Strain differences in delay discounting between Lewis and Fischer 344 rats at baseline and following acute and chronic administration of d-amphetamine

Stimulant drugs have been shown either to increase or decrease rates of delay discounting (impulsive choice). These mixed findings may result from genetic, neurochemical, or environmental factors. Lewis (LEW) and Fischer 344 (F344) rats have neurochemical and behavioral differences that may be relevant to delay discounting and were used to examine effects of acute and chronic administration of d-amphetamine (d-AMP) on impulsive choice using a within-session delay-discounting procedure. Male LEW (n = 8) and F344 (n = 8) rats chose between one food pellet delivered immediately and three food pellets delivered after an increasing delay. Saline and d-AMP (0.1, 0.3, 1.0, and 1.7 mg/kg) were tested acutely and during chronic d-AMP exposure. Choice for the larger reinforcer decreased as the delay to its presentation increased for both strains at baseline. LEW rats made more impulsive choices than F344 rats as indicated by shorter indifference points, and this is consistent with previous research. Acute administration of d-AMP dose dependently increased larger-reinforcer choice and area under the curve (AUC) for LEW, but not F344 rats. During chronic exposure to d-AMP, larger-reinforcer choice and AUC increased relative to acute administration for F344 rats responding in shorter delay series, but not for F344 rats responding in longer delay series or for LEW rats. Differential effects of acute and chronic administration of d-AMP on impulsive choice in LEW and F344 rats may be a result of various factors, including genetic, neurochemical, and environmental variables. Future research should attempt to tease apart the relative contribution of each of these factors on impulsive choice.     

Tachykinin antagonists inhibit the morphine withdrawal response in guinea-pigs

Summary This study was an investigation of the effects of the tachykinin antagonists, spantide and (d-Pro⁴, d-Trp^{7, 9, 10})substance P 4-11, injected intracerebroventricularly (ICV), on the locomotor and behavioural responses of guinea-pigs to substance P (SP) injected ICV and to naloxone-induced morphine withdrawal. SP, 50 nmol, produced increased locomotor activity and behaviour that mimicked the response induced by injection of naloxone hydrochloride, 15 mg/kg, in guinea-pigs treated 2 h previously with morphine sulphate, 15 mg/kg. Spantide or (d-Pro⁴, d-Trp^{7, 9, 10})SP4-11, 10 nmol, reduced the locomotor and behavioural responses to SP and to morphine withdrawal. The results support the suggestion that SP or a related tachykinin might be a mediator of the opioid withdrawal response in the central nervous system as has been proposed for the enteric nervous system.     

The antiepileptic agent gabapentin (Neurontin) possesses anxiolytic-like and antinociceptive actions that are reversed byd-serine

This report describes the activity of the antiepileptic agent gabapentin (Neurontin) in animal models predictive of anxiolysis and analgesia. Gabapentin displayed anxiolytic-like action in the rat conflict test, the mouse light/dark box and the rat elevated X-maze with respective minimum effective doses (MEDs) of 3, 10 and 30 mg/kg. Furthermore, gabapentin also induced behavioural changes suggestive of anxiolysis in the marmoset human threat test with a MED of 30 mg/kg. In the rat formalin test of tonic nociception, gabapentin dose-dependently (30–300 mg/kg) and selectively blocked the late phase with a MED of 100 mg/kg. However, it failed to block carrageenan-induced paw oedema. The intracerebroventricular (ICV) administration of the glycine/NMDA receptor agonistd-Serine, dose-dependently (10–100 μg/animal) reversed the antinociceptive action of gabapentin (200 mg/kg, SC).d-Serine (30 μg/animal, ICV) also reversed the anxiolytic-like effects (in the light/dark box and the rat elevated X-maze) of gabapentin (30 mg/kg). In contrast,l-Serine (100 μg, ICV) failed to block the antinociceptive action of gabapentin. The antinociceptive action of (+)-HA-966 (25 mg/kg, SC), a partial agonist at the glycine/NMDA receptor, was reversed byd-Serine (100 μg/animal, ICV). However,d-Serine (100 μg/animal, ICV) failed to affect the antinociceptive action of a competitive NMDA receptor antagonist CGS 19755 (3 mg/kg, SC). Gabapentin has negligible affinity for the strychnine insensitive [³H]glycine binding site. This indicates that the interaction between gabapentin andd-Serine may not involve the NMDA receptor complex. Gabapentin may represent a novel type of anxiolytic and analgesic agent.     

Discriminative stimulus effects of a centrally administered,delta-opioid peptide (d-Pen2-d-Pen5-enkephalin) in pigeons

The present study assessed the discriminative stimulus effects of the delta-opioid agonist [d-Pen²-d-Pen⁵]enkephalin (DPDPE) in pigeons. Food-restricted pigeons were trained to discriminate between ICV injections of 100 μg [d-Pen²-d-Pen⁵]enkephalin (DPDPE) and saline in a two-key operant procedure; acquisition of discriminative control was rapid (14–28 daily sessions). [d-Ser², Leu⁵, Thr⁶]enkephalin (DSLET) and [d-Ala²]deltorphin II, peptides selective for delta-opioid receptors, produced discriminative stimulus effects similar to DPDPE, and were approximately equipotent to DPDPE. The non-peptidic, delta-opioid agonist BW373U86 (9.032–100 mg/kg, IM) partially generalized to DPDPE. The kappa-opioid agonist U69,593 (0.01–1 mg/kg, IM), and the mu-opioid agonists, DAMGO (0.1–3.2 μg, ICV) and morphine (1–10 mg/kg, IM), did not produce discriminative stimulus effects similar to DPDPE, up to doses that markedly decreased response rates. Naltrindole (0.1 mg/kg, IM), an antagonist selective for delta-opioid receptors, produced approximately a 30-fold reduction in the potency of DPDPE. DPDPE’s discriminative stimulus effect in pigeons appears to be mediated through a delta-opioid receptor; this effect may provide a procedure for assessing delta-opioid receptor function in vivo.     

Differences in morphine reinforcement property in two inbred rat strains: associations with cortical receptors,behavioral activity,analgesia and the cataleptic effects of morphine

The purpose of the current study was to investigate genetic differences between two inbred strains of rats, Fisher-344 (F344/N) and Wistar Albino Glaxo (WAG/GSto), in a number of drug-naive and drug-related behaviors, including oral and intravenous morphine self-administration. F344/N and WAG/GSto rats differed in drug-naive behaviors such as nociception, rearing and sensitivity to lick suppression tests but did not differ in locomotor activity, ambulation or grooming behavior. F344/N rats were less sensitive to thermal stimuli as measured via tail-flick response, and more sensitive to the suppressive effects of intermittent shock in a lick suppression test. The F344/N rats demonstrated a significantly greater amount of rearing in open field tests but did not differ from WAG/GSto rats in locomotor activity, ambulation or grooming behavior. In addition to the behavioral results, naive F344/N and WAG/GSto rats were found to differ in and ₂ receptor concentrations (F344/N>WAG/GSto) and in 5HT₂ and D₂ affinity constants (WAG/GSto>F344/N). These two inbred rat strains also differed in drug-related behaviors. F344/N rats showed significantly greater depression of locomotor activity at morphine 3 mg/kg than WAG/GSto rats. In addition, F344/N rats consumed significantly greater amounts of morphine in a two-bottle choice procedure and morphine maintained significantly greater amounts of behavior during intravenous self-administration sessions. Importantly, drug maintained behavior was significantly greater than with vehicle only in the F344/N rats during operant self-administration sessions.     

Caffeine-induced taste aversions in Lewis and Fischer rat strains: differential sensitivity to the aversive effects of drugs

Lewis (LEW) and Fischer 344 (F344) rat strains have been reported to differ in the aversive effects induced by a number of drugs. The present studies extended this previous work and examined the ability of caffeine to induce taste aversions in the two strains. Specifically, LEW and F344 rats were given access to saccharin and injected with varying doses of caffeine (0, 0.32, 1.0 and 3.2 mg/kg—Experiment 1; 0, 10, 18 and 32 mg/kg—Experiment 2). Additionally, the effects of caffeine on locomotor activity were examined in Experiment 2. At low doses (Experiment 1), caffeine failed to induce taste aversions in either strain. At higher doses (Experiment 2), aversions were induced that were strain dependent. Specifically, caffeine induced taste aversions in both strains at 32 mg/kg, while 18 mg/kg caffeine was effective in inducing aversions only in the LEW strain. Caffeine increased activity in both strains with no strain difference. This demonstration adds to the growing list of drugs on which the LEW and F344 strains differ in relation to their affective properties. Given that drug use and abuse are a function of the balance of the rewarding and aversive effects of drugs, understanding such strain differences may provide insight into the biological (and genetic) factors impacting abuse vulnerability.     

Spontaneous and apomorphine-induced locomotor changes parallel dopamine receptor differences in two rat strains

Two inbred strains of rats (F344 and Buffalo) were tested for differences in spontaneous and apomorphine-induced inhibition of locomotor activity. F344 rats showed greater percentage decreases in locomotion after apomorphine (0.25, 1.0 and 2.5 mg/kg) compared to the Buffalo strain. F344 rats also showed higher levels and slower habituation of spontaneous locomotor activity. F344 rats had previously been shown to have significantly higher densities of D₂-dopamine receptors in the striatum and olfactory tubercle and also more apomorphine-induced stereotypy when compared to Buffalo rats. These results confirm and extend previous studies suggesting that genetic differences in brain D₂-dopamine receptors can predict behavioral differences in locomotor activity.     

Neurotensin-induced hypothermia in the rat: structure-activity studies

Neurotensin (NT), an endogenous brain tridecapeptide, produces hypothermia after intracerebroventricular administration in rats and mice. The hypothermie potency of a series of structural analogues of neurotensin has been studied. [d-Arg⁹]-NT, NT_9–13 and physalemin were devoid of hypothermie activity. The most potent peptides studied in reducing body temperature of cold-exposed rats were bombesin and [d-Tyr¹¹]-NT. [d-Arg⁸]-NT, [Phe¹¹]-NT, [d-Pro⁷]-NT, NT-MHMe [d-Pro¹⁰]-NT and NT_8–13 possessed significant hypothermie activity, though the latter two compounds were the least active. These results indicate that the C-terminal end of the neurotensin molecule is essential for hypothermie activity.     

Dopamine depletion augments endogenous opioid-induced locomotion in the nucleus accumbens using bothμ1 andδ opioid receptors

The aim of this study is to analyze further the opioid receptor subtypes involved in the augmentation of behavioral activity after dopamine depletion in the nucleus accumbens of rats. Initially, the opioid receptors involved in the augmentation of locomotion produced by endogenous opioids were evaluated by microinjection of kelatorphan, an inhibitor of proteolytic enzymes that inactivates enkephalin, with or without specific antagonists forμ ₁ orδ-opioid receptors, naloxonazine or naltrindole, respectively. Kelatorphan produced a dose-dependent increase in horizontal photocell counts and vertical movements. At all doses examined the behavioral response was augmented in rats sustaining accumbal dopamine lesions. The augmentation in dopamine-depleted rats was partially blocked by naloxonazine or naltrindole. Since the motor stimulant response to intra-accumbens microinjection of theδ-opioid agonist, [d-penicillamine^2,5]-enkephalin, was not augmented in a previous study, we tested the behavioral response to a new endogenousδ-opioid agonist, [d-Ala²] deltorphin I. The locomotor response to deltorphin was slightly augmented in dopamine-depleted rats. These data suggest that the augmentation in the motor response elicited by endogenous opioids after dopamine lesions in the nucleus accumbens involves bothμ ₁ andδ-opioid receptors.     

Effects of stress modulation on morphine-induced conditioned place preferences and plasma corticosterone levels in Fischer, Lewis, and Sprague–Dawley rat strains

Rationale There is a direct relationship between hypothalamic–pituitary–adrenal axis (HPA) reactivity and susceptibility to drug use in outbred rats. Specifically, manipulations that increase or decrease HPA activity also increase or decrease drug intake, respectively. Interestingly, this relationship has not been established in the inbred Fischer (F344) and Lewis (LEW) rat strains that are often used as animal models of susceptibility to drug use.Objective The present study investigated the effects of manipulations known to affect HPA activity on morphine-induced conditioned place preference (CPP) in male LEW, F344, and Sprague–Dawley (SD) rats.Materials and methods In experiment 1, animals were exposed to an injection of methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) and 2-h restraint stress prior to the conditioning of a morphine-induced place preference (1, 4, or 10 mg/kg subcutaneous). In experiment 2, animals were chronically exposed to corticotropin-releasing hormone type 1 receptor antagonist, antalarmin, prior to CPP training. The effects of DMCM/restraint and antalarmin on corticosterone levels were examined in experiments 3 and 4.Results In outbred rats, DMCM/restraint increased both HPA activity and morphine-induced CPP, while antalarmin decreased CPP and produced a slight, but nonsignificant, decrease in corticosterone levels. In the inbred rats, however, DMCM/restraint increased plasma corticosterone yet decreased place preferences in the LEW strain, and antalarmin treatment decreased plasma corticosterone but increased place preferences in the F344 strain.Conclusions These data suggest that the relationship between stress and drug use may be nonmonotonic. The use of these inbred strains in genetic analysis of drug addiction may require reexamination.     

Comparison of the discriminative and antinociceptive effects of morphine and its glucuronide metabolites after central or systemic administration in the rat

 The potential of centrally (ICV) or systemically (SC) administered M6G to substitute for morphine in a drug discrimination task was characterized in the present study. Rats with a cannula in the lateral cerebral ventricle were trained to discriminate between injections of morphine (3 mg/kg, SC) and saline using a discrete-trial avoidance/escape procedure. Substitution tests were conducted with SC or ICV morphine, morphine-3-β-d-glucuronide (M3G), or morphine-6-β-d-glucuronide (M6G) and response latency in a tail-flick test was measured before each session began. The stimulus effects of morphine (ED₅₀=1.02 mg/kg SC or 2.1 μg/kg ICV) were fully shared by M6G, with potency dependent on route of administration (ED₅₀=3.12 mg/kg SC or 0.34 μg/kg ICV). The stimulus effects of M6G were highly correlated with its antinociceptive activity (r=0.84 SC or 0.46 ICV) and, at equipotent systemic doses, they lasted longer (t1/2=391 min) than those of morphine (t1/2=185 min). M3G was inactive in both procedures by both routes of administration. Naltrexone SC, given 30 min prior to testing, completely attenuated the stimulus effects of ICV M6G (AD₅₀=0.011 mg/kg), indicating that they are mediated by opioid receptors. The results of this study suggest that M6G might contribute to the interoceptive effects of morphine that underlie its potential for abuse. Received: 29 January 1998 / Final version: 21 March 1998     

Selective potentiations in opioid analgesia following scopolamine pretreatment

The effects of the muscarinic receptor antagonist scopolamine upon analgesia induced by d-ala-d-leu-enkephalin (DADL), beta-endorphin (BEND) and morphine were examined. While scopolamine (10 mg/kg, IP) significantly potentiated the analgesic responses following DADL (40 g, ICV) and morphine (5 mg/kg, SC) on the jump test, it failed to alter significantly BEND (1 g, ICV) analgesia.     

Strain differences in response to escapable and inescapable novel environments and their ability to predict amphetamine-induced locomotor activity

Rationale. Locomotor response to novelty predicts locomotor and reinforcing effects of psychostimulant drugs in outbred rats. Among Lewis and Fischer 344 (F344) inbred rats this association is less clear, perhaps due to strain-selective differences in responses to novelty. Objective. We examined responses to novel inescapable and escapable environments and to novel objects in these strains. Methods. Experiment 1 utilized a place conditioning procedure. Rats were confined to one side for 8 days and then allowed access to both this (familiar) and the novel sides. Experiment 2 assessed locomotor response within an inescapable environment. On another occasion, contacts with novel objects within a novel environment were tabulated. Corticosterone levels and fecal boli were measured. Whether these responses predicted amphetamine-induced locomotor activity was determined. To further assess genetic contributions to this association, experiment 3 assessed novelty responses in F1 hybrid Lewis-F344 rats. Results. Lewis rats showed greater novelty-seeking behavior in the escapable environment but lower locomotor activity in the inescapable environment compared to F344 rats. There were no strain differences in novel object contacts, corticosterone, or fecal boli responses. Baseline corticosterone levels and activity levels in the novel environment were positively correlated with amphetamine activity based on data from all rats. However, novelty and amphetamine-induced activity showed non-significant negative correlations in F344 and Lewis rats. Yet, F1 rats showed a significant positive correlation between these variables, even though some of their other responses were Lewis-like or F344-like. Conclusions. These data suggest that responses to different novelty situations are strain-dependent. Electronic Publication     

Strain differences between Lewis and Fischer 344 rats in the modulation of dopaminergic receptors after morphine self-administration and during extinction

The Lewis (LEW) and Fischer 344 (F344) rat strains have been used as a model to study genetic vulnerability to drug addiction and they differ in their dopaminergic systems. We have studied the variation in the D1-like and D2-like receptors in distinct brain regions of LEW and F344 rats that self-administered morphine (1 mg/kg) for 15 days and also after different extinction periods (3, 7 and 15 days). Under basal conditions, binding to D1-like receptors in the olfactory tubercle and substantia nigra, and to D2-like receptors in the Pyriform cortex and hippocampal-CA1 was lower in LEW rats than in F344 rats. Conversely, the LEW rats exhibited stronger D2-like binding in the caudate-putamen. In most brain regions there was a decrease in D1-like binding in LEW rats after self-administration while the F344 animals displayed an increment. Additionally, D2 receptors of LEW rats were down-regulated after self-administration in the caudate-putamen and in the nucleus accumbens (shell and core divisions). Binding to D1-like receptors increased in both strains in the early phases of extinction, while in the later stages a differential regulation was observed between both strains. During the early phases of extinction only F344 rats showed alterations in D2-like receptor binding, however in the latter phases a specific modulation occurred in both strains. These differences in basal D1-like and D2-like receptor binding, and their differential modulation after self-administration and during extinction, may be reflected in the greater vulnerability to opiate addiction shown by LEW strain.     

Morphine-induced place conditioning in Fischer and Lewis rats: acquisition and dose-response in a fully biased procedure

The Fischer (F344) and Lewis (LEW) rat strains differ on a variety of behavioral assays examining the effects of morphine, with many of the differences observed during acquisition of behavioral responses. The results of these studies and others examining endogenous physiology and the biochemical effects of morphine suggest that F344 rats are more sensitive to morphine than LEW rats. However, LEW animals have shown greater conditioned place preferences (CPP) to 4 mg/kg than F344 rats. CPP is a popular assay of drug reward in which acquisition of the preference can be measured across multiple conditioning cycles, yet this aspect of CPP has not been assessed in F344 and LEW rats. As part of an ongoing effort to fully characterize the conditioned rewarding effects of abused drugs in these strains, the present study assessed the effects of 0, 1, 4 and 10 mg/kg subcutaneous (SC) morphine in adult male F344 and LEW rats (n=12/strain/dose). A fully biased place conditioning procedure was employed where morphine's effects were paired with the initially non-preferred chamber on Day 1, saline was paired with the preferred chamber on Day 2 and drug-free access to the entire apparatus was allowed on Day 3. This conditioning and testing regimen was repeated for four consecutive cycles. The F344 animals acquired CPP at 1 mg/kg only; this effect emerged after only two conditioning cycles. LEW rats never acquired a CPP at any dose tested. Peak blood morphine levels following SC injections of 1, 4 or 10 mg/kg revealed no significant strain or dose effects. These behavioral data are consistent with the hypothesis that F344 rats are more sensitive to the rewarding effects of morphine than LEW rats. Additional implications for the Fischer-Lewis model of drug abuse and the utility of CPP acquisition procedures are discussed.     

Genetic differences in the development of physical dependence on pentobarbital in four inbred strains of rats

Fischer 344 (F344), Lewis (LEW), spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats were chronically fed food containing pentobarbital on an escalating drug dosage schedule over a period of 47 days. During treatment, the growth curve in LEW, SHR and WKY rats was suppressed as compared with the respective controls. Motor incoordination was evaluated by a rotarod performance test. The ranking of the motor incoordination was as follows: WKY much greater than LEW greater than SHR greater than F344. After substitution of normal food for the pentobarbital-admixed food, various signs of pentobarbital withdrawal occurred. The withdrawal signs from pentobarbital in F344, LEW and SHR rats were mild as compared with those in WKY rats. The order of the severity of withdrawal signs in four inbred strains was parallel to that for motor incoordination. These results suggest that the differences between strains in withdrawal can be attributed to differences in the degree of chronic CNS depression produced by pentobarbital.     

Inbred rat strain comparisons indicate different sites of action for cocaine and amphetamine locomotor stimulant effects

Cocaine and amphetamine produce several behavioral effects, most notably locomotor stimulation. Biochemically, evidence suggests specific involvement of dopaminergic systems, although not necessarily identical sites, in mediating cocaine- and amphetamine-induced locomotor stimulation. This study examined the effects of cocaine or amphetamine on locomotor activity in rats from the ACI, F344, LEW and NBR inbred strains. Dose-dependent increases in locomotor activity were found for both drugs in all strains. However, large potency and efficacy differences were found. Further, significant strain by drug interactions were found, in that the strain rank order for stimulant response to the two drugs was not identical. Since striatal dopaminergic neurons influence locomotor activity, we also assessed ligand affinity and receptor density of dopamine transporters and dopaminergic D₁ and D₂ receptors in striatal tissue from these same strains of rats. No differences in these receptor binding parameters were found. These findings support the conclusion that these two drugs produce their locomotor stimulant effects through different sites of action, and that genetic differences in response to these drugs at the behavioral level do not appear to be mediated significantly by differences in structure or number of striatal dopaminergic sites. The further use of genetic methods, however, may aid in determining the specific sites of action of these widely used stimulant drugs.     

Morphine-induced conditioned taste aversions in the LEW/N and F344/N rat strains

Previous reports have shown that the LEW/N and F344/N inbred rat strains display a differential sensitivity to cocaine in a number of preparations, with the LEW/N rats displaying an increased sensitivity to both the reinforcing and aversive effects of cocaine (relative to the F344/N rats). Given that the LEW/N rats are also more sensitive to the reinforcing effects of morphine than the F344/N strain, the present experiment examined the ability of morphine to condition taste aversions in the LEW/N and F344/N strains to determine if the general sensitivity to cocaine generalizes to another drug of abuse. Specifically, on four conditioning trials, 35 LEW/N and 33 F344/N female rats were allowed access to a novel saccharin solution and then injected with varying doses of morphine (0, 10, 32 and 56 mg/kg). On intervening recovery days, subjects were allowed 20-min access to water. Following the fourth trial, a final aversion test was administered. The F344/N rats, but not the LEW/N rats, rapidly acquired morphine-induced taste aversions at all doses of morphine. Pharmacokinetic differences between the strains were also assessed. Specifically, 10 mg/kg morphine (or vehicle) was administered to subjects of both strains and plasma morphine levels were analyzed at 0.5, 2 and 4 h postinjection. No differences in plasma levels between the strains were observed. Unlike with cocaine, the LEW/N rats do not seem generally sensitive to morphine (relative to the F344/N rats). Rather, the differential sensitivity of the two strains to these compounds seems to be preparation dependent. Possible mechanisms underlying the differential sensitivity evident in the strains were discussed.     

Effects of μ and δ opioid agonists and antagonists on affective vocal and reflexive pain responses during social stress in rats

The present experiments evaluated the influence of intraventricular μ and δ opioid receptors on affective vocal and reflexive responses to aversive stimuli in socially inexperienced, as well as defensive and submissive responses in defeated, adult male Long-Evans rats. Defeat stress consisted of: (1) an aggressive confrontation in which the experimental intruder rat exhibited escape, defensive and submissive behaviors [i.e., upright, supine postures and ultrasonic vocalizations (USV)], and subsequently, (2) protection from the resident stimulus rat with a wire mesh screen for 10–20 min. Defeat stress was immediately followed by an experimental session with tactile startle (20 psi). The μ opioid receptor agonists morphine (0.1–0.6 μg ICV) and [D-Ala²-N-Me-Phe⁴-Gly⁵-ol]-enkephalin (DAMGO; 0.01–0.3 μg ICV), and the δ opioid receptor agonist [D-Pen^2,5]-enkephalin (DPDPE; 10–100 μg ICV) dose-dependently decreased startle-induced USV and increased tail-flick latencies in socially inexperienced and defeated rats. Of greater interest, morphine, DAMGO and DPDPE increased the occurrence of the submissive crouch posture, and defeated rats were more sensitive than socially inexperienced rats to the startle-induced USV-suppressive and antinociceptive effects of morphine and DPDPE. The antinociceptive effects of DAMGO were likewise obtained at lower doses in defeated rats. Finally, the USV-suppressive effects of morphine and DAMGO were reversed with the μ receptor antagonist naltrexone (0.1 mg/kg IP), but the USV-suppressive effects produced by DPDPE were not reversed with the δ receptor antagonist naltrindole (1 mg/kg IP). These results confirm μ, but not δ opioid receptor activation as significant in affective vocal, passive-submissive behavior, as well as reflexive antinociception. Furthermore, similar to previous studies with restraint and electric shock stress, the facilitation of μ opioid effects on vocal responses and antinociception is consistent with the proposal that defeat stress activated endogenous opioid mechanisms. Received: 23 September 1997/Final version: 15 January 1998     

Phencyclidine-induced abnormal behaviors in rats as measured by the hole board apparatus

Rationale: Phencyclidine (PCP) and methamphetamine (MAP) are known as psychotomimetic agents. Both agents produce behavioral alterations in animals. Objective: The present study investigated the difference in behavioral alterations in rats induced by these two psychotomimetic agents using the hole board apparatus (HBA). In addition, mechanisms underlying PCP-induced behavioral changes were also investigated. Methods: After the administration of PCP (1–4 mg/kg SC) or MAP (1–4 mg/kg SC), locomotor activity and dipping behavior were assessed using HBA. Effect of selective NMDA antagonists, (+)MK801 and 3-((±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), on rat behaviors were also assessed. The effects of d-alanine (d-Ala), a coagonist of NMDA receptors, or neuroleptics, haloperidol, clozapine and risperidone, on PCP-induced behavioral changes were investigated. Results: PCP increased locomotor activity and decreased exploratory behaviors of rats in HBA. On the other hand, MAP increased locomotor activity but did not decrease exploratory behaviors. (+)MK-801 produced hyperactivity as well as decreased exploratory behaviors, eliciting behavioral changes very similar to those of PCP. CPP decreased the exploratory behavior but failed to produce hyperactivity. d-Ala attenuated both behavioral changes induced by PCP. Three neuroleptics tested here inhibited hyperactivity but did not attenuate decreases in exploratory behavior. Conclusion: These results suggest that PCP-induced decrease in exploratory behavior are attributable to antagonism of NMDA receptors and may not involve dopaminergic transmission via D₂ receptors. Received: 24 May 1999 / Final version: 16 August 1999