections. MDMA selectively depleted 5-HT in the cortex, hippocampus, striatum, brainstem and in the cervical portion of spinal cord. However, 5-HT levels were not changed in the thoracic and lumbar segments of the spinal cord. Thus, a functional consequence of repeated MDMA administration in rats was to enhance morphine-induced antinociception in association with reductions in brain and cervical spinal cord 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Posterior spinal artery infarct.

Acute medullary syndrome developed in a patient in whom glue had been inadvertently injected into the right posterior radiculomedullary artery during endovascular occlusion of a spinal dural arteriovenous fistula at T-11. MR imaging 40 days after the procedure showed signal changes and contrast enhancement in the posterior and right lateral column at T10-11. Circumscribed signal changes in the same areas without contrast enhancement were seen 4 months later. MR imaging was able to show this posterior spinal artery infarct.

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.

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.

Effect of nimodipine on drinking behavior measured in the runway: comparison and interaction with (+/-)-amphetamine.

The aim of the present study was to evaluate the ability of the calcium channel blocker (CCE), nimodipine (NIM), to interact with (+/-)-amphetamine (AMPH) in modifying ingestive behavior. Rats performed in a water-reinforced runway paradigm with multiple trials. Water was available in sufficient quantity to produce satiety under control conditions as measured by a decline in response rate over the session. NIM and AMPH, given alone, did not produce significant effects on performance but produced behavioral changes when administered in combination. In particular, the combination of the highest doses (13 mg/kg i.p. NIM plus 0.56 mg/kg i.p. AMPH) initially depressed both running and drinking, whereas in later trials it increased running rate, without producing a parallel increase in water intake. These results suggest that NIM enhances AMPH-produced inhibition of drinking, whereas it first depresses and then enhances the AMPH-mediated runway performance, suggesting the rate dependency of this latter effect.

Khat chewing spread to the Somali community in Rome.

The habit of chewing Khat (Catha edulis) to experience its euphorizing and psychostimulant effects has prevailed for centuries among the inhabitants of the Horn of Africa and the Arabian peninsula. In recent years, air transport has removed the major obstacle to the diffusion of Khat, its perishableness. Khat is now air-freighted to Europe and we were able to buy some in Rome. We report the results of interviews with 20 members of the Somali community in Rome, who had continued their habit of chewing Khat whilst abroad. They asserted that they gathered together whenever possible, but preferably at weekends, to chew moderate quantities of Khat (one bundle, about 400 g). The customary habit of drinking tea or other soft drinks containing methylxantines during Khat sessions was maintained and very few subjects admitted drinking alcohol. In this small study sample, Khat chewing still seems to be a social event, as it is in Somalia.

The alpha 1-blocker dapiprazole inhibits diuresis but not drinking and feeding induced by U-50,488H.

To further explore the interaction between opiates and catecholamines in the control of water balance, we studied the effects of the alpha 1-adrenoceptor antagonist dapiprazole on the modifications in drinking and diuresis produced by U-50,488H (a selective kappa-opiate agonist), morphine, naloxone, and amphetamine in rats. Because animals were maintained in a free-feeding paradigm and water intake is also controlled by feeding (prandial drinking), food intake was also measured. At doses administered (3-6 mg/kg, IP), dapiprazole had no effect on basal food and water intake or on diuresis. Nor did it modify changes in feeding and drinking produced by U-50,488H, morphine, naloxone, and amphetamine. It did, however, antagonize the diuretic effect of both U-50,488H and amphetamine. In addition, suppression of diuresis was obtained by combining doses of dapiprazole and morphine or naloxone that were devoid of antidiuretic effects when administered independently. A further experiment showed that diuresis produced by water load was also prevented by dapiprazole. alpha 1-Adrenoceptors thus appear to play a role in the regulation of water balance in a condition of free access to water, inhibiting diuresis without affecting drinking.

Dapiprazole, a selective alpha-1 adrenoceptor antagonist, inhibits diuresis but not polydipsia produced by amphetamine in rats.

Chronic amphetamine administration has been found to produce diuresis and polydipsia in rats. We have found that dapiprazole acutely suppresses the diuretic, but not the ingestive, effects of amphetamine. To see whether diuresis is the physiological stimulus driving amphetamine-mediated polydipsia, we injected rats daily with d,l-amphetamine and the alpha-1 adrenergic antagonist dapiprazole. Throughout 19 days of treatment, dapiprazole completely prevented the increased urine output produced by amphetamine, but did not affect the development of polydipsia. This finding rules out a renal site of the primary action for amphetamine-mediated polydipsia and proposes water and electrolyte imbalance produced by chronic amphetamine administration as a model of the polydipsia and hyponatremia that develop in some psychotic patients.

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.

Opiatergic modulation of preparatory and consummatory components of feeding and drinking.

We present data here indicating that stimulation of kappa but not mu opiate receptors influences motivational and consummatory aspects of feeding and drinking. To differentiate mu and kappa mechanisms controlling preparatory (appetitive) and consummatory components of ingestive behavior, the effects of morphine (MORPH), compound U50488H (U50) and naloxone (NAL) were studied in rats trained to negotiate a straight runway using food or water as a reinforcer. At doses that increase feeding and drinking in conditions of free access to food and water (i.e., 1-2 mg/kg IP), MORPH affected neither food- nor water-maintained runway performance. Since 1 mg/kg of NAL is also devoid of effects, mu-opiate mechanisms are probably not involved in food- or water-maintained behavior. Pharmacological manipulation of kappa-opiate mechanisms had complex effects. At 5 mg/kg, NAL accelerated satiation, depressing food intake, without affecting running. U50 did not increase food intake, but accelerated running for food, an effect that was antagonized by a high dose of NAL (5 mg/kg). These findings suggest that motivational and consummatory components of food-maintained runway performance are both activated by kappa-opiate mechanisms. NAL also reduced water intake but had minimal influences on running. In contrast, U50 depressed both water intake and runway performance; rather than being antagonized, these effects were slightly enhanced by NAL. The combined antidipsic and diuretic effects of U50 suggest that kappa-opiate mechanisms play a dissipatory role in water balance. However, the similar antidipsic effects of U50 and NAL, and the fact that NAL did not antagonize the antidipsic effects of U50, suggest that U50 may reduce drinking by mechanisms other than kappa-opiate agonism.