Potentiation by naltrexone of d-amphetamine-induced behavioral suppression and its reversal by clonidine

Rats were trained to perform a fixed ratio-15 operant for food reinforcement during a 30 minute daily session. Naltrexone, in doses up to 45 mg/kg administered 15 min before the behavioral session, failed to disrupt responding. However, 0.3 and 1.0 mg naltrexone/kg produced a dose related potentiation of the operant behavioral suppression induced by 1.0 mg d-amphetamine/kg injected immediately before the session. The naltrexone/d-amphetamine combination also produced excessive salivation and postural abnormalities not seen when either drug was administered alone. [A subsequent study indicated that the salivation induced by naltrexone in combination with d-amphetamine may require previous exposure to naltrexone and/or d-amphetamine.] Blockade of dopamine receptors with pimozide did not modify the interaction. Functional noradrenergic blockade with a low dose of clonidine significantly reversed the potentiated suppression, of operant behavior, as well as the excessive salivation and abnormal posture. These data suggest that there is an important noradrenergic component to the interaction of naltrexone with d-amphetamine. The impressive interaction of behaviorally inactive doses of naltrexone with a moderate dose of d-amphetamine reported here for rats may have clinical implications for detoxified opiate addicts maintained on naltrexone in antagonist therapy programs.     

The effects of MIF-I, beta-endorphin and alpha-MSH on d-amphetamine induced paradoxical behavioral thermoregulation: possible involvement of the dopaminergic system

The neuropharmacological basis for d-amphetamine induced paradoxical behavioral thermoregulation remains unclear. This study examined thermoregulatory behavior of rats in a runway device that housed a heat source at one end and in which locomotion along the length of the runway could be observed. Sprague Dawley rats were pretreated with IP injections of saline, beta-endorphin, MIF-1, or alpha-MSH, with a repeat injection after 30 min. In a second experiment, d-amphetamine was administered as the repeat drug for all Ss. The results showed clear differences for heat-source-on vs. heat-source off. All peptides induced hypermotility, although no differentiated effects for the peptides on d-amphetamine induced paradoxical behavioral thermoregulation were found. These findings are discussed in light of the theoretical possibilities that: (a) a ceiling effect exists; (b) there are separate control systems for maintaining body temperature and another for behavioral thermoregulatory responses, and (c) other neurotransmitters may be involved in such induced paradoxical behavioral thermoregulation.     

Sensitization and habituation of command neurons during a defensive reflex in grape snails

All investigated neurones were classified into functional groups depending on their participation in unconditioned avoidance reflex of pneumostome closure. Habituation was produced by tactile stimuli applied with a frequency of 0.1 c/s. Spike responses of neurons participating in processing sensory information habituated gradually, while reactions of command neurones of avoidance behaviour became sensitized to the second or third stimulus of the series. Behavioral reaction was sensitized in parallel with command neurones in spite of habituation in other types of nerve cells. A conclusion is drawn that behavioral habituation is due to waning of responses in all the participating neurones, but the independnet process of sensitization is due to sensitization of command neurones. Probable mechanisms of neuronal sensitization are discussed.     

Prenatal stress alters reproductive responses of rats in behavioral estrus and paced mating of hormone-primed rats

Adult female offspring of dams exposed to gestational stress (prenatal stress, PNS) may show altered reproductive behavior, exploration in novel environments, and/or social interactions than do their non-PNS counterparts. These behavioral differences may be more readily observed in a seminatural, paced mating paradigm, in which females have greater control of their sexual contacts, than in a standard mating situation. Adult offspring of dams exposed to restraint and lights for 45 min on Gestational Days 14-20 (PNS) were compared with those not subjected to stress (non-PNS, control condition). The motor, reproductive, and sociosexual behaviors of hormone-primed (Experiment 1) or cycling adult offspring in behavioral estrus (Experiment 2) were examined following 20 min of restraint stress under bright lights (postnatal stress). Hormone-primed PNS rats displayed less motor behavior in a novel arena than did non-PNS rats. In a standard mating test, hormone-primed PNS females tended to be more aggressive toward the male than were non-PNS rats. In a seminatural mating situation, hormone-primed PNS females showed increased avoidance behavior, such as longer latencies to the initial intromission, greater return latencies following mounts and intromissions, and more exiting subsequent to mounts and intromissions, than did non-PNS rats. PNS rats in behavioral estrus had decreased incidence and intensity of lordosis, and fewer solicitation behaviors, in both standard or paced mating situations, in which latency to and number of mounts were also increased. Thus, hormone-primed PNS rats exposed to restraint showed more avoidance behaviors in paced mating situations, while cycling PNS rats in behavioral estrus had greater disruption of reproductive responses in standard or paced mating paradigms than did non-PNS control rats.     

Critical role of the hypothalamic pituitary adrenal axis in amphetamine-induced sensitization of behavior

Behavioral sensitization can be observed with repeated administration of amphetamine where the intensity of motor stimulation increases over time. The process of sensitization has been well characterized, however, the neurochemical mechanisms that are critical for the development of sensitization are not known. In the present study, the role of the hypothalamic pituitary adrenal axis (HPA) in the development of behavioral sensitization to amphetamine was explored by pretreating rats with an intravenous administration of an antiserum to corticotropin-releasing factor in a volume that has been shown to block significantly stress- and cocaine-induced activation of the HPA. Four groups of eight rats were pretreated intravenously with either heparinized saline or CRF antiserum and subcutaneously with saline or d-amphetamine in a balanced design. The rats were then returned to their home cages and left undisturbed for seven days after which they were given three consecutive behavioral tests with saline SC, 0.75 mg/kg d-amphetamine SC, and 3.0 mg/kg d-amphetamine SC. The rats pretreated with intravenous CRF antiserum showed a significant attenuation of the development of d-amphetamine-induced sensitization but the antiserum did not alter the magnitude of the behavioral response to the initial, sensitizing dose of d-amphetamine. These results suggest that activation of the hypothalamic pituitary adrenal axis may be of critical importance to the development of behavioral sensitization to amphetamine.     

Sex and estrous cycle differences in the display of conditioned defeat in Syrian hamsters

We have reported that there is a sex difference in the behavioral response to social defeat in hamsters. While previously defeated male hamsters fail to display normal territorial aggression and instead produce submissive/defensive behavior, a phenomenon that we have termed conditioned defeat (CD), only a small portion of previously defeated females exhibit CD. In Experiment 1, we tested the hypothesis that CD varies over the estrous cycle and found that previously defeated female hamsters tested on diestrus 2 and proestrus were more likely to exhibit CD than were females tested on diestrus 1 and estrus. In Experiment 2, we found that regardless of hormonal status, non-defeated females displayed normal territorial aggression, indicating that the behavioral changes observed in Experiment 1 were not due to a cyclic variation in submissive behavior independent of a previous defeat encounter. In Experiment 3, we found that females tested 4 days after defeat responded similarly to those tested 1 day after defeat suggesting that the hormonal status of females on the day of testing is a more important determinant of the behavioral response to defeat than is the hormonal status on the day of defeat training. Finally, in Experiment 4, we monitored anxiety-like behaviors in diestrous 1 and proestrous females in an open field arena and found that there was no effect of cycle on any of the observed behavioral measures, suggesting that the observed differences in CD are not the result of differences in generalized anxiety-like behaviors across the estrous cycle.     

The ACTH-(4-9) analog ORG 2766 and desglycinamide9-(Arg8)-vasopressin reverse the retrograde amnesia induced by disrupting circadian rhythms in rats

Disrupting circadian organization by exposing rats to a shifted illumination schedule after training for passive avoidance and shuttle box avoidance behavior resulted in retrograde amnesia as evidenced by impaired performance during retention and extinction testing respectively. A single treatment with either the ACTH-(4-9) analog ORG 2766 or desglycinamide9-(Arg8)-vasopressin (DGAVP) 1 hour prior to the retention of passive avoidance or extinction of shuttle box avoidance behavior restored the behavioral impairment. It is suggested that these peptides may be useful to relieve memory deficits induced by disturbances in circadian organization.     

Mephedrone in Adolescent Rats: Residual Memory Impairment and Acute but Not Lasting 5-HT Depletion

Mephedrone (4-methylmethcathinone, MMC) is a popular recreational drug, yet its potential harms are yet to be fully established. The current study examined the impact of single or repeated MMC exposure on various neurochemical and behavioral measures in rats. In Experiment 1 male adolescent Wistar rats received single or repeated (once a day for 10 days) injections of MMC (30 mg/kg) or the comparator drug methamphetamine (METH, 2.5 mg/kg). Both MMC and METH caused robust hyperactivity in the 1 h following injection although this effect did not tend to sensitize with repeated treatment. Striatal dopamine (DA) levels were increased 1 h following either METH or MMC while striatal and hippocampal serotonin (5-HT) levels were decreased 1 h following MMC but not METH. MMC caused greater increases in 5-HT metabolism and greater reductions in DA metabolism in rats that had been previously exposed to MMC. Autoradiographic analysis showed no signs of neuroinflammation ([¹²⁵I]CLINDE ligand used as a marker for translocator protein (TSPO) expression) with repeated exposure to either MMC or METH. In Experiment 2, rats received repeated MMC (7.5, 15 or 30 mg/kg once a day for 10 days) and were examined for residual behavioral effects following treatment. Repeated high (30 mg/kg) dose MMC produced impaired novel object recognition 5 weeks after drug treatment. However, no residual changes in 5-HT or DA tissue levels were observed at 7 weeks post-treatment. Overall these results show that MMC causes acute but not lasting changes in DA and 5-HT tissue concentrations. MMC can also cause long-term memory impairment. Future studies of cognitive function in MMC users are clearly warranted.     

Comparative analysis of haloperidol effects on passive avoidance retention in aggressive and submissive mice

The effects of haloperidol on retention of avoidance during its extinction in C57BL/6J mice were shown to depend on a behavioral stereotype (aggressive or submissive). In submissive mice, haloperidol (0.5 mg/kg) injected an hour before training stabilized retrieval of the conditioned reflex in repeated testings (up to 17 days) as compared to its fast extinction in control animals. In aggressive mice, on the contrary, haloperidol reduced the retention of the memory trace retrieval. It is suggested that divergent haloperidol effects on extinction of passive avoidance in mice with alternative behavioral strategies are determined by the features of organization of the mesolimbico-cortical dopaminergic system and emotional state, in particular, anxiety.     

Development of tolerance in rats to the hypothermic effects of D-amphetamine and apomorphine

Rats given d-amphetamine (15 mg/kg i.p.) or apomorphine (10 mg/kg i.p.) and placed in a cold environment (4°C) developed marked hypothermia. After daily injections of either drug for seven weeks, the maximal hypothermic responses to d-amphetamine or apomorphine were reduced to 72% and 19% of those obtained initially. Subsequent injection of ET-495, a central dopamine receptor stimulant, caused rectal temperature to decrease only 72% and 49% as much as in control animals. The hypothermic response to apomorphine was also depressed in d-amphetamine-treated animals. These observations suggest that the tolerance to the hypothermic effects of both d-amphetamine and apomorphine that develops is due at least in part to alterations in the sensitivity of dopamine receptors.     

Blocking of conditioned taste avoidance induced by wheel running

In Experiment 1, compared to non-reinforced presentation of a food stimulus (A → no US), the association of a food stimulus with wheel running (A → US) blocked subsequent avoidance of a distinctive flavor (X), when both the food and flavor were followed by wheel running (AX → US). Experiment 2 replicated and extended the blocking effect, demonstrating that the amount of avoidance of X after AX → wheel training depended on the correlation between A-alone trials and wheel running—the predictiveness of the A stimulus. The present study is the first to demonstrate associative blocking of conditioned taste avoidance (CTA) induced by wheel running and strongly implicates associative learning as the basis for this kind of avoidance.     

Reversal of amphetamine induced polysome dissociation by neuroleptic agents in rat brain

Administration of d-amphetamine to rats causes the dissociation of brain polysomes in a dose-dependent manner. Further, the dose of d-amphetamine required to induce a stereotypic state in rats coincides with the dose needed to cause polysome dissociation. The enantiomeric form, i.e. 1-amphetamine, is ineffective in inducing both the behavioral and biochemical changes even at a dose as high as 30 mg/kg. Clinically potent neuroleptics such as haloperidol and chlorpromazine can effectively reverse the polysome dissociation as well as the behavioral changes induced by a near toxic dose of d-amphetamine (15 mg/kg).     

Acute effects of d-amphetamine on the differential reinforcement of low-rate (DRL) schedule behavior in the rat: comparison with selective dopamine receptor antagonists

Amphetamine and it analogs have been shown to affect operant behavior maintained on the differential reinforcement of a low-rate (DRL) schedule. The aim of the present study was to investigate what specific component of the DRL response is affected by d-amphetamine. The acute effects of d-amphetamine on a DRL task were compared with those of the selective dopamine D1 and D2 receptor antagonists, SCH23390 and raclopride, respectively. Pentylenetetrazole and ketamine were also used as two reference drugs for comparison with d-amphetamine as a psychostimulant. Rats were trained to press a lever for water reinforcement on a DRL 10-s schedule. Acute treatment of d-amphetamine (0, 0.5, and 1.0 mg/kg) significantly increased the response rate and decreased the reinforcement in a dose-related fashion. It also caused a horizontal leftward shift in the inter-response time (IRT) distribution at the doses tested. Such a shifting effect was confirmed by a significant decrease in the peak time, while the mean peak rate and burse response remained unaffected. In contrast, both SCH23390 (0, 0.05, and 0.10 mg/kg) and raclopride (0, 0.2, and 0.4 mg/kg) significantly decreased the total, non-reinforced, and burst responses. The de-burst IRT distributions were flattened out as shown by the dose-related decreases in the mean peak rate for both dopamine antagonists, but no dramatic shift in peak time was detected. Interestingly, neither pentylenetetrazole (0, 5, and 10 mg/kg) nor ketamine (0, 1, and 10 mg/kg) disrupted the DRL behavioral performance. It is then conceivable that d-amphetamine at the doses tested affects the temporal regulation of DRL behavior. The effectiveness of d-amphetamine is derived from its drug action as a psychostimulant. Taken together, these data suggest that different behavioral components of DRL task are differentially sensitive to pharmacological manipulation.     

Valproate enhances fluid consumption suppressed by shock or neophobia, but not by partial satiation or d-amphetamine, in rats

The effects of sodium valproate (100 and 300 mg/kg) on fluid consumption in water deprived rats were assessed. Drinking was inhibited to approximately equal extents by a water pre-load, by d-amphetamine (1.5 mg/kg), by neophobia and by shock at mild (0.3mA) or moderate (0.5mA) intensities, the latter condition having an enhanced level of deprivation also. At both doses valproate significantly enhanced drinking in the neophobia, mild shock and moderate shock conditions but failed to increase drinking suppressed by pre-load or d-amphetamine. It is concluded that the increases in drinking suppressed by neophobia or shock which valproate induces are due to anxiolytic actions of the drug and not non-specific enhancement of fluid consumption. The present results also constitute a further parallel between the actions of valproate and those of benzodiazepines.     

Effects of metals on fish behavior: a review

Synopsis Behavioral toxicity tests, if properly designed, can be used in conjunction with standard acute lethality tests, chronic full or partial life cycle tests, and early life stage toxicity tests to add ecological realism to toxicant assessments and the regulations made as an outgrowth of these assessments. Changes in certain fish behaviors, especially cough rate and avoidance reactions, are very sensitive indicators of sublethal exposure to metals. Other tests involving predator avoidance, feeding behavior, learning, social interactions, and a variety of locomotor behaviors show promise but have been insufficiently studied to judge their sensitivity or utility. No behavioral tests have been standardized and few have been verified in the field. We discuss the behavioral tests that have been used with metals, examine their sensitivity compared with standard laboratory toxicity tests, and assess the potential ecological significance of the behavioral changes observed.Journal Paper No. .1-11959 of the Iowa Agriculture and Home Economics Experiment Station, Ames, IA 50011. U.S.A. Project No. 2627.     

Substance P enhancement of inhibitory avoidance learning: mediation by the N-terminal sequence.

Experiments were performed to investigate the effects of intraperitoneally administered undecapeptide substance P (SP), its N-terminal fragment SP(1-7) (SPN) and the C-terminal analog [pGlu6]-SP(6-11) (SPC) on inhibitory avoidance learning, using a one-trial up-hill avoidance task. In Experiment 1 rats were injected with either SP (50 micrograms/kg), SPN (3.3, 33, 167, 333 micrograms/kg) or SPC (2.7, 27, 134, 268 micrograms/kg) immediately after the training trial. Controls received the diluent vehicles. When tested 24 hr later, rats injected with 50 micrograms/kg SP (37 nmol/kg) and 167 micrograms/kg SPN (185 nmol/kg) exhibited longer step-up latencies than vehicle-treated controls. None of the other doses of SPN nor of the C-terminal fragment influenced performance. In Experiment 2, 167 micrograms/kg SPN or vehicle was injected posttrial either immediately or 5 hr after the training trial. Retention latencies 24 hr later were longer for rats treated with 167 micrograms/kg SPN immediately after the training trial. Performance of the SPN 5-hr delay group did not differ from that of the vehicle-injected controls, ruling out proactive effects of SPN on recall.     

Chemosensory Adaptation to Lysozyme and GTP Involves Independently Regulated Receptors in Tetrahymena thermophila

ABSTRACT. Chemosensory adaptation is seen in Tetrahymena thermophila following prolonged exposure (ten minutes) to micromolar concentrations of the chemorepellents lysozyme or guanosine triphosphate (GTP). Since these cells initially show repeated backward swimming episodes (avoidance reactions) in these repellents, behavioral adaptation is seen as a decrease in this repellent-induced behavior. The time course of this behavioral adaptation is paralleled by decreases in the extents of surface binding of either [³²P]GTP or [³H]lysozyme in vivo. Scatchard plot analyses of repellent binding in adapted cells suggests the behavioral adaptation is due to a dramatic decrease in the number of surface binding sites, as represented by decreased Bmax values. The estimated K_D values for nonadapted cells are 6.6 μM and 8.4 μM for lysozyme and GTP binding, respectively. Behavioral adaptation and decreased surface receptor binding are specific for each repellent. The GTP adapted cells (20 μM for ten minutes) still respond behaviorally to 50 μM lysozyme and bind [³H]lysozyme normally. Lysozyme adapted cells (50 μM for ten minutes) still bind [³²P]GTP and respond behaviorally to GTP. All the behavioral and binding changes seen are also reversible (deadaptation). Neomycin was shown to be a competitive inhibitor of [³H]lysozyme binding and lysozyme-induced avoidance reactions, but it had no effect on either [³²P]GTP binding or GTP-induced or avoidance reactions. These results are consistent with the hypothesis that there are two separate repellent receptors, one for GTP and the other for lysozyme, that are independently downregulated during adaptation to cause specific receptor desensitization and consequent behavioral adaptation.     

Cocaine, in contrast to D-amphetamine, does not cause axonal terminal degeneration in neostriatum and agranular frontal cortex of Long-Evans rats

Continuous three day administration via implanted minipumps of cocaine hydrochloride (50-450 mg/kg/day, sc and 100-250 mg/kg/day, iv) did not produce axonal degeneration in frontal agranular cortex or neostriatum that was detectable by Fink-Heimer silver staining or tyrosine hydroxylase immunolabeling. This is in contrast to the extensive axonal degeneration detectable in these regions following d-amphetamine sulfate (10-60 mg/kg/day) administered following an identical protocol. Doses of cocaine and amphetamine were equated using three measures: 1) weight loss, 2) lethality and 3) behavioral activation. Thus, cocaine resembles other catecholamine reuptake blockers and does not cause the neurodegenerative changes characteristic of other abused drugs that interact with the brain's dopamine systems.     

Extending mathematical principles of reinforcement into the domain of behavioral pharmacology

Mathematical principles of reinforcement (MPR) attempts to integrate the empirical laws of reinforcement schedules that have accumulated over the decades. MPR is based on three principles: incentives excite behavior; there are temporal constraints on responding; and coupling of responses to reinforcers strengthens behavior [Behav. Brain Sci. 17 (1994) 105]. In the present paper MPR is extended into the domain of behavioral pharmacology, specifically to model the effects of D-amphetamine on operant behavior. In Experiment 1a, a five-component multiple fixed-ratio schedule was designed to generate behavioral baselines that were subsequently used to assess drug effect. In Experiments 1b and 1c, the quality and quantity of reinforcer were manipulated. The data generated by the three experiments were consistent with MPR. In Experiment 2, MPR was used to model the effects of D-amphetamine on rats responding under the five-component multiple fixed-ratio schedule. According to the model, the rate-decreasing effects of D-amphetamine were due primarily to motor disruption and secondarily to increased impulsivity; at the highest dosages, D-amphetamine also may have decreased the incentive value of food.