Showing papers in "Pharmacology, Biochemistry and Behavior in 1987"

Interactions between sucrose, pain and isolation distress.

Abstract: Two experiments were conducted that establish an opioid-based, functional-relationship between the taste of sucrose, pain threshold and distress vocalization in isolated 10-day-old albino rats. In the first experiment intraoral infusion of sucrose virtually doubled heat-withdrawal latencies. This elevation was naltrexone (0.5 mg/kg b.wt.) reversible. In the second experiment sucrose infusions caused a rapid and sustained diminution of distress vocalizations in rats totally isolated from dam and siblings. These are the first demonstrations of a causal relationship between a positive affective system and ones mediating pain and stress.

Contents of monoamines in forebrain regions of alcohol-preferring (P) and -nonpreferring (NP) lines of rats.

Abstract: The contents of monoamine neurotransmitters and metabolites were assayed in the frontal cortex, nucleus accumbens and anterior striatum of rats from the selectively bred alcohol-preferring P and nonpreferring NP lines Lower levels of serotonin (20–30%) in all three brain regions of P as compared with NP rats lends support to the hypothesis that a decreased metabolic activity and/or innervation by serotonin neurons is associated with the abnormally high volitional intake of ethanol Of additional interest, however, were the approximately 25% lower contents of dopamine and its major metabolites in the nucleus accumbens of the P rats This observation may indicate that P rats have a specific deficiency in the dopaminergic projections from the ventral tegmental area to the nucleus accumbens and, since the accumbens is an important structure in brain reward circuitry, it might also be an important determinant of the excessive volitional intake of alcohol by P rats

Acute and chronic ethanol treatments alter GABA receptor-operated chloride channels.

Abstract: The effect of ethanol exposure in vitro on the GABA receptor-operated chloride channel was evaluated by monitoring 36Cl- influx in a membrane vesicle suspension (microsacs) prepared from mouse cerebellum. These experiments directly demonstrate ethanol augmentation of muscimol-stimulated chloride flux. DBA/2J mice were made tolerant to and dependent on ethanol by administration of an ethanol containing liquid diet for 7 days. Exposure to physiologically relevant concentrations of ethanol (10-45 mM) in vitro potentiated muscimol stimulation of 36Cl- uptake in control (pair-fed) membranes, but had no effect on cerebellar microsacs from tolerant/dependent mice. Muscimol stimulation of 36Cl- uptake was not different for pair-fed and ethanol-treated mice. Augmentation of muscimol-induced 36Cl- flux by in vitro ethanol was abolished by a single 4 g/kg injection of ethanol. This "acute tolerance" occurred within 5 min and disappeared within 24 hr after ethanol treatment. The reduced sensitivity of ethanol treated (chronic and acute) mice to ethanol potentiation of muscimol stimulated 36Cl- uptake offers a biochemical correlate to the phenomenon of ethanol tolerance. Moreover, the findings suggest that this biochemical tolerance develops rapidly following a single hypnotic dose of ethanol.

Corticotropin-releasing factor administration elicits a stress-like activation of cerebral catecholaminergic systems

Abstract: The cerebral content of the biogenic amines, dopamine (DA), norepinephrine (NE), and serotonin (5-HT) and their catabolites 30 min after CRF or saline injections was determined using HPLC with electrochemical detection. Injection of CRF (1.0 μg) into the lateral ventricles (ICV) of mice produced a behavioral activation in which their motor movements appeared as bursts of activity followed by periods of immobility. CRF administration (ICV or SC) did not alter the concentrations of DA, NE, tryptophan, 5-HT, or 5-hydroxyindoleacetic acid (5-HIAA) in any brain region measured. ICV CRF increased the concentrations of dihydroxyphenylacetic acid (DOPAC), the major catabolite of DA, and of 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG), the major catabolite of NE, in several brain regions. DOPAC:DA ratios were consistently increased in prefrontal cortex, septum, hypothalamus, and brain stem relative to animals injected with saline. MHPG:NE ratios were also increased in the prefrontal cortex and hypothalamus, with a marginal effect (p=0.06) in brain stem. SC CRF significantly increased DOPAC:DA in prefrontal cortex, and MHPG:NE in prefrontal cortex, hypothalamus and brain stem. Pretreatment with naloxone did not prevent any of the neurochemical responses to ICV CRF, but naloxone alone increased DOPAC:DA in medial profrontal cortex, and decreased MHPG:NE in nucleus accumbens in CRF-injected mice. These results suggest that administration of CRF either centrally or peripherally induces an activation of both dopaminergic and noradrenergic systems in several regions of mouse brain. The pattern resembles that we observe in mice following stressful treatments such as footshock or restraint, but the effect of CRF on noradrenergic systems is less pronounced. Also, brain free tryptophan which is consistently increased in all brain regions by footshock or restraint was not altered by CRF. Thus CRF triggers a response in CNS catecholamine systems that resembles, but does not precisely mimic, that observed following commonly used stressors. This activation of CNS catecholamine metabolism may be related to some of the behavioral effects of CRF, but not all of them because naloxone, which prevents the effects of CRF on exploratory behavior, did not alter the catecholamine responses to CRF.

GABAergic mechanisms of analgesia: an update.

Abstract: Both directly acting (GABAA and GABAB agonists) and indirectly acting GABAergic agents (GABA uptake inhibitors and GABA-transaminase inhibitors) produce analgesia in a variety of animal test systems. Analgesia produced by GABAA agonists is probably due to a supraspinal action, although spinal sites may also play a role. GABAA agonist analgesia is insensitive to naloxone, bicuculline, picrotoxin and haloperidol, but is blocked by atropine, scopolamine and yohimbine suggesting a critical role for central cholinergic and noradrenergic pathways in this action. The lack of blockade by the GABAA antagonist bicuculline is difficult to explain. Both bicuculline and picrotoxin have intrinsic analgesia actions which may not necessarily be mediated by GABA receptors. The GABAB agonist baclofen produces analgesia by actions at both spinal and supraspinal sites. Baclofen analgesia is insensitive to naloxone, bicuculline and picrotoxin, and blockade by cholinergic antagonists occurs only under limited conditions. Catecholamines are important mediators of baclofen analgesia because analgesia is potentiated by reserpine, alpha-methyl-p-tyrosine, phentolamine, ergotamine, haloperidol and chlorpromazine. A role for serotonergic mechanisms is less well defined. Methylxanthines, which produce a clonidine-sensitive increase in noradrenaline (NA) turnover, increase baclofen analgesia by a clonidine-sensitive mechanism. Both ascending and descending NA pathways are implicated in the action of baclofen because dorsal bundle lesions, intrathecal 6-hydroxydopamine and medullary A1 lesions markedly decrease baclofen analgesia. However, simultaneous depletion of NA in ascending and descending pathways by locus coeruleus lesions potentiates baclofen analgesia suggesting a functionally important interaction between the two aspects. Baclofen analgesia within the spinal cord may be mediated by a distinct baclofen receptor because GABA does not mimic the effect of baclofen and the rank order of potency both of close structural analogs of baclofen as well as antagonists differs for analgesia and GABAB systems. The spinal mechanism may involve an interaction with substance P (SP) because SP blocks baclofen analgesia, and desensitization to SP alters the spinal analgesic effect of baclofen. GABA uptake inhibitors produce analgesia which is similar to that produced by GABAA agonists because it is blocked by atropine, scopolamine and yohimbine. Analgesia produced by GABA-transaminase inhibitors is similar to that produced by GABAA agonists because it can be blocked by atropine, but it is potentiated by haloperidol while THIP analgesia is not.(ABSTRACT TRUNCATED AT 400 WORDS)

Anxiogenic effects of methyl-β-carboline-3-carboxylate in a light/dark choice situation

Abstract: Doses of benzodiazepine, clorazepate, and also of the inverse agonist of the benzodiazepine receptor, beta-CCM, which failed to present sedative or postictal depressive effects, were at first determined in a free exploratory situation. Then, the effects of clorazepate dosed at 1.0, 2.0 and 4.0 mg/kg and beta-CCM dosed at 1.0 and 2.5 mg/kg were studied in the light/dark box choice procedure. Clorazepate tended to produce an increase of the time spent by mice in the lit box as well as of the number of transitions between the two boxes, whereas the dose of 1.0 mg/kg of beta-CCM had opposite effects. The benzodiazepine antagonist RO 15-1788 completely counteracted the anxiolytic effects of clorazepate dosed at 2.0 mg/kg and the anxiogenic effects of beta-CCM.

Effects of apomorphine and amphetamine on patterns of locomotor and investigatory behavior in rats

Abstract: Rats were tested in a Behavioral Pattern Monitor after various doses of either amphetamine or apomorphine in order to characterize their behavioral profiles, including patterns and sequences of holepokes, rearings and locomotor movements. To enable direct comparisons between the behavioral effects of the two stimulants, doses and times for each drug were selected with which locomotor hyperactivity was the predominant behavioral response. Although both drugs increased the total amount of locomotor activity, amphetamine induced a relatively varied behavioral profile while apomorphine induced repetitive behavior with a restricted range of responses. These contrasting effects of the stimulants were interpreted as reflective of their differing modes of action with regard to central dopaminergic systems. It is suggested that, in the dose range used, the release of dopamine by amphetamine is coupled to neuronal firing and therefore this release increases behavioral activity without altering the normal response repertoire of the animal. Conversely, the direct agonist action of apomorphine results in a restricted and perseverative behavioral pattern because its activation of forebrain dopamine receptors is independent of the normal physiological pattern of dopaminergic neuronal firing.

The influence of estrous cycle and intrastriatal estradiol on sensorimotor performance in the female rat.

Abstract: The influence of estrous cycle and intrastriatal implants of 17 beta-estradiol (17 beta-estradiol). 17 alpha-estradiol (17 alpha-estradiol) or cholesterol on the number of footfaults made by female rats traversing a narrow suspended beam was investigated. Female rats made fewer footfaults on estrus than on other days of the cycle. This was true when testing occurred during either the light or dark phase of the light:dark cycle. Intrastriatal implants of 30% 17 beta-estradiol for 6 hours resulted in a significant improvement in sensorimotor performance as soon as 4 hours after hormone implant and persisting for days. In contrast, intrastriatal implants of either 30% 17 alpha-estradiol or cholesterol had no influence on performance. The extent of hormone diffusion away from the implant cannula was minimal, and the resulting concentration of 17 beta-estradiol in the striatum was less than 10 pg/mg. It is concluded that estradiol has a direct, stereospecific effect in the striatum that influences performance of a skilled motor act in the female rat.

Facilitation of the expression but not the acquisition of latent inhibition by haloperidol in rats.

Abstract: In the latent inhibition (LI) paradigm, nonreinforced preexposure to a stimulus retards subsequent conditioning to that stimulus. The administration of haloperidol in both the preexposure and the conditioning stages was found to enhance LI in the conditioned emotional response (CER) procedure (Weiner and Feldon, 1986). The present experiments investigated the effects of 0.1 mg/kg haloperidol administration on LI in a two-way avoidance procedure, consisting of two stages: preexposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; and conditioning, in which the animals acquired a two-way avoidance response with the tone serving as the warning signal. Experiments 1 and 2 tested whether the administration of haloperidol confined to the preexposure stage, where learning to ignore the nonreinforced stimulus takes place, would suffice to enhance the LI effect. In Experiment 1, preexposure and conditioning were conducted 24 hr apart. LI was obtained in both the placebo and haloperidol conditions, but the effect was not more pronounced under the drug. In addition, haloperidol-treated animals exhibited impaired avoidance performance. In Experiment 2, preexposure and conditioning were given 72 hr apart. With this interval, haloperidol did not affect avoidance performance. However, also under these conditions, the magnitude of the LI effect was not larger in the haloperidol-treated groups, indicating that the administration of the drug in the preexposure stage alone did not suffice to enhance LI. In experiment 3, haloperidol was administered in both the preexposure and the conditioning stages, given 24 hr apart. In addition, animals were re-tested in avoidance 24 hr later without the drug. Haloperidol-treated animals showed poorer avoidance performance in both the initial conditioning and the re-test. However, in both tests, haloperidol groups showed a significantly larger LI effect than placebo controls. The implications of these findings for the effects of haloperidol on LI and learning are discussed.

Long term administration of some antipsychotic drugs increases body weight and feeding in rats. Are D2 dopamine receptors involved

Abstract: Long term administration of the antipsychotic drugs thioridazine, trifluoperazine, haloperidol, and sulpiride increased body weight in rats. This effect was found to be sex dependent, that is, while female rats were prone to gain weight, male rats did not. Chlorpromazine and fluphenazine decreased body weight in male rats but did not affect females. The mechanism of body weight gain was investigated with sulpiride. A linear relationship between dose of sulpiride and body weight gain was found. Also, sulpiride increased caloric intake, and both actions were counteracted by bromocriptine, a specific D2 receptor agonist. These results confirm that antipsychotic drugs affect feeding and body weight and suggest that hyperphagia and body weight gain might be mediated by blockade of dopamine receptors of the D2 type.

Naloxone inhibits mating and conditioned place preference for an estrous female in male rats soon after castration

Abstract: Three experiments were conducted to assess the role of endogenous opioids in controlling mating behavior and sexual reward in the male rat. In Experiment 1 SC administration of naloxone (0.5, 1.0, 5.0, or 10.0 mg/kg) significantly reduced mounting and ejaculation in male rats tested 14, but not 7 days, after castration. In Experiment 2 naloxone (5.0 mg/kg) administered SC to gonadally intact males, which had ejaculated repeatedly with one female until they were sexually sated, significantly inhibited the resumption of mating after the reintroduction of a female partner. One interpretation of these results is that naloxone attenuated the reward experienced by castrated and sexually sated males in the presence of an estrous female, thereby disrupting males' coital performance. This hypothesis was tested in Experiment 3 using a conditioned place preference paradigm in which males copulated with an estrous female in an initially "non-preferred" (white) compartment, whereas on alternate days they remained alone in an initially "preferred" (black) compartment. After 10 such conditioning sessions, males were either castrated or sham-operated. They later were given free access to both compartments in the absence of an estrous female. Seven days after conditioning and surgery, sham-operated, naloxone-injected males and both groups of castrates spent significantly less time than sham-operated, saline-injected controls in the initially "non-preferred" compartment. Fourteen days after conditioning and surgery castrated, naloxone-treated males spent significantly less time in the "non-preferred" compartment than males in the other three groups. Endogenous opioids may play an important role in the interpretation by males of the incentive motivational stimuli which emanate from an estrous female.

Methcathinone: a new and potent amphetamine-like agent.

Abstract: The purpose of the present investigation was to examine the effect of N-monomethylation of phenylisopropylamine derivatives on amphetamine-like activity. In tests of stimulus generalization using rats trained to discriminate 1.0 mg/kg of (+)-amphetamine from saline, the N-monomethyl derivatives of 1-(X-phenyl)-2-aminopropane, where X = 2,4-dimethoxy (2,4-DMA), 3,4-dimethoxy (3,4-DMA), 2,4,5-trimethoxy (2,4,5,-TMA), and 2-methoxy-4,5-methylenedioxy (MMDA-2), did not produce amphetamine-appropriate responding at the doses evaluated. However, the N-monomethyl derivative of cathinone (i.e., methcathinone), like cathinone, resulted in stimulus generalization. Further studies with this agent revealed that (a) in the amphetamine-trained animals, methcathinone (ED50 = 0.37 mg/kg) is more potent than racemic cathinone or racemic amphetamine (ED50 = 0.71 mg/kg in both cases), (b) methcathinone is capable of inducing release of radioactivity from [3H]dopamine-prelabeled tissue of rat caudate nucleus in a manner similar to that observed with cathinone, amphetamine, and methamphetamine, and (c) methcathinone is more potent than cathinone as a locomotor stimulant in mice as determined by their effect on spontaneous activity. The results of the present study provide evidence for a structural analogy between the prototypic psychostimulants amphetamine/methamphetamine and cathinone/methcathinone, and lend further support to the concept that amphetamine and cathinone correspond in their pharmacological effects.

A role for serotonin and beta-endorphin in the analgesia induced by some tricyclic antidepressant drugs

Abstract: The analgesic effect of acute or chronic nortriptyline, amitriptyline and their effects on morphine induced analgesia were evaluated in the rat. Clomipramine and amitriptyline, but not Nortriptyline, induce analgesia, while all potentiate the effect of morphine when administered acutely. The analgesic effect of clomipramine is blunted by both the serotonin antagonist metergoline and the opiate receptor blocker naloxone, thus indicating an involvement of both the serotoninergic and endogenous opioid system. The involvement of the serotoninergic system is confirmed by the similar results obtained with the serotonin precursor 5-hydroxytryptophan administered alone or together with morphine. A relation between the serotoninergic and the endogenous opioid systems is also shown by the increase in hypothalamic beta-endorphin concentrations elicited by all the drugs used after acute or chronic treatment, with the only exception of nortriptyline, that has been shown to exert its effects mainly through the noradrenergic system. In conclusion, the analgesic effect of clomipramine and amitriptyline and their potentiation of morphine induced analgesia seems to be related to an activation of the endogenous opioid system mediated by serotonin.

Oral ethanol reinforcement in the rat: Effect of the partial inverse benzodiazepine agonist RO15-4513

Abstract: The partial inverse benzodiazepine agonist RO15-4513 has been found to reverse the sedating and anti-conflict effects of acute ethanol administration. In non-food or fluid-deprived rats, orally self-administering 10% ethanol in an operant situation, RO15-4513 resulted in a dose-dependent suppression on ethanol intake. Doses of 0.3, 1.0 and 3.0 mg/kg suppressed responding from approximately 25% to 60% respectively. A dose of 0.1 mg/kg had no significant effect upon responding. These findings were discussed in terms of the potential independence of brain mechanisms related to ethanol reinforcement and sedation.

The effect of raising or lowering tryptophan levels on aggression in vervet monkeys

Abstract: were given amino acid mixtures that were tryptophan-free (T-), nutritionally balanced (B), or contained excess tryptophan (T+). The T- mixture caused a marked decrease in plasma tryptophan and the T+ mixture a large increase. Behavioral observations were made on the animals after administration of the amino acid mixtures both during spontaneous activity and while the (fasted) animals were competing for food newly placed in the feeder. The only effect of the biochemical manipulations on spontaneous aggression was an increase in aggression of the male animals with the T- mixture. During competition for the food the T- mixture increased and the T+ mixture decreased aggression in the males, while the T+ mixture decreased aggression in females. These data indicate that brain 5-hydroxytryptamine can influence aggression in a primate and suggest that altered tryptophan levels can influence aggression more reliably at higher levels of arousal. Vervet monkeys Aggression Tryptophan 5-Hydroxytryptamine THE neuroanatomical pathways of the brain that are served by the neurotransmitter 5-hydroxytryptamine (5HT) have been shown to play an important inhibitory role for a number of behavioral states including arousal, sensitivity to pain, sexual behavior, activity levels, sensitization and habitua- tion to novel stimuli, irritability and aggression [29,45]. The relationship between 5HT function and aggression has been the focus of a particularly large number of studies many of which have employed parachlorophenylalanine (PCPA) as a means of depleting 5HT. PCPA is a relatively specific inhibitor of 5HT synthesis [22]. Thus, PCPA has been shown to increase irritability [22], to facilitate muricide in rats [13, 30, 34, 38] and cats [8], filicide (pup killing) in rats [6], and grillicide (cricket-killing) in mice [23]. These effects may be partially or completely reversed by administration of the 5HT precursor 5-hydroxytryptophan [6, 8, 13, 30, 34, 38] or fiuoxetine, a selective inhibitor of 5HT uptake into presynaptic terminals [1]. Also, PCPA has been reported to potentiate brain stimulated (ventromedial hypothalamus) af- fective attack in cats [21], isolation-induced aggression [28] or territorial aggression [39] in mice, shock elicited aggres- sion in rats [37,41], and spontaneous aggression in monkeys [36]. Although reports of no effect or of a decrease in ag- gression following PCPA treatment have also been made [5, 24, 25], for the shock-elicited aggression paradigm at least, the inconsistency seems to be due to differences in choice of test parameters between studies [41]. Depletion of brain 5HT by means of electrolytic lesions of midbrain raphe nuclei [17, 46, 49, 50] or administration of the selective 5HT neurotoxins 5,6-dihydroxytryptamine (DHT) and 5,7-DHT [3, 16, 19] also facilitates aggression in various animal models. Again these effects may be reversed by ad- ministration of the 5HT precursors tryptophan or 5- hydroxytryptophan [19,50]. Conversely, treatment with drugs that are belived to increase 5HT neurotransmission [15, 27, 32, 40] has been shown to decrease aggressivity. A non-pharmacological approach to the study of the rela- tionship between 5HT and aggression has been the use of tryptophan-free diets to lower brain 5HT. Because the syn- thesis of 5HT depends on tryptophan availability [48], limit- ing dietary tryptophan leads to depletion of brain 5HT levels [2, 11, 14]. Feeding rats a tryptophan-free diet for 4 to 6 days has been reported to induce mouse killing in non-killer rats and to decrease attack latencies of killer rats [14]. The diet reduced brain 5-hydroxyindole levels by about 30% whereas supplementation of this diet with tryptophan reversed the effect on both aggression and brain 5HT. Another study [20] confirmed the finding that a tryptophan-free diet increases 1Requests for reprints should be addressed to Dr. S. N. Young, Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montreal, Canada H3A 1A1. 503

Interactions of diazepam and caffeine: behavioral and subjective dose effects in humans.

Abstract: The effects of diazepam (DZ) (0, 10, and 20 mg) and caffeine (CAF) (0, 200, 400, and 600 mg) alone and in combination were examined in nine healthy male subjects using a within-subject experimental design in which all subjects received all twelve possible dose combinations. Drug effects were assessed using various psychomotor and cognitive performance tasks, staff (observer) ratings of subject behavior, and subject ratings of mood and drug effect. DZ treatment alone impaired performance on all tasks and produced staff and subject ratings indicative of sedative drug effects. CAF treatment alone facilitated performance on two psychomotor tasks requiring rapid reaction speed and increased staff ratings of subject restlessness and subject ratings of tension, alertness, arousal, and CAF symptoms. CAF generally antagonized the DZ-induced ratings of sedation and impairment of psychomotor performance; however, CAF did not consistently antagonize the DZ impairment of immediate recall or delayed recognition memory performance. DZ antagonized the CAF-induced staff-rated restlessness, and subject-ratings of tension, alertness, arousal and CAF symptoms. The results generally support the hypothesis that DZ and CAF produce antagonistic effects through functionally opposing mechanisms, however, the observed effects of drug combinations are dependent on the specific doses being tested and on the measures of drug effect being examined.

Interactions between oxiracetam, aniracetam and scopolamine on behavior and brain acetylcholine.

Abstract: The effect of cognition-enhancing agents oxiracetam and aniracetam on scopolamine-induced amnesia and brain acetylcholine decrease was investigated in the rat. Acetylcholine levels were measured by means of a gas-chromatographic method. Scopolamine (0.63 mg/kg IP 60 min before training) prevented the acquisition of a passive avoidance conditioned response ("step through": retest 30 min after training) and brought about a 64, 56 and 42% decrease in acetylcholine level in the cortex, hippocampus and striatum respectively. Oxiracetam (50 and 100 mg/kg IP) administered 30 min before scopolamine reduced the scopolamine-induced amnesic effect and decrease in acetylcholine level in the cortex and hippocampus, but not in the striatum. Lower and higher doses of oxiracetam were ineffective. Aniracetam (100 mg/kg PO) also prevented scopolamine-induced amnesia but attenuated acetylcholine decrease in the hippocampus only. Aniracetam (300 mg PO) reduced acetylcholine decrease in the hippocampus but did not prevent scopolamine-amnesia. In conclusion, oxiracetam and aniracetam exert a stimulatory effect on specific central cholinergic pathways. However, a direct relationship between cognition-enhancing properties and cholinergic activation needs further confirmation.

Quantitative determination of the effects of catecholaminergic agonists and antagonists on the rewarding efficacy of brain stimulation.

Abstract: The effects of amphetamine, clonidine, molindone, pimozide and yohimbine on the rewarding efficacy of electrical stimulation of the medial forebrain bundle in the rat were determined from the effects of these drugs on the rate-frequency function, which is the plot of the rat's rate of pressing a lever against the frequency of the pulses in a rewarding train of fixed duration. These catecholaminergic agonists and antagonists produced dose-dependent alterations in the measurable rewarding efficacy, but only up to a factor of about 2, even though the method is capable of measuring 25-30-fold changes. At elevated doses, the effects on rewarding efficacy became unmeasurable, because the animals would not consistently self-stimulate at any parameters of stimulation. Amphetamine (0.5-3 mg/kg) enhanced rewarding efficacy. Clonidine (0.05-0.4 mg/kg), molindone (0.25-1 mg/kg) and pimozide (0.1-0.6 mg/kg) attenuated it. Pimozide and clonidine were equipotent despite their radically different receptor affinities. The effects of pimozide, clonidine and amphetamine were approximately additive (amphetamine cancelled the effects of pimozide and clonidine, while clonidine augmented the effect of pimozide). The alpha 2 antagonist yohimbine (0.05-10 mg/kg) had the same effect as the alpha 2 agonist clonidine (attenuation of rewarding efficacy), but these effects did not combine additively: yohimbine neither cancelled nor augmented the effect of clonidine. It is suggested that catecholaminergic agonists and antagonists do not alter the magnitude of the rewarding signal by acting on postsynaptic receptors in the reward pathway; rather, they may drive beyond functional limits a variable that is crucial to the proper recording of the magnitude of the rewarding signal.

Sex and day-night differences in opiate-induced responses of insular wild deer mice, Peromyscus maniculatus triangularis

Abstract: We examined the effects of mu and kappa opiate agonists on the day- and night-time nociceptive, locomotory and ingestive behaviors of an island population of wild male and female deer mice, Peromyscus maniculatus triangularis. The prototypical mu opiate agonist, morphine, had significant analgesic and locomotory effects, which were blocked by naloxone, and the specific delta opiate antagonist, ICI 154, 129, respectively. The specific kappa opiate agonist, U-50,488, had significant analgesic actions and inhibitory effects on locomotor activity, as well as stimulating feeding. Significant day-night variations occurred in the analgesic and activity responses, with the mu and kappa opiate agonists having significantly greater effects at night. There were also prominent sex differences in responses; male deer mice displaying significantly greater levels of mu and kappa opiate-induced analgesia and alterations in activity than female animals. These sex differences in opiate-induced effects were most pronounced at night, female deer mice displaying reduced day-night rhythms of responsiveness. These results demonstrate the existence of significant day-night rhythms and sex differences in the mu and kappa opiate behavioral responses of a wild population of rodents.

Digiscan activity: Automated measurement of thigmotactic and stereotypic behavior in rats

Abstract: Visual measures of stereotypy, margin time (thigmotaxis or wall-hugging), and center time were correlated with automated measures using a revised 16 beam version of the Digiscan Animal Activity Monitor System. Rats were injected with d-amphetamine (1.25, 2.5, 5.0 and 10.0 mg/kg), scopolamine (1.25 and 2.5 mg/kg) or saline and drugs were found to increase center time and decrease margin time in a dose-dependent manner, with the maximum effect occurring with 1.25 and 2.5 mg/kg, respectively. At higher doses, an opposite effect was observed. Extremely high correlations between visual and automated recordings of both margin time and center time were found. Since thigmotaxic or wall-hugging behavior has been used as an indicator of emotionally in rats the results of the present study suggest that these two locomotor variables may be useful additions to the Digiscan multivariate analysis of locomotor behavior. It was also found that a redefinition of stereotypic behavior improved its correlation with visual measurements compared to earlier studies.

Cocaine modulation of central monoaminergic neurotransmission.

Abstract: Extracellular microelectrode studies were conducted to test the effects of cocaine HCl on the activity of spontaneously firing single serotonergic dorsal raphe (DRN), noradrenergic locus coeruleus (LC) and dopaminergic ventral tegmental (VTA) and zona compacta (ZC) neurons, and cerebellar Purkinje neurons (PC) in urethane anesthetized rats in vivo. Cocaine (0.0625-4 mg/kg) predominantly inhibited all of the central monoaminergic neurons and predominantly activated cerebellar Purkinje neurons. Cocaine (1 mg/kg, IV) failed to potentiate the inhibitory effects of LC stimulation on PC neurons. The temporal effects of intravenous cocaine on arterial pressure (i.e., pressor response) were not directly correlated with the effects on neurons. Cocaine did not decrease the amplitude or slope of neuron action potentials, and the effects of cocaine on firing rate were not shared by similar doses of procaine. Reserpine pretreatment (10 mg/kg, IP) attenuated the effects of cocaine (1 mg/kg, IV) on DRN, LC, and PC neurons. Specific adrenoceptor antagonists antagonized the inhibitory effects of cocaine on LC (piperoxane, yohimbine) and VTA (haloperidol) neurons. These results suggest that the central effects of cocaine on presynaptic monoaminergic neurons may in part be mediated by augmented monoamine neurotransmission at autoreceptors and that the effects of cocaine on postsynaptic target cells (PC) may be more complex, requiring the analysis of both pre- and postsynaptic elements.

Social structure and ethanol consumption in the laboratory rat

Abstract: When mixed-sex groups of rats in established colonies were given free access to 4% and then 8% ethanol solutions, relative ethanol consumption for individual subjects was consistent over the two solutions, with some subordinate males consuming much more ethanol than any of the dominant males Overall, subordinate male consumption was significantly higher than that of dominants, suggesting that the social stress of subordination may be a factor in ethanol consumption Offensive attack was reduced under 8% consumption conditions, compared to the pre-ethanol level The significant negative correlation between initial offense level and the level of offense seen under 8% ethanol consumption agrees with previous work suggesting that more offensive males show a differential decline in offense with ethanol Female colony members consumed significantly more ethanol than males, with some suggestion of increased drinking in response to social stresses This pattern of results suggests that the colony situation may provide an important model for investigation of the relationship between social stress and ethanol consumption

Long-lasting effects of escalating doses of d-amphetamine on brain monoamines, amphetamine-induced stereotyped behavior and spontaneous nocturnal locomotion.

Abstract: The repeated intermittent administration of relatively low doses of amphetamine (AMPH) produces an enduring hypersensitivity to the motor stimulant effects of AMPH (behavioral sensitization), and this is accompanied by enhanced mesotelencephalic dopamine (DA) utilization/release In contrast, chronic treatment with very high doses of AMPH does not produce sensitization, but is neurotoxic, resulting in the depletion of brain DA (and often other monoamines) However, gradually escalating doses of AMPH provide protection against the neurotoxic effects of higher doses given later Therefore, the purpose of the present experiment was to determine if a regimen of gradually escalating doses of AMPH, culminating in much higher doses than usually used to study sensitization, would produce neural and behavioral changes associated with AMPH neurotoxicity (DA depletion) or behavioral sensitization (increased DA utilization) Female rats were given 60 injections (2/day) of increasing (1 to 10 mg/kg) doses of d-AMPH, culminating in rats receiving 20 mg/kg/day for four consecutive days This treatment did not deplete brain DA or serotonin, but did produce a long-lasting enhancement (at least 12 days) in striatal and nucleus accumbens DOPAC concentrations, and DOPAC/DA ratios These neurochemical changes were accompanied by an enduring hypersensitivity to the stereotypy-producing effects of a subsequent AMPH 'challenge' In contrast to this enhanced response to a challenge, AMPH-pretreated rats showed a marked reduction in spontaneous nocturnal motor activity It is concluded that rats can be given escalating doses of AMPH, which mimic to some extent the AMPH 'runs' common in addicts and that this produces neural and behavioral changes consistent with the development of sensitization; not neurotoxicity

Chronic ethanol tolerance through free-choice drinking in the P line of alcohol-preferring rats

Abstract: The objective of this study was to determine if the selectively bred P line of alcohol-preferring rats would develop behavioral (neuronal) tolerance with free-choice drinking of ethanol. Adult, male P rats were divided into four groups. One group (FCE) received food, water and a 10% (v/v) ethanol solution ad lib, while the control group (C) had only food and water. The other two groups received either a liquid diet containing 5% (v/v) ethanol (LDE) or a control liquid diet (LDC). All groups were kept on their respective feeding regimens for 14 days. The mean (±SEM) ethanol intakes for the FCE and LDE groups were 6.8±0.5 and 9.9±0.4 g ethanol/kg body wt./day, respectively. A shock-motivated jumping task recovery to a criterion of 75% of the performance level achieved with training. All rats were tested twice, once on the day before beginning their feeding regimens (day 0) and again 14 days later. Tolerance was assessed from differences in time of recovery to criterion performance and in blood alcohol concentrations (BACs) at recovery on day 0 vs. day 14. The mean recovery times for the C, FCE, LDC, and LDE groups on day 0 were 177±6, 170±6, 143±10 and 153±13 minutes, respectively, and the BACs were 219±6, 222±19 and 214±6 mg%, respectively. On day 14, the FCE and LDE groups exhibited tolerance with shorter recovery times of 80±7 and 70±9 minutes and higher BACs at recovery of 273±5 and 286±14 mg%, respectively. No significant differences in time of recovery or BACs were observed between days 0 and 14 for the C and LDC groups. The results demonstrated that free-choice consumption of 10% ethanol by P rats is sufficient to produce behavioral/neuronal tolerance which is similar in magnitude to that seen for P rats given ethanol in a liquid diet.

The effects of 8-hydroxy-2-(di-n-propylamino)tetralin and other serotonergic agonists on performance in a radial maze: a possible role for 5-HT1A receptors in memory.

Abstract: A group of ten rats was trained to obtain food pellets in an 8-arm radial maze. The effects of pretreatment with (+)-Lysergic acid diethylamide (+)-tartrate (LSD), m-trifluoromethylphenylpiperazine (TFMPP), 5-methoxy-N,N-dimethyltryptamine oxalate (5-MeO-DMT), racemic 8-hydroxy-2-(di-n-propylamino)tetralin HBr (8-IH-DPAT), and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole succinate (RU 24969) were then evaluated. All drugs were administered IP 15 min before testing. With the exception of an increased rate of responding at a dose of 0.1 mg/kg of 8-OH-DPAT, all drugs produced a dose-related decline in response rate. In addition, LSD, RU 24969, and 8-OH-DPAT caused a statistically significant decrease in efficiency of responding. Of the three, 8-OH-DPAT was clearly the most active. Doses of 0.3, 1.0, and 3.0 mg/kg resulted in efficiencies of 61%, 53%, and 44%, respectively. The present results taken in light of 8-OH-DPAT's preferential binding to 5-HT1A receptors, the high density of these receptors in hippocampus, and the observation that the number of 5-HT1A receptors is decreased in Alzheimer's disease, suggest a possible role for this serotonergic receptor subtype in memory.

Mice genetically selected for differences in open-field activity after ethanol

Abstract: Starting from a population of genetically heterogeneous mice, selective breeding is being used to develop lines differing in sensitivity to ethanol-induced open-field activity. Mice are tested twice for 4 min in an open field. The first test is between min 2–6 after injection of saline. Twenty-four hr later, a similar test is performed after injection of ethanol (1.5 g/kg). Two independent FAST lines are being selected for ethanol-induced increases in activity, and two independent SLOW lines are being selected for ethanol-induced decreases. After four generations of selection, the lines have diverged significantly. These lines should be useful for exploring the neuropharmacological basis for the activating and rewarding properties of ethanol.

Evaluation of the role of norepinephrine in the reinforcing effects of psychomotor stimulants in rhesus monkeys

Abstract: Rhesus monkeys were surgically prepared with intravenous catheters and allowed to self-administer cocaine (0.03-0.1 mg/kg/injection) under a fixed-ratio 10 schedule of drug delivery during daily 2-hour experimental sessions. When responding was stable for cocaine, saline or various doses of nisoxetine, a selective norepinephrine (NE) reuptake blocker, was substituted for cocaine for 5-7 consecutive sessions. Nisoxetine failed to maintain self-administration responding at any dose in 3 of 4 monkeys tested. Pre-session administration of the selective alpha 1 NE receptor blocker prazosin (0.2-1.6 mg/kg, IV, 15 minutes pre-session) did not systematically alter cocaine self-administration in any monkey. The results are in contrast to what has been found with DA agonists and antagonists and are consistent with the belief that NE does not play a primary role in the reinforcing properties of psychomotor stimulants.

Effects of systemic and intracranial amphetamine injections on behavior in the open field: a detailed analysis.

Abstract: Systemic injections of amphetamine result in profound changes in the behavior of animals in an open field. There is an increase in activity, certain species-typical behaviors are produced, and there is a tendency for any elicited behavior to be repeated in a stereotyped way. The present study examined the contributions of dopamine terminal regions to these effects in rats by microinjecting amphetamine directly into one of six discrete sites (medial frontal cortex, nucleus accumbens, anteromedial caudate nucleus, ventrolateral caudate nucleus, amygdala, or the region surrounding the area postrema) and making detailed behavioral observations. This data compared with the behavior of systematically injected rats that were also observed in the open field. An observer recorded the occurrence of twelve categories of behavior and recorded photocell beam interruptions during five post-injection observation periods. The results confirmed and extended previous accounts of the behavior of systematically injected rats, adding increased snout contact with the environment as an additional effect of amphetamine. Intracranial injections produced changes in activity level from several of the injection sites but there was no increase in the species-typical behaviors associated with stereotypy. Changes in the occurence of some recorded behaviors were produced by injections into most of the sites and these data are presented in detail.

Increased adult behavioral ‘despair’ in rats neonatally exposed to desipramine or zimeldine: An animal model of depression?

Abstract: Occurrence of depressive behavior at mature age was studied in rats exposed neonatally to antidepressant drugs. Early antidepressant treatments have been shown to increase voluntary alcohol consumption and the percentage of rapid-eye-movement (REM) sleep relative to total sleep time in adult rats as well as to cause long-lasting reduction in the concentrations of monoamines in the forebrain. In the present study rats were daily given either 5 mg/kg desipramine or 25 mg/kg zimeldine from the 7th to the 18th postnatal days. When they were 2 months and 5 months of age behavioral ‘despair’ was studied by using a modified version of Porsolt's swim-test. At both ages the desipramine-treated and zimeldine-treated rats expressed lengthened immobility times in the water pail. The findings indicate that neonatal exposure of rats to desipramine or zimeldine induces behavioral ‘despair’ at mature age. Thus, early exposure of rats to antidepressants causes long-lasting behavioral disorders, and, moreover, may be used to devise an animal model of subsequent depression.

Inhibition of mouse killing behavior by serotonin-mimetic drugs: effects of partial alterations of serotonin neurotransmission

Abstract: Rats which do not kill mice and which require mouse killing behavior after partial lesion of the serotonin neurotransmission, either by p-chlorophenylalanine treatment or by electrolytical lesions of dorsal and median raphe nucleus, were treated by IP injection of serotonin-mimetics. The following drugs were used: 5-methoxy-N-N-dimethyl-tryptamine and 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide, serotonin-agonists, fluoxetine and citalopram, inhibitors of serotonin uptake. All these serotonin-mimetics inhibit mouse killing behavior without apparent secondary effects. When these compounds were tested on killer rats, a stronger antimuricidal effect was observed in rats having altered serotonin neurotransmission. These results support a role for the serotoninergic supersensitivity in a model of aggressive behavior.