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J L Katz

Publications and source records attributed to J L Katz.

At least 19 recordsLinked to original sources
PubMed1992

Evaluation of the neurotoxicity of N-methyl-1-(4-methoxyphenyl)-2-aminopropane (para-methoxymethamphetamine, PMMA).

These studies assessed the neurotoxic potential of N-methyl-1-(4-methoxyphenyl)-2-aminopropane (para-methoxymethamphetamine; PMMA), an amphetamine analog that has surfaced in the illicit drug market. Repeated subcutaneous injections of PMMA caused lasting, dose-related reductions in regional brain concentrations of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), and in the density of [3H]paroxetine-labelled 5-HT uptake sites. Comparison of the neurotoxic potential of PMMA to that of para-methoxyamphetamine (PMA) and 3,4-methyl-enedioxymethamphetamine (MDMA) showed that equivalent doses of PMMA and PMA (80 mg/kg) produced comparable depletions of 5-HT, but that these depletions were not as pronounced as those induced by a lower dose of MDMA (20 mg/kg). Striatal DA was not affected on a long-term basis by any of the ring-substituted amphetamines evaluated in this study. These data suggest that PMMA, like PMA and MDMA, produces long-term (possibly neurotoxic) effects on brain serotonin neurons, but that PMMA is less potent than MDMA as a 5-HT neurotoxin. Further, they raise concern over the illicit use of PMMA since humans could be more sensitive than rodents to the 5-HT neurotoxic effects of PMMA and related drugs.

3,4-Methylenedioxyamphetamine↗
PubMed1992

Effects of cocaine and its quaternary derivative cocaine methiodide on cardiovascular function in squirrel monkeys.

The effects of cocaine and its quaternary derivative cocaine methiodide, which does not cross the blood-brain barrier, were studied on cardiovascular function in squirrel monkeys. In conscious monkeys, cocaine produced clear dose-dependent increases in blood pressure and heart rate, while cocaine methiodide did not. Both cocaine and cocaine methiodide enhanced the effects of norepinephrine in anesthetized animals, suggesting that both inhibit neuronal uptake of norepinephrine; cocaine was approximately 30 times more potent than cocaine methiodide. In anesthetized monkeys both cocaine and cocaine methiodide produced small, short duration pressor effects, although cocaine was at least 10 times more potent than cocaine methiodide. Cocaine's effects in anesthetized animals were clearly blunted in comparison to its effects in conscious animals. These effects of cocaine on blood pressure occurred at doses lower than those required to enhance norepinephrine's effects, indicating that the norepinephrine uptake blocking effects of the drugs cannot fully account for their cardiovascular effects. The greatly enhanced effect of cocaine in conscious animals and the finding that cocaine methiodide had little effect in conscious animals indicates that central mechanisms are involved in the effects of cocaine on cardiovascular function in conscious animals.

Animals↗
PubMed1992

Effects of quinpirole and SKF 38393 alone and in combination in squirrel monkeys trained to discriminate cocaine.

The present study was designed to assess the behavioral similarity of the effects of prototype dopamine receptor-subtype selective agonists and cocaine. Squirrel monkeys (N = 4) were trained with food reinforcement to press one of two levers after administration of IV cocaine (0.3 mg/kg) or the other lever after saline. After training, IV cocaine produced reliable responding on the cocaine lever (greater than 98%), whereas saline produced reliable responding on the alternate lever (greater than 98%). The D2 agonist, quinpirole (0.003-1.0 mg/kg, IM), produced dose-related increases in cocaine-appropriate responding, with maximal effects of 62%. When delivered IV, quinpirole (0.01-0.17 mg/kg) was approximately twice as potent, but no more effective. The D1 agonist, SKF 38393 (0.3-30.0 mg/kg, IM or 3.0-17.0 mg/kg, IV) failed to produce any significant cocaine-appropriate responding. Further, pretreatment with SKF 38393 (either 0.3 or 10.0 mg/kg, IM) did not significantly alter the the quinpirole (0.01-1.0 mg/kg, IM) dose-effect curve. The effects of these drugs differ from those previously reported in rats, suggesting a species difference that may be of importance in evaluating the behavioral pharmacology of cocaine.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Reinforcing effects of enantiomers of N,N-dimethylamphetamine in squirrel monkeys.

Reinforcing effects of the (+)- and (-)-enantiomers of N,N-dimethylamphetamine, a drug that is abused in humans, were studied in squirrel monkeys (Siamiri sciureus) trained under schedules of intermittent cocaine reinforcement. During training, each 30th response produced an injection of cocaine (fixed-ratio schedule), which was followed by a 1-min period during which lights were out and responses had no scheduled consequences (timeout). Sessions in which cocaine injections were scheduled alternated in an irregular sequence with sessions in which saline injections were scheduled. After training, response rates were well maintained by cocaine (response rates approximated 1.4 responses per second) but occurred relatively infrequently during sessions in which saline was injected (response rates approximated 0.3 responses per second). Doses of 10 to 56 micrograms/kg/injection of (+)-N,N-dimethylamphetamine maintained rates of responding significantly higher than those maintained by saline. The (-)-enantiomer did not maintain rates of responding that were higher than those maintained by saline when tested at doses up to 100 micrograms/kg/injection. These findings support previous results indicating that N,N-dimethylamphetamine will function as a reinforcer in laboratory animals. Further, they suggest that the significant reinforcing activity of this drug is restricted to the (+)-enantiomer.

Animals↗
PubMed1992

Selective effects of the D1 dopamine receptor agonist, SKF 38393, on behavior maintained by cocaine injection in squirrel monkeys.

The effects of the dopamine receptor D1 partial agonist, SKF 38393, on behavior maintained by cocaine was assessed in squirrel monkeys (Saimiri sciureus). One group of subjects was trained to press a key under a fixed-ratio 30-response schedule of cocaine injection; when green stimulus lamps were illuminated each 30th response produced an injection (17 micrograms/kg) followed by a 1-min period during which the lights were out and responses had no scheduled consequences. Another group of squirrel monkeys was trained under an identical schedule with food reinforcement. SKF 38393 produced dose-related decreases in rates of responding maintained by either cocaine injection or food presentation. Rates of responding maintained by cocaine were decreased to a greater extent than those maintained by food. The ED50 value for SKF 38393 for responding maintained by cocaine was 2.53 mg/kg (95% CL: 1.22-5.23), whereas that value was 15.63 mg/kg (95% CL: 2.83-86.33) for responding maintained by food. Rates of responding maintained by cocaine were an inverted-U-shaped function of dose. Pretreatment with 3.0 mg/kg SKF 38393 shifted the ascending limb of the cocaine dose-effect curve to the right. These findings suggest that indirect D1-receptor activation plays a role in the reinforcing effects of cocaine, and that drugs acting at D1 receptors may show promise as therapeutic agents in the treatment of cocaine abuse.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Differential antagonism of the effects of dopamine D1-receptor agonists on feeding behavior in the rat.

A series of experiments was conducted to examine the effects of dopamine D1 receptor agonists on food intake in rats. In the first experiment, the D1 agonist SKF 38393 (3.0-30.0 mg/kg) dose-dependently suppressed feeding during a 40 min food-access period, both in food-deprived rats and in non-deprived rats fed a highly palatable diet. Non-deprived rats were more sensitive to these effects of SKF 38393. Using the limited-access, food-deprivation procedure, a comparison was made between the anorectic effects of three D1 agonists with differing intrinsic efficacies and receptor selectivities. Rank order of potencies for reducing food intake was SKF 82958 > SKF 77434 > SKF 38393 (ED50 values: 0.7, 3.6 and 15.7 mg/kg, respectively). Dose-related, surmountable antagonism by the D1 antagonist SCH 23390 (0.01 and 0.03 mg/kg) was only obtained with SKF 82958 (0.1-10.0 mg/kg). In contrast to the other compounds, the effects of SKF 38393 were not appreciably altered by the D1 antagonist. The effects of SKF 82958 were also antagonized by the D2 receptor antagonist spiperone (0.05 and 0.1 mg/kg), although not in a dose-dependent manner. The present results support a role for D1 receptors in central feeding mechanisms. They also suggest that the effects of SKF 38393 on feeding may not be mediated exclusively by the D1 receptor and, further, that SKF 38393 may not serve well in behavioral studies as a prototypical D1 agonist. The results also demonstrate the need for comparisons among several compounds in studies of D1 mediated behavioral effects.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Carbamazepine produces nonspecific effects on cocaine self-administration in rats.

Anecdotal evidence in humans suggest that carbamazepine suppresses cocaine-induced rush and craving. Such claims are unsupported in controlled trials using a placebo control. In the present study, rats were trained to self-administer i.v. cocaine in daily 2-hr sessions in which every tenth lever press delivered 1 mg/kg cocaine. After responding was stable, they were injected before each session with the vehicle for 2 days followed by carbamazepine for 2 days. At a 7 mg/kg dose, carbamazepine was without effect, whereas 15 mg/kg suppressed responding for cocaine only on the second (day 4) day of carbamazepine treatment. With 4 consecutive days of treatment, carbamazepine (15 mg/kg) reduced cocaine-maintained responding slightly, but significantly. In another group of animals trained to lever-press for food reinforcement, carbamazepine (15 mg/kg) also significantly decreased the rate of responding, suggesting that the suppression of responding was not specific to cocaine-reinforced behavior.

Animals↗
PubMed1992

Comparative behavioral pharmacology and toxicology of cocaine and its ethanol-derived metabolite, cocaine ethyl-ester (cocaethylene).

The present study compared the behavioral and toxic effects of cocaine and its ethanol derived metabolite, cocaine ethyl-ester (cocaethylene). Both drugs produced qualitatively similar psychomotor stimulant effects. Cocaine and cocaethylene increased locomotor activity in mice, with cocaine approximately four times more potent than cocaethylene. The durations of action of ED75 doses of each of the drugs were comparable. Each of the drugs also produced stimulation of operant responding in rats. In rats and squirrel monkeys trained to discriminate cocaine injections from saline, cocaine was approximately three to five times more potent than cocaethylene in producing these cocaine-like interoceptive effects. In contrast to the behavioral effects, cocaine and cocaethylene were equipotent in producing convulsions, and cocaethylene was more potent than cocaine in producing lethality. These results suggest that the conversion of cocaine to cocaethylene with simultaneous cocaine and alcohol use may produce an increased risk of toxicity due to a decrease in the potency of cocaethylene in producing psychomotor stimulant effects, and its increased potency in producing toxicity.

Animals↗
PubMed1992

Lasting effects of (+-)-3,4-methylenedioxymethamphetamine (MDMA) on central serotonergic neurons in nonhuman primates: neurochemical observations.

The purpose of this study was to assess the duration of (+-)-3,4-methylenedioxymethamphetamine's (MDMA's) effects on serotonin containing neurons in nonhuman primates. Fifteen squirrel monkeys were used: three served as controls, 12 received MDMA s.c. at a dose of 5 mg/kg twice daily for 4 consecutive days. Two weeks, 10 weeks, 8 months and 18 months after drug treatment, groups (n = 3) of MDMA-treated monkeys, along with controls, were examined for regional brain content of serotonin and 5-hydroxyindoleacetic acid, and for the number of [3H] paroxetine-labeled serotonin uptake sites. Two weeks after MDMA treatment, monkeys showed profound reductions in all three serotonergic presynaptic markers. By 10 weeks, there was evidence of partial recovery in some brain regions (e.g., hippocampus, caudate nucleus, frontal cortex). However, by 18 months, it was evident that recovery did not continue, as serotonergic deficits returned to the level of severity observed 2 weeks after MDMA treatment. This was the case in all brain regions examined except the thalamus and hypothalamus. In the thalamus, the level of serotonin increased to 63% of control, whereas that of 5-hydroxyindoleacetic acid recovered completely. In the hypothalamus, concentrations of serotonin and 5-hydroxyindoleacetic acid were 140 and 187% of control, respectively. These results suggest that MDMA produces lasting effects on serotonergic neurons in nonhuman primates, with most brain regions showing evidence of persistent denervation and some showing signs of reinnervation (thalamus) or possibly even hyperinnervation (hypothalamus). The morphological and functional correlates of these enduring neurochemical changes in the MDMA-treated primate remain to be delineated.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Behavioral effects of novel cocaine analogs: a comparison with in vivo receptor binding potency.

Several novel cocaine analogs, previously shown to be very potent in in vitro binding studies, have been examined for their stimulatory effects on locomotor activity and for their ability to displace [3H]WIN 35,428 binding in vivo in mice. These compounds, like WIN 35,428, lack an ester link between the phenyl group and the tropane ring and have para-substitutions on the phenyl ring. They were much more potent than (-)-cocaine in producing increases in locomotor activity. In addition, they were more potent than (-)-cocaine in inhibiting [3H]WIN 35,428 binding in vivo in mouse striatum. Thus, these compounds demonstrate similar high potency in behavioral tests and in receptor binding assays, both in vivo and in vitro. Results support the hypothesis of a relationship between binding at the dopamine transporter and the behavioral effects of cocaine-like drugs. Further, assuming that maximal occupancy occurs with total displacement of [3H]WIN 35,428 binding in vivo, the data suggest that maximal locomotor effects occur with near total occupancy of transporter binding sites.

Animals↗
PubMed1992

Punishment of schedule-controlled behavior with beta-carboline injections: antagonism and comparisons with other compounds.

Squirrel monkeys were trained to press a key under a multiple schedule of food presentation. In the presence of either green or red stimulus lights, the 30th response produced a food pellet (fixed-ratio schedule). In the presence of the red stimulus lights (punishment component), the first response of each fixed-ratio produced either an i.v. injection of histamine [30.0-100.0 micrograms/kg/injection (inj)] or saline, accompanied by a 200-msec presentation of amber stimulus lights. Sessions in which histamine was injected alternated with sessions in which saline was injected. Another group of subjects was studied under identical schedule conditions except that electric shock was scheduled with the 200-msec stimulus light. During alternate sessions, electric shock at a high or low intensity with the stimulus, or the stimulus alone was scheduled. When performances stabilized, histamine or high intensity electric shock selectively suppressed responding in the punishment component; saline, low intensity electric shock or the stimulus light alone had no effects. Subsequently, different doses of histamine, I-nicotine, cocaine or beta-carboline-3-carboxylic acid ethyl ester (beta-CCE) were substituted for histamine during single sessions. Histamine (17.8-100 micrograms/kg/inj), I-nicotine (32 micrograms/kg/inj) and beta-CCE (10-56 micrograms/kg/inj), but not cocaine (10.0-100.0 micrograms/kg/inj), produced a dose-related selective suppression of responding similar to that obtained with electric shock, suggesting that the drugs were functioning as punishers. Punishment by beta-CCE was antagonized with the benzodiazepine antagonist, flumazenil.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Common mechanisms underlying the proconflict effects of corticotropin-releasing factor, a benzodiazepine inverse agonist and electric foot-shock.

The effects of corticotropin-releasing factor (CRF), a benzodiazepine inverse agonist (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; DMCM) and electric foot-shock on rat conflict behavior were characterized and compared. Rats were trained to lever press under a multiple fixed-ratio schedule (FR 20) of food reinforcement in which responses during the first component were not punished, and the first response of each FR during the second component produced electric shock of an intensity sufficient to suppress responding by 10% to 15%. Intracerebroventricular injection of CRF (0.1-5.6 micrograms) caused a dose-dependent decrease in the rate of responding in both components of the schedule. However, CRF was more potent in decreasing rates of punished responding (proconflict effect). DMCM (10-100 micrograms; i.c.v.) also decreased rates of punished and nonpunished responding and was more potent during the punishment component. The suppression of punished and nonpunished responding by CRF and DMCM was mimicked by increasing the shock intensity (delta = 0.1 to 0.6 mA) during the punishment component. To determine whether CRF, DMCM and electric shock shared common mechanisms for these effects, rats were pretreated with i.c.v. injections of either a CRF antagonist (alpha helical CRF9-41, 50 micrograms), a benzodiazepine agonist (chlordiazepoxide, 10 micrograms) or a benzodiazepine antagonist (flumazenil, 10 micrograms) before the administration of equieffective doses of CRF or DMCM or an increase in shock intensity. Chlordiazepoxide attenuated the effects of all three stimuli. Flumazenil antagonized DMCM and CRF, but not shock, implicating a pharmacologic interaction between CRF and benzodiazepine systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Dexfenfluramine neurotoxicity in brains of non-human primates.

Dexfenfluramine, a drug prescribed for appetite suppression, was evaluated in non-human primates for its potential to produce toxic effects on brain serotonin (5-HT) neurons. Squirrel monkeys received dexfenfluramine subcutaneously twice daily for four days at doses of 1.25 or 5.00 mg/kg. Two weeks later, a dose-related depletion of 5-HT and 5-hydroxyindoleacetic acid was found, together with a reduced number of 5-HT uptake sites. Morphological studies showed acute pathological changes in 5-HT axons, followed by a persistent decrease in 5-HT axon density. Our findings indicate that dexfenfluramine damages central 5-HT neurons in monkeys and raise concern about the potential neurotoxicity of this drug in man.

Animals↗
PubMed1991

Behavioral effects of cocaine alone and in combination with selective dopamine antagonists in the squirrel monkey.

Effects of cocaine, alone and in combination with the dopaminergic antagonists, SCH 23390 and haloperidol were studied in squirrel monkeys trained to respond under fixed-interval schedules of electric-shock presentation. Cocaine at intermediate doses (0.1 and 0.3 mg/kg) increased rates of responding under the fixed-interval schedule and during 1-min timeout periods that separated each fixed-interval component. Higher doses (1.0 - 3.0 mg/kg) decreased response rates. Cocaine also dose-dependently altered the temporal pattern of responding characteristic of behavior under fixed-interval schedules. Haloperidol (0.003-0.1 mg/kg) and SCH 23390 (0.001-0.03 mg/kg) dose-dependently decreased rates of responding. A low dose (0.001 mg/kg) of the selective D1 antagonist, SCH 23390, did not appreciably alter the effects of cocaine. Higher doses (0.003-0.01 mg/kg), which when given alone decreased rates of responding, attenuated the increases in response rates produced by cocaine. In addition, the decreases in response rates produced by the higher dose of cocaine were attenuated by 0.01 mg/kg SCH 23390. The alterations in temporal patterning of responding under the fixed-interval schedule were not antagonized by any dose of SCH 23390. Haloperidol (0.003 mg/kg) did not appreciably alter the effects of cocaine; higher doses (0.01-0.03 mg/kg), which when given alone decreased rates of responding, attenuated the increases in response rates produced by 0.1 mg/kg cocaine. The decreases in response rates under the fixed-interval schedule that were produced by higher doses, or the changes in temporal patterning of responding at any dose of cocaine, were not antagonized by any dose of haloperidol that was studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Discriminative stimulus effects of inhaled cocaine in squirrel monkeys.

Squirrel monkeys (N = 4) were trained with food reinforcement to press one of two levers after administration of IV cocaine (0.3 or 1.0 mg/kg) or the other lever after saline. After training, IV cocaine (0.03-3.0 mg/kg) produced dose-related increases in the percentage of responses on the cocaine lever (ED50 = 0.15 mg/kg). Cocaine delivered IM also produced dose-related increases in cocaine-appropriate responding (ED50 = 0.32 mg/kg), but was approximately half as potent as IV cocaine. Similar relative potency relations were obtained for decreases in response rates produced by cocaine. Prior to some sessions subjects were placed in a Plexiglas chamber and exposed for 60 s to cocaine vapor created with an ultrasonic nebulizer. Exposure to vapor from cocaine solutions (1.0-30.0 mg/ml) produced concentration-dependent increases in cocaine-appropriate responding and decreases in response rates. Exposure to vapor from a 30 mg/ml concentration produced virtually exclusive cocaine-appropriate responding. Concentration-effect curves for inhaled cocaine were similar to dose-effect curves obtained when cocaine was administered by the other routes. The time course of the minimally effective concentration of inhaled cocaine was compared to that of the minimally effective doses of systemically administered cocaine. Inhaled cocaine had a duration of action longer than IV cocaine. The results indicate that inhaled cocaine vapor has effects qualitatively similar to those of IV cocaine, and may have a duration of action longer than that of an IV cocaine dose producing a similar degree of drug-appropriate responding.

Administration, Inhalation↗