Showing papers in "Pharmacology, Biochemistry and Behavior in 1985"

Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing.

Abstract: Spinopetal pathways may be activated by a variety of brainstem manipulations including microinjections of morphine which are known to modulate spinal nociceptive processing. Based on the ability of these manipulations to release spinal noradrenalin; the ability to reverse the antinociceptive effects by intrathecal adrenergic antagonists and the fact that intrathecal injections of noradrenalin mimic the antinociceptive effect, it appears that the descending modulation may be mediated by descending noradrenergic systems. Examination of the spinal receptor systems with intrathecally administered agents indicates that spinal alpha, but not beta adrenergic receptor agonists produce a powerful analgesia as measured on a variety of reflex and operant measures in mouse, rat, cat, primate and man. On the basis of agonist and antagonist structure-activity relationships it appears that a significant effect can be produced in the absence of any detectable effect on motor function by the occupation of spinal receptors. Distinguishable alpha 1 receptors also appear “analgetically-coupled,” but their effects are uniformly contaminated by signs of cutaneous hyperreflexia at doses required to produce analgesia. The ordering of potency with which intrathecal adrenergic antagonists reverse the effects of intrathecal noradrenalin is indistinguishable from that of the reversal by these intrathecal agents of the antinociceptive effects evoked by brainstem morphine. This suggests that the population of spinal receptors acted upon by exogenously administered adrenergic agonists and endogenously released noradrenalin have indistinguishable characteristics.

Heterogeneity of alpha-2 adrenergic receptors.

Abstract: Alpha adrenergic receptors are subdivided into alpha-1 and alpha-2 subtypes on the basis of their pharmacologic properties. An evaluation of data from radioligand binding and functional experiments indicates that the receptors classified as alpha-2 are not a homogeneous group. The best example of this heterogeneity is the differences in the pharmacologic properties of alpha-2 receptors in rodent and non-rodent mammalian species. Prazosin generally has a high affinity for rodent alpha-2 receptors, but a low affinity for non-rodent alpha-2 receptors, while oxymetazoline is more potent at non-rodent alpha-2 receptors. A definition of alpha-2 adrenergic receptor subtypes is proposed with prazosin having a lower affinity (200-300 nM) at alpha-2A receptors and a higher affinity (5-10 nM) at alpha-2B receptors. Using this definition, the human platelet appears to have only the alpha-2A subtype, while all the receptors in the neonatal rat lung are of the alpha-2B subtype. The rat brain has roughly equal amounts of alpha-2A and -2B receptors while in the rat submandibular gland, about 85% of the receptors are alpha-2A. The ability to pharmacologically define putative alpha-2 adrenergic receptor subtypes should promote the development of additional subtype selective drugs which will increase our understanding of adrenergic pharmacology and may provide new therapeutic approaches.

Selective memory loss following nucleus basalis lesions: long term behavioral recovery despite persistent cholinergic deficiencies.

Abstract: Rats were trained for several months to perform a radial arm maze task and then given either sham or ibotenic acid lesions of the nucleus basalis magnocellularis (NBM), the primary cholinergic projection to the neocortex. The lesion produced a profound and apparently selective disturbance in memory for recent events. Further testing revealed that although the memory deficit persisted for several weeks, a gradual but complete recovery eventually occurred. Moreover, when these functionally recovered rats were later tested on a passive avoidance task that is normally sensitive to lesions of the NBM, no deficit was found. Thus, the post-lesion recovery of function generalized to a different memory test, upon which no post-lesion practice had been given. Post-mortem determinations revealed that the lesions caused marked neurodegeneration of the NBM, and decreases in both cortical choline acetyltransferase activity and high affinity choline uptake, but had no effect on density of muscarinic receptors. No evidence of neuronal recovery or neurochemical compensatory changes in the cholinergic system was found in the cortical projection areas, lesion site, or in parallel cholinergic systems terminating in the hippocampus or olfactory bulb. These results support the idea that the cortically-projecting cholinergic cells of the NBM normally play an important role in mediating recent memory. However, they also demonstrate that any simple relationship between the function of this brain region and the mediation of recent memory is unlikely. Finally, the results of this study direct attention toward issues related to the mechanisms involved with the recovery of function, and the extent to which degeneration of this brain area may contribute directly to the severe disturbance of cognitive function associated with certain neurodegenerative diseases (e.g., Alzheimer's, Pick's and Parkinson's disease).

Disruption of cocaine and heroin self-administration following kainic acid lesions of the nucleus accumbens

Abstract: In previous experiments we have demonstrated that bilateral infusions of 6-hydroxydopamine (6-OHDA) into the nucleus accumbens result in a drastic reduction in the rate of cocaine self-administration. If this effect is due to the destruction of a presynaptic dopaminergic element in this nucleus, then selective removal of the postsynaptic neuron should also disrupt cocaine self-administration. This hypothesis was tested using the neurotoxin kainic acid. Bilateral kainic acid infusions into the nucleus accumbens resulted in a drastic destruction of cell bodies yet did not damage catecholamine innervation in areas anterior to the accumbens. The effects of these kainic acid infusions were evaluated in rats that had previously acquired cocaine self-administration behavior. These lesions were found to severely disrupt cocaine intake and the degree of damage produced in the accumbens was found to correlate (r = 0.88) with postlesion cocaine intake. These lesions were additionally found to disrupt apomorphine and heroin self-administration. The possibility that these results are due to destruction of systems necessary for stimulant and opiate reward is discussed.

Habituation to repeated stress is stressor specific.

Abstract: Rats were exposed to 15 min of restraint or footshock or forced running in an activity wheel once a day for 10 days. Control groups were handled only. On the 11th day, rats from each stressor group and controls were exposed to 15 min of one stressor in a crossed design such that all combinations of one chronic stressor and one acute stressor were performed. Rats were sacrificed immediately following removal from their home cage or after 15 min stressor exposure on the 11th day and plasma corticosterone and prolactin and pituitary cyclic AMP levels were determined. There were no measured differences in these stress indices among groups of rats sacrificed immediately upon removal from their home cage on day 11 regardless of previous history on days 1 through 10. Plasma corticosterone and plasma prolactin and pituitary cyclic AMP levels were elevated in all rats exposed to any of the three stressors immediately prior to sacrifice as compared to all rats not exposed to stress immediately before sacrifice. However, plasma prolactin and pituitary cyclic AMP responses to each of the 3 stressors were attenuated in rats which had previous exposure to that specific stressor as compared to rats which had previous experience with a different or no stressor. We conclude that habituation results from behavioral experience with a particular stressor rather than biochemical adaptation resulting from repeated challenge to hormonal and neurochemical systems responsive to stress.

Pharmacologic characterization of nicotine-induced conditioned place preference.

Abstract: Rats received subcutaneous injections of either nicotine (0.1 to 1.2 mg/kg) or saline (1.0 ml/kg) immediately prior to conditioning sessions in a conditioned place preference (CPP) paradigm. The drug was paired for 3 conditioning sessions with the non-preferred environment of a 3 compartment place preference apparatus; saline was paired with the preferred environment. The animals were then tested for place preference by determining the proportion of time spent in the preferred compartments during a 15 min test session. Using a statistical method developed for the CPP paradigm, dose-response curves were obtained for the obtained from the control animals. Nicotine's rewarding and aversive effects were linearly correlated with respect to dosage within the range of 0.1–0.8 mg/kg (reward increased and aversion decreased). A decrease in reward and an increase in aversion was measured at the 1.2 mg/kg treatment level. Mecamylamine hydrochloride and hexamethonium bromide (at 1.0 mg/kg of the base or ion, respectively) were also tested using the CPP paradigm. While neither compound produced place preferences when administered alone, mecamylamine did block the rewarding effects of 0.8 mg/kg of nicotine when administered 30 minutes prior to the nicotine conditioning sessions. Hexamethonium did not alter nicotine-induced reinforcement. The data suggest that nicotine and its rewarding effects as measured by CPP are primarily mediated by central rather than peripheral events.

Neuroleptics block the positive reinforcing effects of amphetamine but not of morphine as measured by place conditioning.

Abstract: The role of dopamine brain systems in mediating the rewarding effects of opiates and stimulants was investigated using the conditioned place preference paradigm. The effects of the neuroleptics α-flupentixol (0.8 mg/kg, IP) and haloperidol (1.0 mg/kg, IP) were tested against the place preferences produced by morphine sulphate (1.0 and 5.0 mg/kg, SC), d-amphetamine sulphate (1.0 mg/kg, IP) and cocaine hydrochloride (5.0 mg/kg, IP). Amphetamine place preference was successfully blocked but neuroleptic pretreatment had no effect on the place preferences produced by cocaine and morphine. α-Flupentixol alone produced no place conditioning. These results support the hypothesis of dopamine involvement in amphetamine reward. However, morphine reward, as measured by the conditioned place preference paradigm, appears not to be critically dependent on brain dopamine systems.

Oral ethanol self-administration in the rat: effect of naloxone.

Abstract: Rats responding on a two lever concurrent for ethanol and water, were injected with 5, 10, or 20 mg/kg naloxone hydrochloride 30 min prior to a 30 min session. Only the 20 mg/kg dose had any effect, a decrease in responding for ethanol of up to 50% compared to saline control injection sessions. There were no systematic effects upon water responding. An additional study using sucrose and water as the fluid concurrently available failed to find any effects of naloxone on sucrose responding at the same doses. The effect upon ethanol responding was found not to resemble a pattern of extinction, but rather was best described as a general overall reduction in responding. The relation of these findings to the direct involvement of the endogenous opiate system in ethanol reinforcement is discussed.

Pimozide decreases the positive reinforcing effect of sham fed sucrose in the rat.

Abstract: Rats with chronic gastric cannulas were intraperitoneally injected with the dopamine receptor antagonist pimozide (0.25 mg/kg) before sham feeding 5, 10, 20, or 40% (w/v) sucrose solutions. Amount of sham intake after control injections increased as a function of sucrose concentration. At each concentration, the rate of sham feeding was greatest during the initial 3 min of sham feeding and subsequently decelerated. Pimozide inhibited sham feeding rate, and the temporal pattern of decreases in sham feeding rate after pimozide were similar to those produced by decreasing the concentration of sucrose sham fed. These data extend previous reports of the inhibitory effect of pimozide on ingestion of sweet fluids by eliminating the possibility that the effect was the result of pimozide facilitating postingestional inhibitory mechanisms. Further, pimozide did not appear to produce fatigue or sedation, or to reduce the rats' motor capacity to sham feed. Therefore, these data are consistent with the hypothesis that central dopaminergic synaptic activity mediates the reinforcing effects of sweet taste that drive sham feeding.

The conditioned place preference is affected by two independent reinforcement processes.

Abstract: The conditioned place preference method for measuring the affective properties of reinforcing events was studied using treatments of known affective value. The size of the place aversion observed increased with dose when the reinforcer was injections of lithium chloride. The size of the place preference observed increased with concentration when the reinforcer was drinking sucrose solutions. However, when the reinforcer was solutions of saccharin (that were consumed in the same amounts as the sucrose solutions) no place preferences were observed. This finding was explained in terms of the dual reinforcement hypothesis [20] which postulates that although sucrose and saccharin both have positive affective properties (based on their tastes) only sucrose has memory improving properties (based on its post-ingestive action). It was therefore proposed that conditioned place preferences depend on the activation of both affective and memory improving processes. This hypothesis was confirmed by the observation of place preferences with a saccharin solution as the reinforcer when the pairing trials were followed by non-contingent, post-pairing injections of glucose or amphetamine (both of which are known to improve memory). Therefore, behavior in the place preference method depends upon both the affective and the memory improving properties of the reinforcers under test.

Pharmacological and clinical effects of buspirone.

Abstract: Clinical trials have demonstrated that buspirone (BuSpar) is effective in the treatment of anxiety with efficacy and dosage comparable to diazepam or chlorazepate. Buspirone has a unique structure and a pharmacologic profile which distinguishes it from the benzodiazepines. Because it lacks the anticonvulsant, sedative, and muscle-relaxant properties associated with other anxiolytics, buspirone has been termed "anxioselective." Animal studies suggest that it lacks potential for abuse, and this finding is supported by clinical investigations. Further preclinical work supports the contention that buspirone lacks liability to produce physical dependence or to significantly interact with central nervous system depressants such as ethanol. Moreover, biochemical investigations have not identified any direct interaction of buspirone with the benzodiazepine-gamma-aminobutyric acid-chloride ionophore complex. Pharmacologic studies on the molecular level indicate that buspirone interacts with dopamine and serotonin receptors. Recent behavioral, electrophysiological, and biochemical studies have clearly demonstrated that early hypotheses that buspirone might be considered a neuroleptic are no longer tenable. Recent evidence indicates that other neurotransmitter systems (serotonin, norepinephrine, acetylcholine) mediate buspirone's effects. It is hoped that future studies can define the mechanism by which buspirone alleviates the clinical manifestations of anxiety.

Toward understanding ethanol's capacity to be reinforcing: a conditioned place preference following injections of ethanol.

Abstract: Rats that had previously consumed a 6% ethanol (ETOH) solution daily for 26 days and rats without such a history served as subjects in a test for the ability of ETOH to establish a conditioned place preference. The time of putative conditioning was from 4 to 8 min after injections of ETOH, 1 g/kg. The combination of programming the period of putative conditioning to be shortly after injections and using rats habituated to drinking ETOH allowed a conditioned place preference to emerge after only a few conditioning trials. Such a result potentially reveals features of the way ETOH achieves its reinforcing capability and sets the stage for understanding the mechanism of that reinforcement.

Distribution and function of peripheral alpha-adrenoceptors in the cardiovascular system.

Abstract: alpha-Adrenoceptors may be subdivided based on their anatomical distribution within the synapse. Presynaptic alpha-adrenoceptors are generally of the alpha 2-subtype and modulate neurotransmitter liberation via a negative feedback mechanism. Postsynaptic alpha-adrenoceptors are usually of the alpha 1-subtype and mediate the response of the effector organ. Although this "anatomical" subclassification is generally applicable, many exceptions exist. A more useful classification of alpha-adrenoceptor subtypes is based on a pharmacological characterization in which selective agonists and antagonists are used. Peripheral alpha-adrenoceptors are critical in the regulation of the cardiovascular system. Postsynaptic alpha-adrenoceptors in arteries and veins represent a mixed population of alpha 1/alpha 2-adrenoceptors, with both subtypes mediating vasoconstriction. In the peripheral arterial circulation, postsynaptic vascular alpha 1-adrenoceptors are found in the adrenergic neuroeffector junction, whereas postsynaptic vascular alpha 2-adrenoceptors are located extrajunctionally. In the venous circulation, it appears that alpha 2-adrenoceptors may be predominantly junctional, whereas alpha 1-adrenoceptors may be predominantly extrajunctional. It has been proposed that junctional alpha-adrenoceptors will respond predominantly to norepinephrine liberated from sympathetic neurons, whereas extrajunctional alpha-adrenoceptors likely respond to circulating catecholamines. The functional role of extrajunctional alpha-adrenoceptors may be more important in disease states such as hypertension and congestive heart failure where circulating levels of catecholamines may be high and contribute to the maintenance of elevated vascular resistance. alpha 2-Adrenoceptors are also associated with the intima and may play a role in the release of an endogenous relaxing factor from the endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Endorphins and food intake: kappa opioid receptor agonists and hyperphagia.

Abstract: Evidence from studies which utilise either opiate receptor agonists and antagonists strongly indicate a role for endorphinergic mechanisms in the control of feeding responses. Two means by which these compounds may exert an effect on feeding can be singled-out. Firstly, emerging evidence suggests that the process of achieving satiety (terminating a meal, or choice of a commodity) may be accelerated following treatments with opiate receptor antagonists. Secondly, the preference for highly palatable solutions (sweet solutions have received most attention) in two-bottle tests is blocked after injection of opiate receptor antagonists. This finding has been interpreted in terms of the abolition of the reward or incentive quality associated with the particularly attractive flavour. These two mechanisms of action may represent two aspects of a single, fundamental process. Following an introduction to rat urination model of in vivo kappa agonist activity, the consistent effect of several kappa agonists (including the highly selective U-50,488H) to stimulate food consumption is described. Recognising that members of the dynorphin group of endogenous opioid peptides are kappa receptor ligands, some with a high degree of selectivity, and the evidence the dynorphins and neo-endorphins produce hyperphagia in rats is particularly interesting. Such lines of evidence lead to the hypothesis that peptides of the dynorphin group may act endogenously to promote the expression of normal feeding behaviour.

Sensory blockade of smoking satisfaction

Abstract: Cigarette smokers were presented with controlled doses of cigarette smoke to determine wheter the resulting reduction in cigarette craving depended upon perceiving the sensory qualities of the smoke. Cigarette craving was assessed before and after inhaling controlled doses of smoke in two conditions: (1) Local anesthesia of the upper and lower respiratory airways, induced by mouth rinsing, gargling and inhalation of a mist containing the topical anesthetic lidocaine; and (2) no-anesthesia control, in which all solutions were saline. A sham smoking procedure was presented in both conditions. Craving and ad lib smoking behavior were also assessed 30 minutes after controlled smoking. The results indicated that smoke, as opposed to sham puffs, significantly reduced reports of cigarette craving, and local anesthesia significantly blocked this immediate reduction in craving produced by smoke inhalation. Puffs were also rated as less desirable in the anesthesia condition. Thirty minutes after smoking, craving was no different in the anesthesia and saline control conditions. However, craving as well as smoking intake in both conditions was less when smoke had been given previously than in the sham smoking control. These results suggest that sensory cues accompanying inhalation of cigarette smoke are important determinants of immediate smoking satisfaction. However, the sustained effects of smoke intake on subsequent smoking behavior (30 min later) may be mediated by processes other than sensory stimulation of the respiratory tract, such as plasma nicotine levels.

Acute alcohol intoxication and body composition in women and men.

Abstract: The present study was a direct experimental comparison of administering equivalent alcohol doses based on body weight and estimated total body water to 12 women and 12 men. Each subject participated in two experimental sessions separated by at least three days. Two doses of 95% ethanol were administered in a randomized, counterbalanced order: 0.66 ml/kg of body weight, and 1.2 ml/l of total body water. Women were tested during the midfollicular phase of their menstrual cycle when plasma concentrations of estrogen and progesterone have been found to be lower than other phases of the cycle. When given doses equated for body weight, women reached significantly higher peak blood alcohol concentrations than men. No sex differences were found when equivalent doses based on total body water were administered. This differential effect of dose determination was not reflected in self-reported levels of alcohol intoxication. The anthropometric equations used to estimate total body water provided a practical, reliable method for equating alcohol doses.

Effects of prenatal exposure to morphine on the development of sexual behavior in rats

Abstract: Females exposed to morphine sulfate in utero (5–10 mg/kg twice a day on days 11–18 of gestation) displayed precocious vaginal opening and had increased body weight from the 8th week after weaning. In addition, there was a substantial inhibition in adult feminine sexual behavior. Male rats that received either morphine or saline prenatally did not show any body weight differences, and most of the measures of masculine sexual behavior did not differ between the two groups. However, the male rats exposed to morphine had a significantly shorter post-ejaculatory intromission latency than the saline controls. Examination of cytosol estrogen receptor levels in the hypothalamus-preoptic area (HPOA) of both saline and morphine sulfate-treated female rats revealed essentially identical patterns of depletion and replenishment. Additionally, estrogen treatment was equally effective at inducing HPOA progestin receptor synthesis in both groups. These results show that prenatal morphine treatment at the times and dose level administered disrupts the development of reproductive function in females but has only minor effects on male reproductive function.

Introduction to symposium on endorphins and behavioural processes; review of literature on endorphins and exercise.

Abstract: The first symposium on endorphins and behavioural processes in Britain was held by the British Psychological Society in March 1985. Against a background of the explosive history of the discovery of endogenous opioids, problems of terminology, and basic mechanisms and concepts, five papers reflect the main fields in which outstanding progress has been made: analgesia, feeding, reward mechanisms, social behaviour and aggression, and addiction. A review of the literature on endorphins and exercise stresses both the value and limitations of trying to unravel a fashionable subject. Endorphin research is multi-disciplinary and highly complex, with tricky technical and conceptual problems and inevitable lack of consensus. Investigators should be more aware of the crucial role that outcomes of behaviour experiments play in the attribution of function to opioid systems.

The D1 dopamine receptor antagonist, SCH 23390 reduces locomotor activity and rearing in rats.

Abstract: Dopamine receptors have been found to be of at least two types, and interest has focused on the possible differential role played by each in the control of behavior. The recent finding that SCH 23390 selectively blocks D1 receptors has provided a new tool. To examine the contribution of D1 receptors to locomotor activity and rearing, rats were injected SC with doses of 0.01, 0.1 and 1.0 mg/kg and monitored for 3 hr in photocell cages. SCH 23390 suppressed both behaviors in a dose-dependent fashion. These results suggest that D1 receptors participate in dopamine's control of locomotor activity and rearing.

Prenatal nicotine affects fetal testosterone and sexual dimorphism of saccharin preference

Abstract: In order to study effects of nicotine on fetal gonadal axis and sexually dimorphic behavior, time-pregnant Sprague Dawley rats were implanted on gestational day (GD) 12 with an osmotic minipump containing either nicotine tartrate, tartaric acid or saline. Others were sham-operated on GD 12 or left untreated. Male fetuses of all control groups displayed the characteristic rise in plasma testosterone at GD 18 (as compared to GD 17 and 19); this was abolished by nicotine. Adult offspring of untreated or tartaric acid-treated dams exhibited a marked sexual dimorphism in their preference for saccharin-containing drinking water at 0.06-0.25%. No such sex difference was seen in offspring of nicotine-treated rats. In controls, the sexes differed with respect to the proportion of rats with high saccharin preference. In the group of males prenatally exposed to nicotine, the proportion of animals with high preference increased to the female level. These data indicate that prenatal exposure to nicotine can interfere with the development of the male gonadal axis and with the organization of sexually dimorphic behavior.

Scopolamine degrades spatial working memory but spares spatial reference memory: dissimilarity of anticholinergic effect and restriction of distal visual cues.

Abstract: The influence of the centrally active anticholinergic, scopolamine hydrobromide, on working and reference memory was studied in rats tested in a 12-arm radial maze. Both 0.25 and 0.5 mg/kg doses of the drug increased the number of working memory (WM) but had no effect on reference memory (RM) errors. A lower dose (0.125 mg/kg) was ineffective, as was the peripherally active anticholinergic, scopolamine methylbromide (0.5 mg/kg). Some of the behavioral effects of anticholinergic on spatial memory are mimicked by blindness or eliminating distal visual cues. If distal visual cues were more important for maintining accurate WM than for RM, the selective effect of scopolamine on WM could be easily explained. But surrounding the maze with a curtain to eliminate extramaze cues increased RM errors without significantly increasing WM errors. Thus, selective effect of anticholinergics on spatial memory in the radial maze qualitatively different from the effect of restricting distal visual cues and musse from some other action of the drug.

Separate neural substrates of the locomotor-activating properties of amphetamine, heroin, caffeine and Corticotropin Releasing Factor (CRF) in the rat

Abstract: Destruction of dopamine terminals within the nucleus accumbens (N.Acc.) with 6-hydroxydopamine blocked the locomotor activating properties of d-amphetamine, but not caffeine or corticotropin-releasing factor (CRF). Infusion of muscimol into the region of nucleus accumbens efferent terminals in the substantia innominata and lateral preotic region (SI/LPO) blocked amphetamine-, but not caffeine- or CRF-stimulated locomotion. These muscimol infusions also blocked heroin-stimulated locomotion. These results suggest that amphetamine, acting through a process dependent on N.Acc. dopamine transmission, stimulates locomotion by decreasing GABAergic activity within this N.Acc.-SI/LPO projection; heroin, known to act through a process dependent on N.Acc. opiate receptor activation, also stimulates locomotion by decreasing GABAergic activity within the SI/LPO; caffeine and CRF produce their activation through different neural substrates.

Effects of 6-OHDA lesions of the central medial nucleus accumbens on rat intravenous morphine self-administration.

Abstract: The function of dopaminergic innervations of the central medial nucleus accumbens in the processes maintaining intravenous morphine self-administration was assessed by lesioning with 6-OHDA and comparing drug intake with sham-vehicle treated littermates. Localized bilateral lesions of this structure resulted in significant increases in morphine intake shifting the dose-effect relationship to the right with twice the dose necessary to maintain prelesion rates of self-administration. Content of dopamine and dihydroxyphenylacetic acid was decreased in the nucleus accumbens after the lesion, but unchanged in the adjacent pyriform cortex and anterior caudate nucleus-putamen, while serotonin was significantly decreased in the pyriform cortex. High affinity uptake measurements also suggested nucleus accumbens dopaminergic and pyriform cortex serotonergic innervations to be affected by the lesion. The shift to the right in the dose effect relationship after the lesion suggests these neuronal systems to be excitatory to the processes mediating self-administration.

The inhibitory effect of diazepam on defensive burying: Anxiolytic vs. analgesic effects

Abstract: The hypothesis that analgesic mechanisms might account for the suppressive effect of diazepam on defensive burying was tested in four experiments. In the first experiment, 1 mg/kg of diazepam had no appreciable effect on rat's latency to escape from a painful heat stimulus, but reliably suppressed defensive burying behavior. There was no significant relationship between the diazepam-treated rats' latency to escape and their duration of burying. Rats in Experiment 2 were injected with diazepam during a delay between shock and testing, so that they could not be experiencing the putative analgesic effect of diazepam during the shock. In spite of this, diazepam produced a significant suppression of burying compared to saline control. In the next experiment, the effect of diazepam on defensive burying was assessed in the complete absence of painful stimulation by exposing the rats to a novel stimulus known to elicit burying behavior. Diazepam suppressed burying behavior to the novel stimulus in a dose-dependent fashion. Finally, the ability of 10 mg/kg of naloxone to reverse the suppressive effect of 1 mg/kg of diazepam was assessed in Experiment 4. Naloxone failed to reverse the suppressive effect of diazepam and had no significant effect on defensive burying by itself, suggesting that the modulating influence of diazepam on rats' defensive burying behavior did not depend upon endogenous opiate mechanisms. Taken together, the results of the four experiments did not support the view that benzodiazepines produce their anxiolytic effects through analgesic mechanisms.

Effects of the β-carboline, FG 7142, in the social interaction test of anxiety and the holeboard: Correlations between behaviour and plasma concentrations

Abstract: The behavioural effects of the β-carboline FG 7142 were investigated in the social interaction test of anxiety and the holeboard test of exploration and locomotor activity. FG 7142 (5–20 mg/kg) produced a significant decrease in the time spent in social interaction by pairs of rats, without an accompanying decrease in motor activity. This anxiogenic effect was highly correlated with the plasma concentrations of FG 7142 for the rats receiving 5 and 10 mg/kg doses, but not for those receiving the 20 mg/kg dose. In the holeboard, FG 7142 had no effect on exploratory head-dipping at the doses tested, but selectively reduced locomotor activity and the number of rears. The profile of FG 7142 in these tests is compared with those of the β-carbolines, B-CCE and B-CCP.

A facilitatory role for serotonin in the sexual behavior of the female rat.

Abstract: The peripheral administration of the serotonin type 2 receptor (5-HT2) antagonist pirenperone inhibited sexual receptivity in ovariectomized female rats primed either chronically with estradiol benzoate (EB), or acutely with EB plus varying doses of progesterone. An inhibition occurred at 50, 100 and 150 but not 25 micrograms/kg pirenperone. Increasing the dose of progesterone did not attenuate the inhibitory effect of pirenperone. Two other 5-HT2 antagonists, ketanserin (2.5 mg/kg) and spiperone (250 micrograms/kg), also inhibited receptivity in females primed with EB and progesterone. The inhibitory effect of pirenperone on receptivity was attenuated by the 5-HT agonist quipazine (3 mg/kg), though quipazine alone had no effect on receptivity. Whereas the 5-HT antagonist methysergide (3 mg/kg) failed to have an effect on receptivity in EB-primed females, methysergide co-administered with quipazine facilitated receptivity. Pirenperone also inhibited proceptivity in females primed with EB and progesterone. Although quipazine did not attenuate the pirenperone-induced inhibition of proceptivity, quipazine alone increased proceptivity. Moreover, quipazine facilitated proceptivity in EB-primed rats whether progesterone was present or absent. The results suggest that 5-HT may serve both a facilitatory and inhibitory role in female sexual behavior, perhaps reflecting 5-HT2 and 5-HT1 receptor activity, respectively.

Evidence that tolerance develops to the anxiolytic effect of diazepam in rats

Abstract: The development of tolerance to the anxiolytic effect of diazepam was studied using suppression of defensive burying as an animal model of anxiolytic action Although tolerance to the suppressive effect of diazepam was not apparent after chronic administration of diazepam when the rats were tested with a low-intensity shock, anxiolytic tolerance was detected under exactly the same drug regimen when the rats were tested with somewhat higher intensity shocks: under the latter conditions, chronically treated rats buried significantly more than acutely treated rats Furthermore, this tolerance effect did not appear to depend upon the injection environment, the control vehicle, or the strain of rat; under each of these experimental variations rats chronically treated with diazepam buried significantly more than acutely treated rats when they had received a moderately high intensity shock These results suggested that tolerance to the anxiolytic effects of benzodiazepines may be detectable when the stimuli eliciting anxiety are relatively intense

Norepinephrine, clonidine, and tricyclic antidepressants selectively stimulate carbohydrate ingestion through noradrenergic system of the paraventricular nucleus

Abstract: Using a self-selection feeding procedure, the present experiments examined the impact of central and peripheral injection of the alpha-adrenergic agonist clonidine (CLON) and the tricyclic antidepressant drugs amitriptyline (AMIT) and chlorimipramine (CIMIP) on nutrient selection in the adult male rat. In tests with mixed diets or with separate sources of the 3 macronutrients (carbohydrate, protein, and fat) simultaneously available, the following results were obtained: Peripheral and paraventricular nucleus (PVN) injection of CLON stimulated total food intake and preferentially increased ingestion of carbohydrate. Little or no change in protein or fat intake was observed. This pattern of response is similar to that observed with norepinephrine. PVN injection of AMIT and peripheral injection of CIMIP also selectively enhanced carbohydrate intake. These drug effects on carbohydrate selection occurred under a variety of conditions, including with mixed diets and pure dietary nutrients; under ad lib and restricted feeding conditions; in short (1 hr) as well as long (6 hr) test intervals; and in the absence or presence of a change in total calorie intake. Based on this and other evidence, it is proposed that noradrenergic neurons innervating the PVN in the rat play a role in regulating carbohydrate selection, and that this neurochemical system mediates the stimulating action of CLON and antidepressants on carbohydrate ingestion.

Hypothalamic sites sensitive to morphine and naloxone: Effects on feeding behavior

Abstract: Three experiments investigated the feeding response of brain cannulated rats to hypothalamic injection of norepinephrine (NE), the opiate agonist morphine sulfate (MO) and the opiate antagonist naloxone (NAL). Morphine elicited feeding in a dose-dependent manner when injected into the paraventricular nucleus (PVN) of satiated rats, at doses of 0.78 to 100 nmoles, with a threshold dose of 1.56 nmoles. Naloxone, at doses of 3.13 to 200 nmoles, was injected into the PVN of food-deprived rats and was found to produce a dose-dependent suppression of feeding (threshold dose of 6.25 nmoles). Animals with brain cannulas aimed at the PVN, the perifornical hypothalamus (PFH), the dorsomedial (DMN) and ventromedial (VNM) nuclei were compared for their sensitivity to the feeding stimulatory effects of NE and MO (except in the DMN) and the feeding suppressive effects of NAL. Consistent with earlier reports, the PVN-cannulated animals exhibited a reliable increase in feeding after NE injection; the VMN cannula yielded a small feeding response, whereas the DMN and PFH were insensitive to NE. Morphine, in contrast, strongly stimulated eating after administration into PFH, as well as the PVN, apparently dissociating the NE and MO eating responses. The VMN, however, was generally unresponsive to both MO and NE. With regard to NAL's suppressive effect on feeding, the PVN and PFH, which were sensitive to MO, also exhibited responsiveness to opiate antagonism suggesting the existence in these areas of opiate receptors that modulate feeding. This contrasts with the DMN, where NAL had no effect on feeding and the VMN, where NAL was sensitive in the absence of MO responsiveness. These mapping studies suggest that the opiate receptors affecting eating behavior are mowst dense within the PVN and PFH but are either less dense or have variable responsiveness within the DMN and VMN.

Failure to establish a conditioned place preference with ethanol in rats.

Abstract: Previous studies have demonstrated that many drugs of abuse are able to produce a conditioned place preference in rats. We sought to determine if ethanol, injected in a wide range of doses, could also produce a conditioned place preference. Statistical analysis of our results indicated that the IP administration of the drug (50, 100, 150, 300, 600, 800, or 1000 mg/kg) failed to produce either a conditioned place preference or aversion compared to vehicle injected control rats. Under similar testing conditions a conditioned place preference was obtained with amphetamine (2 mg/kg) and this preference was not secondary to conditioned hyperactivity. In another experiment, rats were injected with ethanol through indwelling jugular cannulae at doses similar to those reported [24,26] to support (1, 2 mg/kg) or not to support (8 mg/kg) self-administration by rats. We also failed to obtain a conditioned place preference using these doses. Blood and brain ethanol levels, determined 1, 2 or 5 minutes after the administration of 2 mg/kg (IV) indicated very low ethanol levels. These results may suggest that rats do not self-administer ethanol for its intoxicating properties, and that the affective state produced by ethanol administration per se is not readily conditionable to environmental cues.