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Psychopharmacology (v.141, #2)

Ganglioside GM1 attenuates scopolamine-induced amnesia in rats and mice by R. H. Silva; L. F. Felicio; R. Frussa-Filho (pp. 111-117).
 Some experimental evidence suggests that the beneficial effects of monosialoganglioside GM1 on learning and memory could be related to an improving effect in central cholinergic function. The present study investigates the effects of GM1 on the memory impairment induced by scopolamine in rats or mice tested in passive (PA) and discriminative avoidance (DA) tasks, respectively. Wistar EPM-1 male rats and Swiss EPM-M1 male mice were treated daily IP with 50 mg/kg GM1 or saline for 7 or 14 days, respectively. Twenty-four hours after the last injection, GM1-treated animals received 1 mg/kg scopolamine (GM1-SCO) and saline-treated animals received 1 mg/kg scopolamine (SAL-SCO) or saline (SAL-SAL) IP. Twenty minutes later, the animals were submitted to PA or DA conditioning, and tests were performed 24 h later. The latency in entering the dark chamber of the PA apparatus (LD) presented by SAL-SCO rats was significantly decreased when compared to that presented by SAL-SAL animals. GM1-SCO animals showed an increased LD when compared to SAL-SCO animals and were not significantly different from SAL-SAL rats. GM1-SCO and SAL-SAL (but not SAL-SCO) mice spent significantly less time in the aversive enclosed arm of the discriminative avoidance apparatus when compared to the time spent in the non-aversive enclosed arm. The results are consistent with the interpretation that GM1 attenuates scopolamine-induced amnesia. Although not eliminating the participation of other transmitter systems, the present study indicates a possible role of central cholinergic transmission in the action of this compound on learning and memory.

Keywords: Key words Memory; Learning; Monosialoganglioside; Scopolamine

Effects of test conditions on the outcome of place conditioning with morphine and naltrexone in mice by A. Y. Bespalov; Mary E. Tokarz; Scott E. Bowen; Robert L. Balster; P. M. Beardsley (pp. 118-122).
 Drug administration during test trials can increase the expression of place conditioning, offering an opportunity to determine the specificity of this enhanced response. Prior to training, Swiss-Webster mice spent similar durations in each of the distinctive compartments of a two-compartment box during three 900-s tests. During a 4-day conditioning period, daily injections of morphine (5–20 mg/kg, SC) or vehicle were differentially paired with one of two compartments of the box using an unbiased place conditioning procedure. Post-conditioning tests were conducted 2 and 3 days after the last conditioning day. Mice pre-treated during post-conditioning tests with vehicle did not show significant preference for the morphine-paired compartment when conditioned with morphine. Pretreatment with morphine (2.5–30 mg/kg, SC) led to a dose-dependent increase in time spent in the morphine-paired compartment. Post-conditioning tests in other groups of mice were conducted with heroin (0.1–3 mg/kg), fentanyl (0.01–0.3 mg/kg), cocaine (10–30 mg/kg) and pentobarbital (10–30 mg/kg), and results suggested that none of the tested drugs facilitated the expression of the morphine-conditioned place preference. In another experiment, naltrexone (0.1–10 mg/kg, SC) was administered as the conditioning drug. When tested with naltrexone (0.1–10 mg/kg), there was a dose-dependent avoidance of the naltrexone-paired compartment. Overall, the present data indicated that: (1) failure to exhibit place preference or place aversion when tested in a drug-free state does not imply the failure of conditioning procedure; and (2) effects of the morphine cue reinstatement during the post-conditioning tests appeared to be related to the unique pharmacological profile of the morphine stimulus.

Keywords: Key words Place conditioning; State-dependency; Stimulus properties; Morphine; Fentanyl; Heroin; Cocaine; Pentobarbital; Naltrexone; Mice

Repeated neonatal maternal separation alters intravenous cocaine self-administration in adult rats by K. Matthews; Trevor W. Robbins; Barry J. Everitt; S. B. Caine (pp. 123-134).
 Behavioural responses to psychostimulant drugs can be profoundly affected by early environmental influences. The aim of this study was to describe the effects of repeated brief separations of rat pups from their dams during the early neonatal period on cocaine self-administration behaviour as adults. Lister hooded rats exposed to a repeated maternal separation procedure (REMS) showed altered acquisition and maintenance of cocaine self-administration as adults, the effects being dose and gender-dependent. Overall, the patterns of acquisition of self-administration across three doses of cocaine (0.05, 0.08 and 0.5 mg/injection) suggested a rightward shift in the acquisition dose-effect functions for the REMS animals relative to control animals. At 0.05 mg/injection, there was a retarded acquisition of cocaine self-administration in male and female neonatally separated rats. At 0.08 mg/ injection there was a facilitated acquisition in female neonatally separated subjects. After establishment of stable self-administration of the training dose, in the same cohort of subjects, rightward and downward shifts in the cocaine self-administration dose-effect functions were determined for female and male REMS subjects, respectively, relative to their controls. The dose-effect function for both female groups was shifted to the left of that of the respective male groups, although the lighter body weights of the females meant that they administered a higher unit dose per unit body weight than the males. Whereas male REMS subjects tended to self-administer less cocaine than the controls at the dose eliciting maximal responding (0.03 mg/injection) and to make fewer lever responses overall at each dose tested, female REMS subjects self-administered significantly more cocaine than their respective controls at a dose of 0.03 mg/injection. There was no differential sensitivity to the rate-altering effects of the selective dopamine D2 receptor antagonist, eticlopride, or to the selective dopamine D1 receptor antagonist, SCH 23390. These data provide further evidence that altered early environment affects drug-taking behaviour in a developmentally specific and gender-specific manner, with the effects of neonatal separation contrasting with previously published data on the effects of post-weaning isolation rearing.

Keywords: Key words Maternal separation; Cocaine; Intravenous self-administration; Mesolimbic dopamine; Reward; Eticlopride; SCH 23390

Increased sensitivity to the locomotor depressant effect of a dopamine receptor antagonist during cocaine withdrawal in the rat by B. A. Baldo; Athina Markou; George F. Koob (pp. 135-144).
 The effect of a dopamine receptor antagonist on locomotor activity was examined during withdrawal from either self-administered or experimenter-administered cocaine. In the self-administration experiment, the locomotor response to a challenge injection of cis-flupenthixol was assessed in photocell cages at 4 h after the cessation of a 12-h cocaine self-administration session. Rats which had self-administered cocaine, and were challenged with cis-flupenthixol (0.05 mg/kg), were found to be hypoactive relative to controls. In the experimenter-administered cocaine experiment, animals were given eight IP injections of 15 mg/kg cocaine over a 9.5-h period, for a total of 120 mg/kg. At 4, 8, and 24 h (tested in three separate groups of rats) after cessation of the eight injections, the locomotor response to a challenge injection of saline or cis-flupenthixol was tested. Cocaine-treated animals displayed a dose-dependent, heightened sensitivity to the locomotor depressant effects of 0.05 mg/kg and 0.2 mg/kg cis-flupenthixol 4 h post-cocaine, whereas they did not show increased sensitivity to 0.05 mg/kg cis-flupenthixol 8 or 24 h post-cocaine. However, cocaine-treated animals displayed a mild hypoactivity 8 h post-cocaine. In a separate group of animals, a dose-response experiment was performed which indicated that a dose of cis-flupenthixol as high as 0.2 mg/kg was required to produce locomotor depression in cocaine-naive rats. The results of this study support clinical observations of dopamine antagonist-precipitated motor dysfunction in abstinent cocaine abusers, and lend further support to the hypothesis that alterations in dopaminergic neurotransmission consequent to prolonged cocaine exposure are partly responsible for some of the symptoms of cocaine withdrawal.

Keywords: Key words cis-flupenthixol; Cocaine; Dopamine receptor antagonist; Locomotor activity; Self-administration; Psychomotor stimulant; Withdrawal

Effects of continuous oral nicotine administration on brain nicotinic receptors and responsiveness to nicotine in C57Bl/6 mice by J. A. Sparks; J. R. Pauly (pp. 145-153).
 The route of drug delivery is an important consideration in studies that evaluate the long-term biobehavioral adaptations that occur in response to chronic drug administration. Continuous infusions (intravenous or subcutaneous) or intermittent intraperitoneal (or subcutaneous) injections are the most commonly utilized routes of chronic drug delivery in these studies. The purpose of the present study was to determine the effects of chronic oral nicotine exposure on sensitivity to nicotine and brain nicotinic cholinergic receptors in female C57Bl/6 mice. Mice were randomized to different treatment groups that received 2% saccharin, containing 0–200 μg/ml nicotine (free base). In preliminary experiments, radiotelemetry devices were implanted in the mice; consumption of the nicotine-containing drinking solution caused a significant increase in home-cage nocturnal (but not diurnal) activity and also altered circadian alterations in body temperature. Oral nicotine exposure resulted in dose-related elevations in plasma levels of cotinine, a primary nicotine metabolite. Continuous exposure (30 days) to oral nicotine (200 μg/ml) resulted in the expression of significant tolerance to the locomotor depressant and hypothermic actions of acute nicotine challenge. This tolerance was accompanied by a significant increase in brain nicotinic receptor number assessed by quantitative autoradiography using [3H]-cytisine (α4 nAChr) and [125I]-α-bungarotoxin (α7 nAChr) as radioligands. These results suggest that chronic oral nicotine delivery to female C57Bl/6 mice results in behavioral and biochemical changes that resemble changes that occur following other routes of chronic nicotine delivery.

Keywords: Key words Nicotine; Cytisine; α-Bungarotoxin; Autoradiography; Oral; Circadian rhythm; Tolerance

Locomotor response to MDMA is attenuated in knockout mice lacking the 5-HT1B receptor by Kimberly Scearce-Levie; Sandya S. Viswanathan; R. Hen (pp. 154-161).
3,4-Methylenedioxymethamphetamine (MDMA) is a psychoactive drug of abuse which is increasingly popular in human recreational drug use. In rats, the drug has been shown to stimulate locomotion while decreasing exploratory behavior. MDMA acts as an indirect agonist of serotonin (5-HT) receptors by inducing 5-HT release by a 5-HT reuptake transporter-dependent mechanism, although it is not known which 5-HT receptors are important for the behavioral effects of the drug. In order to examine the role of specific 5-HT receptors, we assessed the behavioral effects of MDMA on knockout mice lacking the 5-HT1B receptor. Knockout animals show a reduced locomotor response to MDMA, although delayed locomotor stimulation is present in these animals. This finding indicates that the locomotor effects of MDMA are dependent upon the 5-HT1B receptor, at least in part. In contrast, MDMA eliminates exploratory behavior in both normal and knockout mice, suggesting that the exploratory suppression induced by MDMA occurs through mechanisms other than activation of the 5-HT1B receptor. To confirm these findings, we tested the effects of MDMA on the locomotor and exploratory behavior of wild-type mice pretreated with GR 127935, a 5-HT1B/1D receptor antagonist. These mice had an attenuated locomotor response to MDMA, but still exhibited the drug-induced suppression of exploration.

Keywords: Key words 3; 4-Methylenedioxymethamphetamine (MDMA); Serotonin; Locomotion; Exploratory behavior; Knockout mice; Drug abuse; 5-HT1B receptor

Effect of 5-HT2 receptor antagonists on a cranial nerve reflex in the rabbit: evidence for inverse agonism by J. A. Harvey; S. E. Welsh; H. Hood; A. G. Romano (pp. 162-168).
 This study examined the role of the serotonin 5-HT2 receptor in motor function by examining the effect of antagonists on the motor performance of a cranial nerve reflex, the nictitating membrane (NM) reflex of the rabbit. The NM reflex was elicited by varying intensities of a tactile stimulus and the magnitudes of the elicited responses were measured at each intensity. Dose-response curves were obtained for the effects of several 5-HT2 receptor antagonists on response magnitude. d-Bromolysergic acid diethylamide (BOL), LY-53,857 and ketanserin had no significant effect on the magnitude of the NM reflex, indicating that they are neutral antagonists. However, the 5-HT2 receptor antagonists ritanserin, MDL-11,939 and mianserin produced a significant reduction in response magnitude with no significant effects on response frequency, suggesting that they were acting as inverse agonists at the 5-HT2 receptor. The reduction in reflex magnitude produced by mianserin (10 µmol/kg) was fully blocked by BOL (5.8 µmol/kg), supporting the conclusion that mianserin was producing a reduction in reflex magnitude through an effect at the 5-HT2 receptor. The occurrence of inverse agonism suggests the possible existence of constitutive activity in vivo. We conclude that the 5-HT2 receptor (either 2A or 2C) plays an important role in motor function, perhaps by providing a tonic influence on motor systems.

Keywords: Key words Ritanserin; MDL-11; 939; Mianserin; Ketanserin; BOL; LY-53; 857; 5-HT2A/2C receptor antagonists; Nictitating membrane; Motor performance; Rabbit

Sensitization elicited by directly and indirectly acting dopaminergic agonists: comparison using neural network analysis by P. Laudrup; L. J. Wallace (pp. 169-174).
 The major aim of this work was to compare sensitized responses to amphetamine with those of apomorphine. This was done using both a univariant analysis of locomotor activity and a multivariant neural network analysis of five different behaviors. The neural network analysis compares the pattern of behaviors from a treated group to a set of patterns from control conditions and estimates the dose of drug in control conditions that best matches the pattern of behaviors of the treated group. Both methods indicated that repeated administration of 2.0 mg/kg amphetamine but not 0.5 mg/kg amphetamine resulted in sensitization to the administration of a 0.5 mg/kg amphetamine challenge given 10 days following the end of the sensitizing regimen. Both analyses indicated sensitization following repeated administration of 5 mg/kg apomorphine. Studies of cross sensitization were done using a neural network analysis that could distinguish patterns of behavior elicited by amphetamine from those elicited by apomorphine. Such studies indicated that apomorphine elicits an apomorphine-like response in animals sensitized to either apomorphine or amphetamine. In contrast, amphetamine produces an amphetamine-like response in animals sensitized to amphetamine and an apomorphine-like response in animals sensitized to apomorphine. The results indicate that neural network analysis may be a useful tool for analyzing drug effects on patterns of behavior.

Keywords: Key words Sensitization; Neural network analysis; Amphetamine; Apomorphine

In vivo 123I IBZM SPECT imaging of striatal dopamine-2 receptor occupancy in schizophrenic patients treated with olanzapine in comparison to clozapine and haloperidol by J. Tauscher; B. Küfferle; S. Asenbaum; P. Fischer; L. Pezawas; C. Barnas; S. Tauscher-Wisniewski; T. Brücke; S. Kasper (pp. 175-181).
We investigated the degree of striatal dopamine-2 (D2) receptor occupancy in six schizophrenic patients receiving clinically effective antipsychotic treatment with olanzapine 10–25 mg/day in comparison to patients treated with clozapine 300–600 mg/day (n = 6) or haloperidol 5–20 mg/day (n = 10). 123I Iodobenzamide (IBZM) and single photon emission computerized tomography (SPECT) were used for the visualization of striatal D2 receptors. For the quantification of striatal D2 receptor occupancy, striatal IBZM binding in patients treated with antipsychotics was compared to that in untreated healthy controls (n = 8) reported earlier. Olanzapine led to a mean striatal D2 receptor occupancy rate of 75% (range 63–85). Haloperidol-treated patients showed dose-dependently (Pearson r = 0.64; P < 0.05) a significantly higher (P < 0.05) mean occupancy rate of 84% (range 67–94). During clozapine treatment, the mean D2 receptor occupancy of 33% (range < 20–49) was significantly lower than with olanzapine (P < 0.005). The higher striatal D2 receptor occupancy of haloperidol was correlated with the incidence and severity of extrapyramidal motor side-effects (EPS). No clinical relevant EPS occurred during treatment with olanzapine or clozapine. There was no correlation between the degree of striatal D2 receptor occupancy and clinical improvement.

Keywords: Key words Olanzapine; Dopamine D2 receptor; 123I IBZM; SPECT; Atypical antipsychotic drug

Effect of a tyrosine-free amino acid mixture on regional brain catecholamine synthesis and release by Sarah F. B. McTavish; Philip J. Cowen; T. Sharp (pp. 182-188).
We report the effects of a tyrosine (and phenylalanine)-free amino acid mixture on tyrosine levels, ex vivo catecholamine synthesis and in vivo catecholamine release in brain regions of the rat. Administration of a tyrosine-free amino acid load reduced tissue levels of tyrosine (−50% after 2 h) in all brain regions examined (frontal cortex, hippocampus, striatum). The tyrosine-free amino acid mixture also reduced DOPA accumulation: this effect was most marked in striatum (−44%) and nucleus accumbens (−34%), areas with a predominantly dopaminergic innervation. Smaller decreases (−20–24%) were detected in other areas (cortex, hippocampus and hypothalamus). The effect on DOPA accumulation was prevented by supplementing the mixture with tyrosine/phenylalanine. The tyrosine-free amino acid mixture did not alter 5-HTP accumulation in any region. In microdialysis experiments, the tyrosine-free amino acid mixture did not consistently alter striatal extracellular dopamine under basal conditions but markedly, and dose-dependently, reduced the release of dopamine induced by amphetamine. In contrast, the tyrosine-free amino acid mixture did not alter either basal or amphetamine-evoked release of noradrenaline in hippocampus. Overall, these studies indicate that administration of a tyrosine-free amino acid mixture to rats depletes brain tyrosine to cause a decrease in regional brain catecholamine synthesis and release. Dopaminergic neurones appear to be more vulnerable to tyrosine depletion than noradrenergic neurones.

Keywords: Key words Tyrosine depletion; Catecholamine; Dopamine; Noradrenaline; Microdialysis

Involvement of the medial geniculate body in prepulse inhibition of acoustic startle by Jianhua Zhang; Jörgen A. Engel; M. Ericson; L. Svensson (pp. 189-196).
Prepulse inhibition of acoustic startle is the normal reduction in startle response to an intense auditory stimulus when this stimulus is immediately preceded by a weaker prestimulus. Previous studies have shown that several neuroanatomical structures and pathways in the brain are involved in the modulation of prepulse inhibition. In the present study, the functional importance of the medial geniculate body (MG) in the modulation of prepulse inhibition was investigated. To this end, in vivo brain microdialysis probes were used to infuse drugs locally into the MG of awake, freely moving rats simultaneously with startle response and prepulse inhibition measurements in the same animals. Intrageniculate infusion of the sodium channel blocker, tetrodotoxin, significantly reduced prepulse inhibition without affecting baseline startle amplitude. A similar effect was obtained after intrageniculate infusion of the GABAB receptor agonist, baclofen. In addition, intrageniculate infusion of muscimol, an agonist at the GABAA receptor complex, reduced prepulse inhibition, although this effect was obtained at a higher concentration of the drug compared to that of baclofen. These studies suggest that the MG is involved in the modulation of prepulse inhibition and that auditory signals relayed via the MG may be subjected to inhibitory control at this level, involving GABA neurotransmission.

Keywords: Key words Acoustic startle response; Prepulse inhibition; Sensorimotor gating; Schizophrenia; Medial geniculate body; Rat

Differential effects of GABAA and GABAB agonists on sensitization to the locomotor stimulant effects of ethanol in DBA/2 J mice by Julie Broadbent; Wendy E. Harless (pp. 197-205).
 Contemporary theories of drug abuse suggest that behavioral sensitization plays an important role in addiction. However, few studies have examined the mechanisms underlying behavioral sensitization to ethanol. The present study examined the ability of THIP (2, 4, or 8 mg/kg) and baclofen (5.0, 6.25, or 7.5 mg/kg), GABAA and GABAB agonists, respectively, to prevent development of sensitization to the locomotor stimulant effects of ethanol (2 g/kg) in DBA/2 J mice. Ethanol was administered immediately before four 5-min activity trials conducted at 48-h intervals. Administration of ethanol on each of the four trials resulted in behavioral sensitization in control groups. While having few effects on activity when given alone, both GABA agonists completely blocked the acute stimulant response to ethanol on the first trial. Administration of THIP prior to ethanol on each trial failed to prevent development of sensitization. In contrast, all doses of baclofen blocked sensitization. Assessment of blood ethanol levels 15, 50 and 100 min after administration of ethanol indicated that baclofen did not change the pharmacokinetics of ethanol. These results indicate an important role for GABAB receptors, but not GABAA receptors, in development of sensitization to the locomotor stimulant effects of ethanol.

Keywords: Key words GABA agonists; THIP; Baclofen; Sensitization; Ethanol; Locomotor activity; DBA/2 J mice

Effects of benzodiazepine agonists on punished responding in pigeons and their relationship with clinical doses in humans by M. S. Kleven; Wouter Koek (pp. 206-212).
 Anxiolytic drugs generally produce anticonflict effects in both pigeons and rats, although relatively few anxiolytics have been examined in the pigeon and the procedure has not been as completely validated as the rat model. In this study, we examined the antipunishment effects of a variety of benzodiazepine agonists in pigeons and compared the relationship between their potencies to engender anxiolytic-like effects and their clinical doses in humans. In pigeons whose responding was maintained under a multiple FR30food:FR30food+shock schedule, the benzodiazepine agonists diazepam, flunitrazepam, alprazolam, chlordiazepoxide, lorazepam, flurazepam, bromazepam, medazepam, and clorazepate produced dose-related increases in punished responding, and, with the exception of medazepam, decreased unpunished responding at higher doses. Potencies calculated from the percentage of pigeons showing significant increases in punished responding ranged from 0.081 to 11 mg/kg, and these potencies were invariably lower than those for decreases in unpunished responding by factors ranging from 2.2 to more than 14. The comparison of relative potencies of benzodiazepine receptor agonists in pigeons and humans revealed a high positive correlation (0.90, P<0.005), thus demonstrating the predictive validity of this preclinical animal model for anxiolytic benzodiazepines. The results agree with previous findings of robust anticonflict effects of benzodiazepine receptor agonists and extend further the pharmacological characterization to compounds that have not been examined previously in pigeons.

Keywords: Key words Conflict behavior; Pigeon; Anxiolytic

The GABAA receptor antagonist picrotoxin attenuates most sleep changes induced by progesterone by M. Lancel; Johannes Faulhaber; Florian Holsboer; Rainer Rupprecht (pp. 213-219).
Progesterone has been shown to exert benzodiazepine-like effects on sleep, which suggests that they are mediated by an agonistic modulation of GABAA receptor functioning. To assess the involvement of GABAA receptors, we investigated the sleep responses to one dose of the GABAA antagonist picrotoxin (1.5 mg/kg) and progesterone (90 mg/kg), administered IP to eight rats alone and in combination, during the first 4 post-injection hours. Compared with vehicle, picrotoxin significantly delayed the latency to non-rapid eye movement sleep (non-REMS) and thereby decreased all sleep states, but barely affected the EEG activity within non-REMS. Progesterone significantly shortened non-REMS latency, increased pre-REMS, depressed low-frequency EEG activity (≤8 Hz) and augmented EEG activity in the higher frequencies within non-REMS. Except for the changes in high-frequency EEG activity, picrotoxin attenuated all effects of progesterone. These findings support the notion that GABAA receptors play an important role in the sleep effects of progesterone.

Keywords: Key words Neurosteroids; GABAA receptor; Sleep; EEG spectral analysis; Rat

Effect of nociceptin on alcohol intake in alcohol-preferring rats by Roberto Ciccocioppo; Izabela Panocka; Carlo Polidori; Domenico Regoli; M. Massi (pp. 220-224).
The present study investigated the effect of nociceptin (NC), the endogenous ligand of the opioid-like orphan receptor ORL1, on ethanol intake in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. Acute intracerebroventricular (ICV) injection of 250 or 500 ng/rat of NC, just before access to 10% ethanol (offered 2 h/day), significantly increased ethanol intake. Subchronic (7 days) ICV injection of 500 ng/rat of NC, given just before access to 10% ethanol (for 30 min/day), resulted in a progressive decrease in ethanol consumption. After the end of NC treatment, rats progressively recovered their usual ethanol intake. When NC, 500 or 1000 ng/rat, was tested versus the effect of ethanol in the place conditioning paradigm, NC significantly reduced the increase in time spent in the ethanol-paired compartment after conditioning. This finding suggests that NC reduces the rewarding properties of ethanol in msP rats; thus, they may respond to the acute NC administration by increasing their ethanol intake in an attempt to achieve the usual reinforcing effect of ethanol, whereas subchronic NC treatment may result in extinction of ethanol drinking. The results of the present study suggest that the brain NC mechanisms may represent an interesting target of pharmacological interventions for the treatment of alcoholism.

Keywords: Key words Nociceptin; Orphanin FQ; Alcohol intake; Marchigian Sardinian alcohol-preferring rat

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