Biomedical subjects

L H Gold

Publications and source records attributed to L H Gold.

At least 55 records · Page 3Linked to original sources

PubMed1996

Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil.

Modafinil [(diphenyl-methyl)sulphinyl-2-acetamide] is a novel psychostimulant drug which is effective in the treatment of narcolepsy and idiopathic hypersomnia. It also has neuroprotective effects in animal models of striatal neuropathology. Although the cellular mechanisms of action of modafinil are poorly understood, it has been shown to have a profile of pharmacological effects that differs considerably from that of amphetamine-like stimulants. There is some evidence that modafinil has central alpha 1-adrenergic agonist effects. In the present study modafinil was evaluated for cocaine-like discriminative stimulus effects in rats and for reinforcing effects in rhesus monkeys maintained on intravenous cocaine self-administration. Modafinil, l-ephedrine and d-amphetamine all produced dose dependent increases in cocaine-lever responding, with maximal levels of 67%, 82% and 100%, respectively. Modafinil produced full substitution in four out of the six rats tested while the highest levels of substitution were associated with substantial response rate decreasing effects. Little evidence was obtained that the discriminative stimulus effects of modafinil were produced by alpha 1-adrenergic activation, based upon results of tests performed in combination with prazosin. In the self-administration procedure, modafinil and l-ephedrine functioned as reinforcers in rhesus monkeys. The reinforcing and discriminative stimulus effects of modafinil-required very high doses: modafinil was over 200 times less potent than d-amphetamine and was also less potent than l-ephedrine. These results show that modafinil has some cocaine-like discriminative stimulus effects and, like other abused stimulants, can serve as a reinforcer at high doses.

Adrenergic Agents↗

PubMed1996

Learning impairment in transgenic mice with central overexpression of corticotropin-releasing factor.

The present studies were designed to test the learning and memory capacities of transgenic mice with central overexpression of corticotropin-releasing factor in a forced alternation water T-maze task and in the Morris water maze. In T-maze testing, littermate control mice reached a criterion of 70% correct responses after five days of trials, while the performance of transgenic subjects was still random after the same training. In Morris maze testing, control subjects reached the submerged platform significantly faster (F(1.48) = 4.51, P < 0.05) after three days of trials, while the performance of transgenic mice was unimproved over the same period. The deficit in Morris maze performance in transgenic mice was reversed when the platform was visible above the surface of the water. Pre-test administration of the benzodiazepine anxiolytic, chlordiazepoxide (10 mg/kg), before acquisition training also produced a significant (F(4.40) = 16.61, P < 0.001) and persistent improvement in Morris maze performance in transgenic mice when compared to vehicle-treated transgenic litter mates. Finally, there was no evidence of hippocampal cell loss in transgenic brains. The results suggest that corticotropin-releasing factor-overexpressing mice exhibit a profound learning deficit without sensory or motor-related impairments, and that memory plasticity can be restored by anxiolytic pre-treatment. Thus, constitutive overabundance of brain corticotropin-releasing factor may produce hyperemotionality that interferes with learned behaviors. Stress-related disorders characterized by co-morbid deficits in learning/memory may benefit from pharmacological normalization of brain corticotropin-releasing factor systems.

Animals↗

PubMed1996

Transgenic modeling of neuropsychiatric disorders.

Converging advances in the fields of molecular biology, molecular genetics, cellular biology and embryology have given researchers the tools for the targeted delivery and stable germline transmission of foreign genes (transgenes) in the mouse. In the realm of neuropsychiatry, this so-named transgenic technology has begun to catapult our knowledge of the genetic, molecular and cellular mechanisms in the brain that are linked to a variety of mental disorders as well as normal behavioral processes such as learning and memory. Moreover, the potential for transgenic technology to develop more precise animal models of specific human neuropsychiatric disorders will likely lead to the identification of novel targets for therapeutic intervention and facilitate the preclinical testing of new therapeutic agents. This article examines key issues and highlights recent developments pertaining to the transgenic modeling of neuropsychiatric disorders.

Animals↗

PubMed1995

Coloboma hyperactive mutant exhibits delayed neurobehavioral developmental milestones.

The coloboma mutation (Cm) is a neutron-irradiation induced gene deletion located on the distal portion of mouse chromosome 2. This deletion region includes a gene encoding the synaptic vesicle docking fusion protein, synaptosomal-associated protein of 25 kDa (SNAP-25). The resulting mutation is semi-dominant with heterozygote mice exhibiting a triad of phenotypic abnormalities that comprise profound spontaneous hyperactivity, head bobbing and a prominent eye dysmorphology. Because the expression pattern of two SNAP-25 isoforms begins to change during the first postnatal week, neurobehavioral developmental milestones were examined in order to determine if the expression of the coloboma behavioral phenotype could be detected during this period of postnatal development. The early classification of coloboma mutant offspring may help to further describe the penetrance of this mutation as well as the contribution of developmental changes to the adult behavioral phenotype. The coloboma mutation resulted in delays in some tests of complex motor skills including righting reflex and bar holding. In addition, coloboma mutants were characterized by body weight differences (first appearance day 7) and hyperreactivity to touch (day 11) and head bobbing (day 14). These data demonstrate disruptions in the time course of attaining developmental milestones in coloboma mutants and provide further evidence supporting the hypotheses that alterations in Snap gene expression are associated with functional behavioral consequences in developing offspring.

Aging↗

PubMed1994

Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses.

The brain dopaminergic system is a critical modulator of basal ganglia function and plasticity. To investigate the contribution of the dopamine D1 receptor to this modulation, we have used gene targeting technology to generate D1 receptor mutant mice. Histological analyses suggested that there are no major changes in general anatomy of the mutant mouse brains, but indicated that the expression of dynorphin is greatly reduced in the striatum and related regions of the basal ganglia. The mutant mice do not respond to the stimulant and suppressive effects of D1 receptor agonists and antagonists, respectively, and they exhibit locomotor hyperactivity. These results suggest that the D1 receptor regulates the neurochemical architecture of the striatum and is critical for the normal expression of motor activity.

Analysis of Variance↗

PubMed1994

Prolonged tolerance, dependence and abstinence following subcutaneous morphine pellet implantation in the rat.

Opiate withdrawal is a common occurrence in human opiate addicts that is no life threatening but is hypothesized to be a significant factor which may contribute to drug taking behavior in these opiate dependent individuals. The purpose of this study was to compare the time course for the development of tolerance, dependence and abstinence using a rat model. Rats were made dependent by implantation of 2 morphine pellets s.c. (75 mg morphine base). Morphine implanted rats exhibited analgesia as measured in a tail-dip assay, for up to 12 h post-implant after which the development of tolerance resulted in tail-flick latencies returning to the level of control rats. Withdrawal was evaluated by injection of the opiate antagonist, naloxone (1 mg/kg s.c.). Rating of the abstinence syndrome revealed significant withdrawal signs by 3 h post-implant which became increasingly intense up to 24 h post-implant. Withdrawal could be precipitated for at least 13 days post-implant, while by 18 days post-implant almost no abstinence signs were observed. Plasma morphine levels following implantation of 2 pellets remained relatively stable from 3-12 days post-implantation. These results further extend the characterization of opiate abstinence following subcutaneous pellet implantation. These results also suggest that opiate abstinence develops within the first 24 h and follows the time course of the development of tolerance. The characterization of the evolution of opiate tolerance, physical dependence and abstinence under similar experimental conditions is critical to the design of future studies to examine the neural bases for these phenomena.

Analgesia↗

PubMed1994

Behavioral effects of persistent lymphocytic choriomeningitis virus infection in mice.

Lymphocytic choriomeningitis virus (LCMV) is a nonlytic murine virus that provides a valuable model system for studying the behavioral correlates of CNS viral infection. Newborn or immunosuppressed mice infected with LCMV develop a persistent tolerant infection characterized by continuous viral production. Virus can be found in various body organs including lung, liver, kidney, and brain. In brain, neurons are the predominant CNS cells infected and the greatest number of persistently infected neurons are found in the cerebral cortex, hippocampus, other limbic structures and parts of the hypothalamus. Despite continuous infection throughout the animal's life, neurons show no structural injury or dropout. Mice from the DBA/2J strain were infected with LCMV (1000 plaque-forming units) within 18 h of birth and tested for behavioral function as adults. Plaque assays indicated persistent infection in virus-injected mice. Mice were tested for their ability to learn a Y-maze spatial discrimination to avoid the onset of a mild footshock (0.43 mA). The number of correct avoidance responses made during training was taken as a measure of acquisition performance. The virus-infected mice showed a deficit in acquisition of the Y-maze discrimination compared to that seen in vehicle-injected and noninjected controls. Following additional training to reach control levels of performance, the infected mice and the controls were injected with the cholinergic antagonist scopolamine. Scopolamine (2.0 mg/kg) disrupted the performance of the infected mice significantly more than control performance, suggesting that a cholinergic dysfunction accounted for some of the learning deficit. A separate group of virus-infected mice exhibited hypoactivity during the first exposure to a locomotor testing apparatus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Relative sensitivity to naloxone of multiple indices of opiate withdrawal: a quantitative dose-response analysis.

In addition to classic somatic signs of opiate withdrawal, a number of behavioral measures are known to be sensitive, reliable indices of naloxone-precipitated opiate withdrawal in rats. It has been suggested that some behavioral indices of withdrawal may be more sensitive to precipitation by naloxone than some somatic signs of withdrawal. The purpose of the present study was to permit a quantitative assessment of the relative sensitivity to naloxone of a variety of behavioral and somatic indices of opiate withdrawal. Male Wistar rats were implanted s.c. with either two morphine (each 75 mg of base) or two placebo pellets. No sooner than 3 days after implantation, naloxone dose-response functions were determined with several behavioral paradigms and ratings of a variety of somatic withdrawal signs. In dependent rats, very low (0.004 or 0.01 mg/kg) doses of naloxone produced the following behavioral effects: 1) a reduction in spontaneous locomotor activity, 2) a disruption of schedule-controlled (fixed ratio 15) operant responding for food, 3) an elevation in intracranial self-stimulation thresholds and 4) a conditioned place aversion. These same doses of naloxone produced no significant effects in nondependent (placebo pellet-implanted) rats. The ED50 values for naloxone precipitation of all behavioral signs of withdrawal were below 0.013 mg/kg; the ED50 values for naloxone precipitation of most somatic withdrawal signs were higher. The behavioral measures used in these studies therefore represent highly sensitive indices of opiate withdrawal.

Animals↗

PubMed1993

Effects of NMDA receptor antagonists in squirrel monkeys trained to discriminate the competitive NMDA receptor antagonist NPC 12626 from saline.

Because excitatory amino acids have been implicated in several physiological phenomena, antagonists of excitatory amino acid function may have significant therapeutic potential as anticonvulsants, neuroprotectants and anxiolytics. Drug discrimination procedures in animals have proven useful to compare and contrast the behavioral effects of site-selective NMDA antagonists. In the only previous study using a competitive NMDA antagonist as a training drug, rats were trained to discriminate NPC 12626 (2-amino-4,5-(1,2-cyclohexyl)-7-phosphonohepatanoic acid) from nondrug. The major goal of the present study was to establish and characterize a nonhuman primate model of NPC 12626 discrimination. Adult male squirrel monkeys were trained to discriminate NPC 12626 from saline under a two-lever fixed ratio-30 schedule of food reinforcement. The monkeys required between 80 and 120 training sessions to acquire this discrimination after the training dose had been raised from 3 to 20 mg/kg i.m. The competitive NMDA antagonists CGP 37849 (D,L-(E)-2-amino-4-methyl-5- phosphono-3-pentanoic acid) and CPPene (D-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid) substituted completely for NPC 12626, while the potent noncompetitive NMDA antagonist, dizocilpine (MK-801), did not. These results reflect a profile of discriminative stimulus effects which support that observed in rats and establish a primate model for use in further study of the behavioral effects of the competitive NMDA antagonists.

2-Amino-5-phosphonovalerate↗

PubMed1993

Animal models of drug craving.

Drug craving, the desire to experience the effect(s) of a previously experienced psychoactive substance, has been hypothesized to contribute significantly to continued drug use and relapse after a period of abstinence in humans. In more theoretical terms, drug craving can be conceptualized within the framework of incentive motivational theories of behavior and be defined as the incentive motivation to self-administer a psychoactive substance. The incentive-motivational value of drugs is hypothesized to be determined by a continuous interaction between the hedonic rewarding properties of drugs (incentive) and the motivational state of the organism (organismic state). In drug-dependent individuals, the incentive-motivational value of drugs (i.e., drug craving) is greater compared to non-drug-dependent individuals due to the motivational state (i.e., withdrawal) developed with repeated drug administration. In this conceptual framework, animal models of drug craving would reflect two aspects of the incentive motivation to self-administer a psychoactive substance. One aspect would be the unconditioned incentive (reinforcing) value of the drug itself. The other aspect would be relatively independent of the direct (unconditioned) incentive value of the drug itself and could be reflected in the ability of previously neutral stimuli to acquire conditioned incentive properties that could elicit drug-seeking and drug-taking behavior. Animal models of drug craving that permit the investigation of the behavioral and neurobiological components of these two aspects of drug craving are reviewed and evaluated. The models reviewed are the progressive ratio, choice, extinction, conditioned reinforcement and second-order schedule paradigms. These animal models are evaluated according to two criteria that are established herein as necessary and sufficient criteria for the evaluation of animal models of human psychopathology: reliability and predictive validity. The development of animal models of drug craving will have heuristic value and allow a systematic investigation of the neurobiological mechanisms of craving.

Animals↗

PubMed1992

Evidence for separate neuronal mechanisms for the discriminative stimulus and catalepsy induced by delta 9-THC in the rat.

The cataleptogenic effect of delta 9-THC was compared to its discriminative stimulus effects in rats. The ED50s for the discriminative stimulus and catalepsy were 0.8 and 4.0 mg/kg, respectively, while their time courses were very similar. The ED50 of delta 9-THC for catalepsy in experimentally naive rats was not different from that in rats trained with the drug discrimination procedure, indicating that the cataleptogenic effect was not appreciably attenuated by long-term exposure to low doses of delta 9-THC. Pharmacologically, the catalepsy produced by delta 9-THC more closely resembled that of haloperidol than of morphine, since anticholinergic pretreatment eliminated the delta 9-THC-induced catalepsy while pre-treatment with naloxone had no effect. Although the cataleptogenic effect of delta 9-THC could be pharmacologically manipulated by anticholinergic pre-treatment, its discriminative stimulus effects were not changed in the same animals. These results demonstrate that distinctive mechanisms of action exist for these cannabinoid-induced behaviors.

Animals↗

PubMed1992

Effects of buspirone and gepirone on i.v. cocaine self-administration in rhesus monkeys.

Buspirone and gepirone were evaluated as potential pharmacotherapies for cocaine abuse by studying the effects of acute and repeated treatment on IV cocaine self-administration in rhesus monkeys. Chlorpromazine was also evaluated as a positive control. Effects of IV drug pretreatments were tested during daily 60-min sessions with lever-pressing reinforced under a fixed-ratio 10 schedule of 0.02 or 0.05 mg/kg cocaine infusions. Acute pretreatment with buspirone (0.1 and 0.3 mg/kg, IV) increased rates of cocaine self-administration without disrupting food pellet consumption. Some doses of buspirone also produced changes in rates of cocaine self-administration without altering the within-session pattern of responding. In contrast, acute doses of gepirone had little effect on rates of cocaine self-administration, while disruptions in food consumption and changes in the within-session pattern of cocaine self-administration were obtained at the highest dose of gepirone tested (1.0 mg/kg). When either buspirone (0.1 and 0.3 mg/kg, IV) or gepirone (0.1 mg/kg, IV) were administered daily for 10 days, consistent effects on cocaine self-administration were not observed. Thus, the effects of acute buspirone administration on cocaine-maintained behavior were similar to the effects produced by chlorpromazine and other dopaminergic antagonists, whereas, gepirone was ineffective. These results provide some support for further evaluation of buspirone as a potential pharmacotherapy for cocaine abuse, although its lack of efficacy with repeated treatment is not encouraging. The negative results with gepirone provide less rationale for continued investigations with this drug, possibly because of its lesser involvement than buspirone with dopaminergic neurotransmission.

Animals↗

PubMed1992

The acoustic startle response as a measure of behavioral dependence in rats.

A series of experiments was conducted to assess the sensitivity of the acoustic startle response to chronic morphine administration and naloxone-precipitated withdrawal. Rats were implanted with two subcutaneous pellets containing either 75 mg each of morphine or containing only placebo. In experiment 1, withdrawal induced by 0.05-0.2 mg/kg naloxone dose-dependently decreased the magnitude of the startle response. Physical dependence was confirmed by a naloxone-induced acute weight loss seen in morphine-implanted rats, but naloxone had no effect on startle or body weight in non-dependent animals. In experiment 2, a modified procedure with fewer trials per session and fewer test days was employed. Naloxone (0.2 mg/kg) given 4-5 days after implantation induced large startle-response decreases in morphine-dependent rats while having no effect in placebo-implanted rats. Post-naloxone saline tests revealed no significant differences in startle between morphine and placebo groups. Startle scores were significantly higher in morphine-implanted rats than in placebo rats during a saline test given 3 days following pellet implantation. In a separate group of animals, however, acute IP injections of morphine from 0.3-10 mg/kg had no significant effect on startle amplitude. The effect of repeated pairings of withdrawal with the startle environment was assessed in experiment 3. Morphine-dependent rats startled significantly less if naloxone injections were given before the startle session than if they were administered 4 h later. Conditioned withdrawal effects, expressed during a final test session when all rats received saline, were observed for the body-weight measure but not for the startle response.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗

PubMed1992

A comparison of the discriminative stimulus properties of delta 9-tetrahydrocannabinol and CP 55,940 in rats and rhesus monkeys.

CP 55,940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3- hydroxypropyl)cyclohexanol] is a potent bicyclic analog of delta 9-tetrahydrocannabinol (THC) which has been used as a probe for a cannabinoid recognition site in neural tissue. In the present study, CP 55,490 was evaluated for delta 9-THC-like effects in rats and rhesus monkeys trained to discriminate delta 9-THC from vehicle. Rats trained to discriminate delta 9-THC (3.0 mg/kg i.p.) from vehicle were tested with various doses of delta 9-THC and CP 55,940 at both 30 and 90 min postinjection. Catalepsy was measured immediately after these operant tests using an adaptation of the mouse ring-test. In rats, CP 55,940 substituted for delta 9-THC at both 30 and 90 min postinjection at a dose of 0.1 mg/kg that had minimal effects on rates of responding. Doses of delta 9-THC (greater than 3.0 mg/kg) and CP 55,940 (greater than 0.1 mg/kg) that reduced response rates by greater than 50% also produced substantial increases in catalepsy. CP 55,940 and delta 9-THC had a similar time course for discriminative stimulus effects, but CP 55,940 was about 30 times more potent. In monkeys, the training dose of delta 9-THC ranged from 0.04 to 0.16 mg/kg i.m., adjusted individually to minimize response-rate disruption. After training, monkeys were tested with various doses of delta 9-THC and CP 55,940 at 30 min postinjection.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗

PubMed1992

Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol.

Six novel aminoalkylindole analogs, related structurally to the dual cyclooxygenase inhibitor and nonopioid analgesic pravadoline, were evaluated in the mouse to determine whether their pharmacological profile of activity was similar to that exhibited by delta 9-tetrahydrocannabinol (delta 9-THC). Analog I (C2-H; C3-methoxy-benzoyl) reduced locomotion, but had no other effects (hypothermia, antinociception or ring-immobility) up to 21 mumol/kg. Analogs II and III (C3-naphthoyl; C2-H and C2-methyl, respectively) possessed all properties exhibited by delta 9-THC with ED50 values ranging from 0.68 to 18 mumol/kg. Analog IV (C2-methyl; C3-anthroyl) was devoid of activity. Stereoselectivity was demonstrated by the fact that (+)-WIN-55,212 (one isomer of a semirigid derivative possessing C2-H and C3-naphthoyl substituents) was moderately potent in all tests (ED50 values ranging from 0.25-23 mumol/kg), but (-)-WIN-55,212 was inactive up to 57 mumol/kg. Active aminoalkylindole compounds were generally least effective in the production of hypothermia. Analogs were also evaluated for their ability to produce delta 9-THC-like discriminative stimulus effects in rats. The ED50 for delta 9-THC as a discriminative stimuli for this model was 1.9 mumol/kg. Analog II and III and (+)-WIN-55,212 produced delta 9-THC-like discriminative effects with ED50 values ranging from 0.33 to 4.3 mumol/kg, whereas analogs I, IV and (-)-WIN-55,212 did not. Although reported to be cannabinoid receptor antagonists in vitro, neither analog I, analog IV nor (-)-WIN-55,212 (at 20 mumol/kg) antagonized the in vivo pharmacological effects of delta 9-THC in the mouse or rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗

PubMed1992

Role of different brain structures in the expression of the physical morphine withdrawal syndrome.

The aim of this study was to investigate the neuroanatomical regions implicated in the expression of the physical signs of morphine withdrawal by using local intracerebral injections of methylnaloxonium in dependent rats. Guide cannulas were implanted and aimed at the lateral ventricle, nucleus accumbens, central amygdala, anterior hypothalamus, medial thalamus, periaqueductal gray matter, locus coeruleus and nucleus raphe magnus. After surgery, rats were made physically dependent by s.c. implantation of two 75-mg morphine pellets. Methylnaloxonium, a quaternary derivative of naloxone (31-1000 ng), was administered 72 hr after pellet implantation. Methylnaloxonium administered i.c.v. induced a withdrawal syndrome similar to systemic naloxone, although several signs such as diarrhea, salivation, lacrimation and rhinorrhea did not appear, suggesting possible peripheral mediation. The most sensitive site for methylnaloxonium-precipitated withdrawal was the locus coeruleus. Signs such as jumping, rearing and locomotor activity were particularly frequent after methylnaloxonium injections into the locus coeruleus. Rearing and locomotor activity were also strongly increased after methylnaloxonium administration into the periaqueductal gray matter. Wet dog shakes were mainly observed after methylnaloxonium administration into the anterior preoptic hypothalamus and nucleus raphe magnus. Injections of methylnaloxonium into the amygdala produced a weak withdrawal syndrome, and the nucleus accumbens and medial thalamus were the least sensitive structures. These results suggest that the locus coeruleus, and secondarily the periaqueductal gray matter, play an important role in the precipitation of the physical signs of opiate withdrawal, mainly in the expression of its motor component. The expression of other signs of withdrawal appear to be multisite determined.

Animals↗

PubMed1991

Amphetamine derivatives induce locomotor hyperactivity by acting as indirect serotonin agonists.

Derivatives of amphetamine are potent releasers of both dopamine (DA) and serotonin (5-HT), but the relative contributions of DA and 5-HT release to the behavioral effects of these drugs have not been established. Previously, S-(+)3,4-methylenedioxymethamphetamine (S-(+)MDMA) was found to produce locomotor hyperactivity in rats which was dependent on 5-HT release. The present study found that MBDB (1.25, 2.5, 5.0 or 10.0 mg/kg), the alpha-ethyl derivative of MDMA that produces little or no direct DA release, also induced locomotor hyperactivity that lasted for greater than 60 min after the 5.0 and 10.0 mg/kg doses. MBDB produced spatial patterns of locomotor hyperactivity and suppression of exploratory activity (holepokes and rearings) very similar to the behavioral syndrome produced by MDMA. MBDB-induced hyperactivity was blocked by pretreatment with the selective 5-HT uptake inhibitor fluoxetine (2.5 or 10 mg/kg), suggesting that MBDB produced behavioral effects via uptake-carrier mediated release of 5-HT. Similarly, fluoxetine pretreatment blocked the locomotor hyperactivity produced by S-(+)3,4-methylenedioxyamphetamine (3.0 mg/kg) or p-chloroamphetamine (2.5 mg/kg), supporting a serotonergic basis for the action of these drugs. Tissue levels of 5-HT and its metabolite 5-HIAA were decreased 40 min after administration of S-(+)MDMA (3.0 mg/kg) or MBDB (5.0 mg/kg), and these decreases were prevented by fluoxetine pretreatment. S-(+)MDMA also produced a fluoxetine-sensitive increase of tissue DA levels, suggesting that 5-HT release may indirectly result in increased DA release, although MBDB did not significantly increase DA levels.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Methylenedioxyamphetamine↗

PubMed1991

Evaluation of nefazodone self-administration in rhesus monkeys.

Intravenous self-administration of nefazodone, a potential new antidepressant medication, was evaluated using a substitution procedure in rhesus monkeys. Subjects had established stable rates of responding for cocaine (0.033 mg/kg per infusion) under a fixed-ratio 10 schedule during 60-min sessions each day. Various does of nefazodone hydrochloride (0.03-0.3 mg/kg per infusion) were substituted for cocaine for four consecutive daily self-administration sessions. Compared to rates of responding obtained during saline substitutions, nefazodone failed to function as a reinforcer when substituted for cocaine. In only one monkey, at one dose, did the rate of responding exceed the range of saline responding; an effect not observed in two subsequent replications in that subject. In all three monkeys, the total number of infusions tended to decrease during the 4-day nefazodone substitution and the majority of nefazodone infusions occurred during the first quarter of each session, with few infusions occurring in the latter three-quarters. Overall intake of nefazodone increased as a function of dose per infusion. Such a result is expected when response rates do not vary with dose, which is more likely to occur when a test drug is not a reinforcer. In summary, the present results provide no evidence of reinforcing effects with nefazodone and suggest that it would possess little or no abuse liability.

Animals↗