Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury.

Studies in the rat have pointed to a role for intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of acute tubular necrosis. These studies used antibodies, which may have nonspecific effects. We report that renal ICAM-1 mRNA levels and systemic levels of the cytokines IL-1 and TNF-alpha increase 1 h after ischemia/ reperfusion in the mouse. We sought direct proof for a critical role for ICAM-1 in the pathophysiology of ischemic renal failure using mutant mice genetically deficient in ICAM-1. ICAM-1 is undetectable in mutant mice in contrast with normal mice, in which ICAM-1 is prominent in the endothelium of the vasa recta. Mutant mice are protected from acute renal ischemic injury as judged by serum creatinine, renal histology, and animal survival . Renal leukocyte infiltration, quantitated morphologically and by measuring tissue myeloperoxidase, was markedly less in ICAM-1-deficient than control mice. To evaluate whether prevention of neutrophil infiltration could be responsible for the protection observed in the mutant mice, we treated normal mice with antineutrophil serum to reduce absolute neutrophil counts to < 100 cells/mm3. These neutrophil-depleted animals were protected against ischemic renal failure. Anti-1CAm-1 antibody protected normal mice against renal ischemic injury but did not provide additional protection to neutrophil-depleted animals. Thus, ICAM-1 is a key mediator of ischemic acute renal failure likely acting via potentiation of neutrophilendothelial interactions.

Use of the silver nucleolar organizer region (AgNOR) technique in the differential diagnosis of central nervous system neoplasia.

Because the distinction between gliosis and low-grade astrocytoma may prove difficult by routine light microscopy, we evaluated the silver nucleolar organizer region (AgNOR) technique in making this distinction. The AgNOR impregnation was performed on formalin-fixed, paraffin-embedded tissue from 49 central nervous system (CNS) biopsies: eight normal brain, 14 gliosis, 14 grade 2 astrocytoma (Daumas-Duport scale), two grade 4 astrocytoma, nine medulloblastoma, one metastatic carcinoma, and one choroid plexus papilloma. Quantitative and qualitative differences were found between gliosis and low-grade astrocytomas. In gliosis, AgNOR counts averaged 1.18 +/- 0.11 (SD) AgNOR/nucleus, while in low-grade astrocytomas AgNOR counts averaged 2.22 +/- 0.39 (p less than 0.001). Compound AgNOR were frequent in 9/14 grade 2 astrocytomas and in both grade 4 astrocytomas, whereas compound AgNOR were extremely rare in cases of gliosis. Quantitative and qualitative differences were also found between normal cerebellar internal granular cells and medulloblastoma cells. Cerebellar granular cells averaged 0.90 +/- 0.10 AgNOR/nucleus whereas medulloblastoma cells had an average of 4.52 +/- 0.95 (p less than 0.001). Compound AgNOR were seen in all medulloblastomas but not in internal granular cells. These findings suggest that the AgNOR technique may be a useful adjunct in the diagnosis of CNS neoplasia.

De novo collapsing glomerulopathy in renal allografts.

BACKGROUND: Collapsing glomerulopathy is a recently described form of glomerular injury characterized by capillary collapse and visceral epithelial hypercellularity associated with nephrotic range proteinuria and a rapid, progressive decline in renal function. The lesion has rarely been described in allografts. METHODS: We reviewed 892 allograft biopsies from a population of 1079 recipients who received renal transplants between 1978 and 1996. RESULTS: Five cases of de novo collapsing glomerulopathy were identified (0.6% of biopsies; 3.2% since 1993). None occurred before 1993. The patients were 31 to 66 years of age and they presented 6 to 25 months after transplantation. The 24-hr urinary protein ranged from 1.8 to 11.8 g. All patients and donors were negative for the human immunodeficiency virus and had no risk factors for human immunodeficiency virus infection. Diffuse or focal, global or segmental collapse of glomerular capillaries, swelling and hypercellularity of the visceral epithelium, hyaline arteriolosclerosis, and interstitial fibrosis were characteristic histologic features. Two cases had concomitant glomerular immune complex deposits. Progressive decline in allograft function occurred within 2-24 months after diagnosis, culminating in return to dialysis in all patients. CONCLUSION: Collapsing glomerulopathy can arise in renal allografts as a de novo disease. Although its pathogenesis remains to be clarified, it is important to distinguish this lesion in allografts as it can be associated with rapidly progressive graft failure.

Granulomatous tubulointerstitial nephritis in the renal allograft.

Granulomatous tubulointerstitial nephritis has rarely been described in renal allografts. Of 1,574 renal allograft tissue specimens obtained from 514 patients in the period 1993 to 1998, we report three cases (0.6%) with interstitial nephritis containing multiple noncaseating granulomas. Biopsy specimen 1 was obtained from a 44-year-old woman with a 6-day history of systemic Candida albicans infection and showed multiple granulomas containing budding yeasts. Biopsy specimen 2 was from a 33-year-old man who presented with miliary spread of Mycobacterium tuberculosis 12 days before the allograft biopsy. Biopsy specimen 3 was from a 23-year-old woman who presented with Escherichia coli urinary infection and bacteremia that was treated with antibiotics for 10 days before the biopsy. Granulomatous inflammation in reponse to infectious agents or drugs in immunosuppressed kidney transplant recipients can rarely give rise to allograft interstitial nephritis that is distinct from acute rejection. To our knowledge, there are no prior reports of granulomatous tubulointerstitial nephritis associated with C albicans and E coli infection or antibiotic therapy in human renal allografts.

Etiologies and outcome of acute renal insufficiency in older adults: a renal biopsy study of 259 cases.

Acute renal insufficiency is a common problem, yet one that is frequently reversible with proper diagnosis and treatment. Although it has been argued that a renal biopsy is not needed for diagnosis in most cases of acute renal failure in the elderly, other studies have shown frequent disagreements between clinical and renal biopsy diagnoses in such cases. To investigate the causes of acute renal insufficiency in patients aged at least 60 years who underwent a renal biopsy and possible correlations between biopsy findings and renal survival, we first identified all native renal biopsy specimens from patients aged 60 years or older processed at The University of Chicago Medical Center (Chicago, IL) from 1991 through 1998 and reviewed the clinical records to determine the indication for the biopsy. We then reviewed again the records of those patients who underwent biopsy because of acute renal insufficiency, recorded the primary renal biopsy diagnosis in each of these cases, and obtained follow-up information for patients who underwent biopsy before July 1996. During the study period, 1,065 of 4,264 biopsy specimens (25.0%) received were obtained from patients aged 60 years or older, and acute renal insufficiency was the indication for biopsy in 259 of these patients (24.3%). The most frequent primary diagnoses on these latter biopsy specimens were pauci-immune crescentic glomerulonephritis (GN) with or without arteritis, 31.2% of biopsy specimens; acute interstitial nephritis, 18.6%; acute tubular necrosis (ATN) with nephrotic syndrome, 7.5%; atheroemboli, 7.1%; ATN alone, 6.7%; light chain cast nephropathy (LCCN), 5.9%; postinfectious GN, 5.5%; anti-glomerular basement membrane antibody nephritis, 4.0%; and immunoglobulin A (IgA) nephropathy and/or Henoch-Schönlein nephritis, 3.6%. Eight biopsy specimens (3.2%) showed only benign nephrosclerosis without an apparent cause of acute renal insufficiency, and another six specimens were inadequate. The renal biopsy diagnosis was in agreement with the prebiopsy clinical diagnosis (or differential diagnosis) in 107 of the 161 cases (67%) in which such information was provided. The distribution of diagnoses was similar in patients in the age groups of 60 to 69, 70 to 79, and 80 years or older, although younger age correlated significantly with improved renal and patient survival. The relative risk for progression to end-stage renal disease (ESRD) also increased according to diagnostic categories: LCCN (greatest risk) > GN other than pauci-immune > atheroemboli congruent with pauci-immune crescentic GN > tubulointerstitial diseases other than LCCN (the latter category including ATN with nephrotic syndrome). Development of ESRD correlated significantly with decreased patient survival. In summary, renal biopsy in patients aged 60 years or older with acute renal insufficiency uncovered the cause in greater than 90% of the cases and provided clinically useful information with respect to expectation for renal survival and potential treatment options.

ANCA-associated crescentic glomerulonephritis with mesangial IgA deposits.

Antineutrophil cytoplasmic autoantibodies (ANCA) are commonly associated with a necrotizing and crescentic glomerulonephritis (GN) that is pauci-immune, with few or no glomerular immune complex deposits detectable by immunofluorescence (IF) or electron microscopy (EM). Immunoglobulin A (IgA) nephropathy may also be manifest as a crescentic GN, but it is characterized by mesangial immune complex deposits containing IgA and is rarely associated with myeloperoxidase (MPO)- or proteinase 3 (PR3)-specific ANCA when an enzyme immunoassay is used to detect these antibodies. This report describes six patients with severe crescentic GN with mesangial IgA deposits by IF and mesangial electron-dense deposits by EM in patients with positive ANCA serological test results (four patients, anti-PR3; one patient, anti-MPO; one patient, anti-PR3 and anti-MPO). Patients presented with acute or progressive renal insufficiency, hematuria, proteinuria (nephrotic range in two patients), and hypertension. Three patients had evidence of systemic vasculitis: two patients at initial presentation and one patient later in the clinical course. Renal biopsy specimens showed crescents in greater than 50% of glomeruli in all cases, but only mild, focal and segmental mesangial and endocapillary hypercellularity, more typical of ANCA-associated crescentic GN than of crescentic IgA nephropathy without associated ANCA. Semiquantitative analysis of mesangial and endocapillary cellularity performed on renal biopsy slides from these six patients and from eight ANCA-negative patients with IgA nephropathy and crescents in greater than 50% of glomeruli showed significantly greater hypercellularity in the ANCA-negative cases. Three of five ANCA-positive patients for whom follow-up clinical data were available showed improved renal function after treatment with cyclophosphamide and corticosteroids and have not developed end-stage renal disease 17, 20, and 25 months postbiopsy. The remaining two patients were dialysis dependent at the time of biopsy and have remained so despite treatment with cyclophosphamide and corticosteroids. The findings suggest an overlap syndrome of ANCA-associated crescentic GN and IgA nephropathy that resembles the former both histologically and in its potential to respond to aggressive therapy if detected relatively early in its course.

Smooth muscle-specific actin levels in the urine of renal transplant recipients: correlation with cyclosporine or tacrolimus nephrotoxicity.

Cyclosporine A (CSA) and tacrolimus (FK506) are powerful immunosuppressive agents that have proven useful for antirejection therapy in patients with solid organ transplants, including kidney. However, both drugs are nephrotoxic, each producing similar histological patterns of injury to renal tubules and preglomerular arterioles, and this toxicity is a major cause of renal allograft dysfunction. A renal transplant biopsy presently represents the most reliable means of diagnosing nephrotoxicity caused by CSA or tacrolimus and distinguishing it from acute rejection. Because CSA and tacrolimus nephrotoxicity often involve arteriolar smooth muscle, whereas vascular smooth muscle is rarely involved in acute rejection, we investigated if the appearance of a smooth muscle-specific isoform of alpha-actin (SMA) in the urine of renal transplant recipients about to undergo a biopsy for graft dysfunction correlated with biopsy evidence of CSA or tacrolimus toxicity. Eighty-nine urine samples from 61 patients, plus 6 samples from healthy control subjects, were analyzed in a blinded manner by enzyme-linked immunosorbent assay using a specific anti-SMA monoclonal antibody. For the patient samples, the results of these assays were then correlated with the biopsy findings. Those 40 cases in which the biopsy showed evidence of CSA or tacrolimus nephrotoxicity had a significantly (P < 0.01) greater SMA level in the corresponding urine samples (0.089 +/- 0.126 microgram/mL; mean +/- SD) than the 49 cases without toxicity (0.018 +/- 0.027 microgram/mL) or 6 control subjects (0.003 +/- 0.007 microgram/mL), although there was considerable overlap of SMA values among these groups. The greatest SMA levels were seen in patients with CSA or tacrolimus nephrotoxicity that was likely to be relatively acute, namely those with thrombotic microangiopathy and those without previous biopsy evidence of toxicity. SMA levels correlated significantly with the estimated severity of arteriolopathy on biopsy. In patients with tubular but not arteriolar lesions of CSA or tacrolimus toxicity, the mean SMA level was not significantly greater than that in patients without toxicity. Urine SMA levels in patients with a biopsy specimen showing acute rejection were not significantly different from those in patients without rejection, and there was no correlation between urine SMA level and severity of rejection. Whereas the degree of overlap of SMA levels in patients with and without nephrotoxicity was far too great to consider this assay as a potential alternative to renal transplant biopsy for the diagnosis of nephrotoxicity, the assay may have potential as a marker for active arteriolar injury in renal transplant recipients and other patients receiving CSA or tacrolimus therapy.

The clinical and pathologic implications of plasmacytic infiltrates in percutaneous renal allograft biopsies.

Plasmacytic infiltrates in renal allograft biopsies are uncommon and morphologically distinctive lesions that may represent variants of acute rejection. This study sought significant clinical and pathologic determinants that might have influenced development of these lesions and assessed their prognostic significance. Renal allograft biopsies (n = 19), from 19 patients, with tubulointerstitial inflammatory infiltrates containing abundant plasma cells, composing 32 +/- 8% of the infiltrating mononuclear cells, were classified using Banff '97 criteria. Clonality of the infiltrates was determined by immunoperoxidase staining for kappa and lambda light chains and polymerase chain reaction for immunoglobulin heavy-chain gene rearrangements, using V(H) gene framework 3 and JH consensus primers. In situ hybridization for Epstein-Barr virus encoded RNA (EBER) was performed in 17 cases. The clinical features, histology, and outcome of these cases were compared with kidney allograft biopsies (n = 17) matched for time posttransplantation and type of rejection by Banff '97 criteria, with few plasma cells (7 +/- 5%). Sixteen of 19 biopsies (84%) with plasmacytic infiltrates had EBER-negative (in 14 cases tested) polyclonal plasma cell infiltrates that were classifiable as acute rejection (types 1A [4], 1B [10], and 2A [2]). These biopsies were obtained between 10 and 112 months posttransplantation. Graft loss from acute and/or chronic rejection was 50% at 1 year and 63% at 3 years, and the median time to graft failure was 4.5 months after biopsy. There was no significant difference in overall survival or time to graft failure compared with the controls. Three of 19 biopsies (16%) had EBER-negative polyclonal plasmacytic hyperplasia, mixed monoclonal and polyclonal polymorphous B cell hyperplasia, and monoclonal plasmacytoma-like posttransplantation lymphoproliferative disease (PTLD) and were obtained at 17 months, 12 weeks, and 7 years after transplantation, respectively. Graft nephrectomies were performed at 1, 19, and 5 months after biopsy, respectively. Plasmacytic infiltrates in renal allografts comprise a spectrum of lesions from acute rejection to PTLD, with a generally poor prognosis for long-term graft survival.

The diagnostic value of silver nucleolar organizer region assessment in breast cytology.

Benign and malignant breast lesions in cytologic preparations can be difficult to distinguish. The authors applied the silver nucleolar organizer region (AgNOR) technique to cytologic preparations obtained from surgical specimens to evaluate its diagnostic usefulness in making this distinction. Sixty-two benign and 36 malignant lesions were examined. AgNORs were counted and evaluated using a subjective scoring technique to examine AgNOR size, shape, and clustering. The benign lesions had a mean count of 4.44 AgNORs/nucleus (95% CI, 2.4-6.5) and the malignant cases, 9.52 AgNORs/nucleus (95% confidence interval, 7.4-11.7; P < .0005). The median score for benign cases was 7 and for malignant cases, 13 (P < .0001). With a few exceptions, cases with high counts had high scores. The diagnostic accuracy of combined counting and pattern assessment was 90%. The likelihood ratio for correct diagnosis using AgNOR counting was 14:1 and for AgNOR scoring, 13:1.

Discriminative stimulus properties of CGS 10746B: similarity to dopamine D1 receptor antagonists.

CGS 10746B is an imidazole-derivative related to the atypical antipsychotic clozapine which produces a decrease in dopamine release without altering dopamine metabolism or occupying D2 receptors. Rats were trained on an appetitively-motivated, two-choice, operant task to discriminate 20.0 mg/kg CGS 10746B from its vehicle. CGS 10746B was highly discriminable, producing rapid acquisition of the discrimination, and its effects were dose-responsive allowing generation of an ED50 value of 6.16 mg/kg. Substitution tests were conducted with other typical and atypical antipsychotic compounds: haloperidol, chlorpromazine, clozapine and SCH 23390. Additional tests examined generalization from the CGS 10746B stimulus properties to the calcium channel blocker isradipine, as well as to the anticholinergics atropine, scopolamine and methylscopolamine, as well as to the serotonergic agonist DOI. Clozapine and SCH 23390 were the only substances to substitute for the CGS 10746B stimulus cue. Results are discussed in terms of potential D1 receptor selectivity of CGS 10746B.

Conditioned place preference produced by the psychostimulant cathinone.

Previous work has indicated that the psychostimulant cathinone produces a location preference in the conditioned place preference task. The present study expanded upon this earlier work by examining the dose-response nature of cathinone-induced conditioned place preference, as well as testing its effect upon spontaneous locomotor activity. At doses ranging from 0.2 to 1.6 mg/kg, cathinone produced a conditioned place preference at all but the lowest dose, and the highest dose but not the lowest dose increased locomotor activity. Results are discussed in terms of dopaminergic mediation of conditioned place preference and the relationship between conditioned place preference and locomotion being subserved by the same neuronal system.

Genetic selection for nicotine activity in mice correlates with conditioned place preference.

Genetically heterogenous stock (HS) mice are being used to develop lines which have differential locomotor response to subcutaneously administered (0.75 mg/kg) nicotine. These groups of nicotine-depressed, nicotine-activated or randomly bred control mice were tested as to conditioned place preference using the same dose of nicotine employed to determine their locomotor performance in activity tests. Results indicate that the nicotine-activated mice showed a significantly greater preference to nicotine when compared to the nicotine-depressed mice; this effect was seen in the first generation and continued in the more recently tested third generation. Evidence is offered to support the hypothesis that it is the stimulatory effects of drugs (of abuse) that can be directly correlatable with the strength of their reinforcing effect upon behavior.

Conditioned place preference/aversion to fenfluramine in fawn hooded and sprague-Dawley rats.

The Fawn Hooded (FH) rat strain possesses a genetic platelet storage pool deficiency which leads to an impaired capacity for platelets to store and release serotonin. While the relationship between this deficit and possible alterations in brain serotonergic levels or function remains unclear, numerous behavioral studies have indicated that FH rats exhibit differential responses to serotonergic agonists and antagonist relative to other strains. The current study used the conditioned place preference paradigm to examine the ability of fenfluramine to produce a conditioned place preference (CPP) or aversion (CPA) in FH and Sprague-Dawley (SD) rats. Results indicated that fenfluramine failed to produce CPP or CPA in SD rats, but did produce a CPA in FH rats. Results are discussed in terms of the use of conditioned place preference to assess putative differences in serotonergic functioning in FH rats.

Dopaminergic mediation of the stimulant generalization of nicotine.

1. Experiments were conducted to investigate if the psychostimulant cathinone, like d-amphetamine, would produce generalization of the discriminative stimulus effects of nicotine. 2. Rats were trained to discriminate either 0.8 mg/kg cathinone from its vehicle or 0.8 mg/kg nicotine from its vehicle and, subsequently, administered various doses of the other compound. 3. Results of Exp 1 indicate that animals trained to discriminate cathinone only partially generalize to the effects of 0.8-1.6 mg/kg nicotine. In contrast, animals trained to discriminate nicotine dose-responsively generalize to cathinone doses ranging from 0.1-1.2 mg/kg. 4. Exp 2 served to investigate the effects of the dopamine release inhibiting drug CGS 10746B upon the observed cathinone generalization in nicotine-trained rats. Pretreatment with this compound at doses of 20 and 30 mg/kg significantly attenuated cathinone generalization in these animals. 5. The results are discussed in light of the growing evidence that nicotinic receptors reside upon mesolimbic dopamine neurons and the possibility that the consequent increase in extracellular dopamine may produce the discriminative stimuli, as well as the reinforcing properties, of nicotine.

Place preference and microdialysis studies with two derivatives of methylphenidate.

Conditioned place preference studies with derivatives of dl-threo-methylphenidate (Ritalin) which bear a bromine atom or a methoxy group on the para position of the phenyl ring are reported. Both derivatives, as well as methylphenidate itself, induced a significant increase in place preference when administered i/p to rats at 10 mg/Kg, compared with saline conditioned controls. The change for p-bromomethylphenidate was slightly greater than that seen for methylphenidate or p-methoxymethylphenidate. Extracellular dopamine in the striatum, and locomotor activity, were also increased by i/p administration of p-methoxymethylphenidate (20 mg/Kg) to a similar extent to the increases seen with this dose of methylphenidate or p-bromomethylphenidate in an earlier study (Pan et al. Eur. J. Pharmacol. 264: 177-182, 1994). Administration of p-methoxymethylphenidate failed to abolish increases in extracellular dopamine and locomotor activity induced by subsequent administration of cocaine (20 mg/Kg). It is concluded that the methylphenidate derivatives share the general pharmacological properties of other psychostimulant drugs.

Serotonergic mediation of cocaine seizures in mice.

We used genetically heterogeneous HS mice to investigate the effects of drugs that alter brain concentrations of serotonin on cocaine-induced convulsions and lethality. The racemer of fenfluramine, which increases synaptic serotonin, was coadministered with a dose (60 mg/kg, intraperitoneally) of cocaine that does not produce status epilepticus or death. This drug combination significantly increased the occurrence and decreased the time of onset of status epilepticus, but did not affect lethality. Likewise, 2.5 mg/kg of the D-isomer, of fenfluramine increased the occurrence of status epilepticus. Neither isomer effected lethality. When 2.5 mg/kg cinanserin, a drug that antagonizes postsynaptic serotonergic receptors, was coadministered with a higher (95 mg/kg) dose of cocaine, the time of onset of status epilepticus was significantly increased, whereas lethality was reduced. The results are discussed in light of the action of cocaine upon serotonin neurons and the relationship between seizurogenic activity and cocaine-induced lethality.

Role of dopamine D1 receptors in cocaine lethality.

One group of heterogeneously bred HS mice was assigned to test coadministration of the selective D1 antagonist SCH 23390 with a dose of cocaine (95 mg/kg) that was observed to produce 80% lethality, whereas a second group was tested by cotreatment with the newly developed full-efficacy D1 agonist dihydrexidine (DHX) and a dose of (60 mg/kg) cocaine previously shown to be nonlethal. The mice in the former group displayed decreased lethality going from 80% with coadministered vehicle to 15% after pretreatment with the highest dose (0.45 mg/kg) of SCH 23390. In the other group of mice there was no lethality seen when vehicle or 10 mg/kg DHX was coadministered with 60 mg/kg cocaine, but a dose-responsive increase in lethality with increasing DHX doses; the maximal lethality of 80% occurred when 25 mg/kg DHX was coadministered with cocaine. These results confirm the effects of D1 antagonism decreasing cocaine lethality as reported previously when rats were used, and extend the findings to D1 agonism; both observations evidence a role for the D1 receptor in the lethal effects, be they central, cardiopulmonary, or anesthetic, of cocaine.

The lethal effects of ethanol and cocaine and their combination in mice: implications for cocaethylene formation.

The HS line of mice was used to determine the LD50 values for cocaine and ethanol, as well as for cocaethylene, the enzymatic product of their coadministration. The LD50 of cocaethylene was found to be significantly lower than that of cocaine, and both were more potent in their lethality than ethanol. When a low-lethality dose of cocaine was administered with a nonlethal dose of ethanol, the result was a significant increase in the prevalence of lethality. Thus, the lethal effects of the dose of cocaine used were increased by the dose of ethanol administered such that the two drugs in combination were equipotent to cocaethylene. The results are discussed in light of the ability of the liver, via transestification, to rapidly form cocaethylene from cocaine in addition to ethanol's ability to decrease the catabolism of cocaine. Thus, the possibility exists that the increased lethality observed is produced by both the production of the more lethal cocaethylene and sustained levels of cocaine.

Cocaethylene-induced kindling of seizure effects: cross-specificity with cocaine.

Sensitization and cross-sensitization to the seizurogenic effects of cocaine and cocaethylene were examined in the HS strain of mice. Animals were administered IP injections of either 48 mg/kg cocaine or 32 mg/kg cocaethylene once per day for 4 days. On the fifth day, mice were injected with either the same drug that was administered on days 1-4 or the alternative psychostimulant and the occurrence of seizure activity was recorded. Repeated cocaine administration resulted in the induction of tonic-clonic seizures and status epilepticus in 90% of the animals tested with cocaine on the fifth day. A similar increase in seizure prevalence, noted as a kindling effect, was observed in cocaethylene-treated animals tested with cocaethylene in that 90% of the mice exhibited status epilepticus on the last test day. Significant cross-sensitization was observed only in the group that received cocaethylene following repeated cocaine exposure. However, data obtained from animals injected with cocaine following cocaethylene treatment also were suggestive of cross-sensitization effects. Results are discussed in terms of the potential mechanistic differences between cocaine and its ethanol-derived product, as well as its relevance to cocaine use/abuse.

LSD produces conditioned place preference in male but not female fawn hooded rats.

Male and female Fawn Hooded rats were examined for conditioned place preference (CPP) or aversion (CPA) to lysergic acid diethylamide (LSD). Using a biased design, experimental animals were trained with LSD (0.2 mg/kg, I.P.) administered in conjunction with confinement in either the preferred or nonpreferred location. Control animals received confinement in both locations after administration of saline. Results indicated that rats administered LSD while sequestered in the nonpreferred location spent more time in that location during a nondrug test. This effect, indicative of a conditioned place preference, was exhibited only in male animals. Results are discussed in terms of potential sex differences that may mediate serotonergic sensitivity in the Fawn Hooded rat strain.