Studies on the neuropsychopharmacological profile of fengabine (SL 79229) in mice

The effect of fengabine (a novel benzylidene derivative) on neuropsychopharmacological parameters was investigated in mice. On acute systemic administration, it showed modulatory effects on 1) forced swimming-induced immobility, 2) foot shock-induced aggression, 3) electromaximal shock-induced convulsion, 4) radiant heat-induced nociception and 5) locomotor activity. However, it has no effect on the muscle strength of the animal. The GABAA receptor antagonists reversed its effects on forced swimming-induced immobility and foot shock-induced aggression, implicating a GABAergic involvement in its mechanism of action. But these antagonists failed to reverse its potentiating effect on morphine antinociception, suggesting a possible interaction of the drug with opioid receptors. A potential clinical usefulness of the drug and of GABA agonists in general is commented upon.     

Repeated pretreatment with amphetamine sensitizes increases in cortical acetylcholine release

RATIONALE: Previous studies on the attentional effects of repeated psychostimulant administration in rats suggested the possibility that these effects are mediated via increases in the efficacy of psychostimulants to stimulate cortical acetylcholine (ACh) release. Furthermore, neurochemical data have raised the possibility that increases in nucleus accumbens (NAC) dopamine (DA) release trans-synaptically increase the excitability of basal forebrain corticopetal cholinergic projections, thereby supporting speculations about relationships between the effects of repeated psychostimulant administration on NAC DA and cortical ACh release. OBJECTIVES: To determine whether repeated exposure to amphetamine would potentiate the stimulating effects of the drug on cortical ACh and NAC DA efflux. METHODS: Rats were implanted with microdialysis guide cannula in the medial prefrontal cortex and the shell region of the ipsilateral NAC. Amphetamine (2.0 mg/kg i.p.) or saline (0.9%) was administered every other day for 10 days, for a total of five injections. ACh and DA efflux and locomotor activity were measured on the day of the first and last injections of this pretreatment regimen. All animals were retested following a challenge dose of amphetamine (2.0 mg/kg i.p.) given 10 and 19 days after the last pretreatment injection. RESULTS: The initial injections of amphetamine stimulated ACh and DA efflux and locomotor behavior in both groups. The pretreatment with amphetamine potentiated the ability of the drug to stimulate cortical ACh efflux on day 19 of the withdrawal period. The pretreatment with amphetamine also increased the effects of the challenge dose on motoric activity on day 10. Pretreatment with amphetamine did not result in a significant augmentation of the amphetamine-induced increase in DA efflux in the NAC. CONCLUSIONS: Pretreatment with amphetamine sensitizes the ability of amphetamine to stimulate cortical ACh efflux. These results support the hypothesis that sensitized release of cortical ACh mediated the previously observed hyperattentional impairments in amphetamine pretreated rats. Sensitized cortical ACh release following repeated exposure to psychostimulants may mediate the overprocessing of addictive drug-related stimuli, thus contributing to repeated compulsive addictive drug use.     

Accumbens dopamine-acetylcholine balance in approach and avoidance

Understanding systems for approach and avoidance is basic for behavioral neuroscience. Research on the neural organization and functions of the dorsal striatum in movement disorders, such as Huntington's and Parkinson's Disease, can inform the study of the nucleus accumbens (NAc) in motivational disorders, such as addiction and depression. We propose opposing roles for dopamine (DA) and acetylcholine (ACh) in the NAc in the control of GABA output systems for approach and avoidance. Contrary to DA, which fosters approach, ACh release is a correlate or cause of meal satiation, conditioned taste aversion and aversive brain stimulation. ACh may also counteract excessive DA-mediated approach behavior as revealed during withdrawal from drugs of abuse or sugar when the animal enters an ACh-mediated state of anxiety and behavioral depression. This review summarizes evidence that ACh is important in the inhibition of behavior when extracellular DA is high and the generation of an anxious or depressed state when DA is relatively low.     

Supraadditive effect of d-fenfluramine plus phentermine on extracellular acetylcholine in the nucleus accumbens: possible mechanism for inhibition of excessive feeding and drug abuse

The combination of d-fenfluramine plus phentermine (d-FEN/PHEN) provides a tool for exploring neural mechanisms that control food intake and drug abuse. Prior research suggests that dopamine (DA) in the nucleus accumbens can reinforce appetitive behavior and acetylcholine (ACh) inhibits it. When rats were given d-fenfluramine (5 mg/kg, IP) DA increased to 169% (p < 0.01), and ACh decreased slightly. Phentermine (5 mg/kg, IP) increased extracellular DA to 469% of baseline and ACh increased slightly to 124% (both p < 0.01). The d-FEN/PHEN combination, however, increased both DA and ACh with a supraadditive effect on ACh to 172%. One interpretation is that dFEN/PHEN increases DA like a meal or drug of abuse, while also increasing ACh to stop further approach behavior. This leaves the animal "satiated," as defined by reduced intake of food or drugs.     

Bromocriptine potentiates the behavioural effects of directly and indirectly acting dopamine receptor agonists in mice

Summary After an initial period of depression which lasted up to 90 min following injection, bromocriptine (BRC, 5–20 mg/kg, IP) produced dose-dependent and long lasting (7 h) locomotor stimulation in mice. The locomotor stimulation was antagonised by reserpine, alpha-methyl-p-tyrosine (AMPT) or haloperidol. The blockade by AMPT of BRC's locomotor stimulant effect was reversed by prior treatment of the mice with a low, behaviourally inactive dose of L-Dopa plus benserazide. In mice pretreated with reserpine, BRC enhanced the stimulant action of d-amphetamine. Moreover, in mice pretreated with reserpine plus AMPT, BRC significantly enhanced the locomotor stimulant effect of apomorphine. This ability of BRC to enhance the effect of apomorphine commenced as soon as 20 min after BRC administration and lasted for at least 8 h. The dopamine (DA) uptake inhibitor and DA receptor agonist nomifensine potentiated and prolonged the stimulant effect of BRC while inhibitor of the neuronal uptake of noradrenaline (desipramine) and 5-hydroxytryptamine (fluoxetine) were without marked effect. The results clearly show that BRC, in behavioural terms, has no efficacy per se at the postsynaptic DA receptor and that it requires either DA or the administration of an exogenous agonist such as apomorphine for the expression of its effects.     

Semax potentiates effects of D-amphetamine on the level of extracellular dopamine in the Sprague-Dawley rat striatum and on the locomotor activity of C57BL/6 mice

The synthetic peptide semax (a fragment of ACTH 4-7 Pro-Gly-Pro) enhances the release of extracell dopamine (DA) induced by D-amphetamine (5 mg/kg) in the striatum of Spraig-Dowley (SD) rats and increases the locomotor activity stimulated by D-amphetamine (2 mg/kg) in C57/BL6 mice. The basal content of DA, 3,4-dihydroxyphenylacetic acid (DHPAA), and homovanillic acid (HVA) in dialysate of SD rats was 0.5-1.0, 996 +/- 25, and 761 +/- 37 pmole/ml, respectively (n = 7). D-amphetamine (5 mg/kg) induced a sharp increases in the DA level (up to 20 pmole/ml) 20-40 min after treatment and reduced the extracell DHPAA content to 30% of the basal level for a prolonged time (over the entire experimental period). Preliminary (20 min before D-amphetamine) administration of semax resulted in a greater peak of DA concentration (p < 0.05) and a more pronounced drop in DHPAA level (p < 0.01) as compared to the effects produced by the psychostimulant alone. In behavioral tests on C57/BL6 mice, D-amphetamine (2 mg/kg) increased the locomotor activity to a level of 182% (p < 0.01). Simultaneous introduction of semax (0.6 mg/kg) and D-amphetamine (2 mg/kg) led to a more pronounced increase in the locomotor activity of mice (261%, p < 0.01). It is suggested that the peptide modulates dopaminergic systems involved in the formation of the psychostimulant effect.     

Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-1B (PDE1B) enzyme

PDE1B is a calcium-dependent cyclic nucleotide phosphodiesterase that is highly expressed in the striatum. In order to investigate the physiological role of PDE1B in the central nervous system, PDE1B knockout mice (C57BL/6N background) were assessed in behavioral tests and their brains were assayed for monoamine content. In a variety of well-characterized behavioral tasks, including the elevated plus maze (anxiety-like behavior), forced swim test (depression-like behavior), hot plate (nociception) and two cognition models (passive avoidance and acquisition of conditioned avoidance responding), PDE1B knockout mice performed similarly to wild-type mice. PDE1B knockout mice showed increased baseline exploratory activity when compared to wild-type mice. When challenged with amphetamine (AMPH) and methamphetamine (METH), male and female PDE1B knockout mice showed an exaggerated locomotor response. Male PDE1B knockout mice also showed increased locomotor responses to higher doses of phencyclidine (PCP) and MK-801; however, this effect was not consistently observed in female knockout mice. In the striatum, increased dopamine turnover (DOPAC/DA and HVA/DA ratios) was found in both male and female PDE1B knockout mice. Striatal serotonin (5-HT) levels were also decreased in PDE1B knockout mice, although levels of the metabolite, 5HIAA, were unchanged. The present studies demonstrate increased striatal dopamine turnover in PDE1B knockout mice associated with increased baseline motor activity and an exaggerated locomotor response to dopaminergic stimulants such as methamphetamine and amphetamine. These data further support a role for PDE1B in striatal function.     

Effects of ethanol and 3,4-methylenedioxymethamphetamine (MDMA) alone or in combination on spontaneous and evoked overflow of dopamine, serotonin and acetylcholine in striatal slices of the rat brain

Ethanol (EtOH) potentiates the locomotor effects of 3,4-methylenedioxymetamphetamine (MDMA) in rats. This potentiation might involve pharmacokinetic and/or pharmacodynamic mechanisms. We explored whether the latter could be local. Using a slice superfusion approach, we assessed the effects of MDMA (0.3, 3m) and/or EtOH (2mm) on the spontaneous outflow and electrically evoked release of serotonin (5-HT), dopamine (DA) and acetylcholine (ACh) in the striatum, and for comparison, on 5-HT release in hippocampal and neocortical tissue. MDMA and less effectively EtOH, augmented the outflow of 5-HT in all regions. The electrically evoked 5-HT release was increased by MDMA at 3m in striatal slices only. With nomifensine throughout, EtOH significantly potentiated the 0.3m MDMA-induced outflow of 5-HT, but only in striatal slices. EtOH or MDMA also enhanced the spontaneous outflow of DA, but MDMA reduced the electrically evoked DA release. With fluvoxamine throughout superfusion, EtOH potentiated the effect of MDMA on the spontaneous outflow of DA. Finally, 3m MDMA diminished the electrically evoked release of ACh, an effect involving several receptors (D2, 5-HT2, NMDA, nicotinic, NK1), with some interactions with EtOH. Among other results, we show for the first time a local synergistic interaction of EtOH and MDMA on the spontaneous outflow of striatal DA and 5-HT, which could be relevant to the EtOH-induced potentiation of hyperlocomotion in MDMA-treated rats. These data do not preclude the contribution of other pharmacodynamic and/or pharmacokinetic mechanisms in vivo but support the hypothesis that EtOH may affect the abuse liability of MDMA.     

Role of the dopamine transporter in the differential cocaine-induced locomotor activation of inbred long-sleep and short-sleep mice.

The locomotor-stimulant effects of cocaine, mediated through inhibition of the dopamine transporter (DAT), can be influenced by environmental factors. Previously, we found that following a short exposure to the testing environment, cocaine induces greater locomotor activation in inbred long-sleep (ILS) mice, compared to inbred short-sleep (ISS) mice. In the present study, all animals received prolonged habituation to the testing chambers prior to cocaine injection, and the results were compared with those from our previous study. When mice were tested with saline on day 1 and with either saline or cocaine (10-20 mg/kg) on day 2, we observed significant locomotor stimulation in ILS, but not ISS, mice at all tested doses of cocaine. Thus, prolonged habituation does not alter the differential responsiveness of these two strains of mice to cocaine. We found no strain differences in striatal cocaine levels. However, [3H]WIN 35,428 binding studies showed a lower number of striatal DATs in ILS, compared to ISS, mice. In vivo analysis of striatal DAT activity revealed not only that ILS mice cleared exogenously applied DA more slowly than ISS mice, but also that cocaine (10 mg/kg) decreased DA clearance selectively in ILS mice. Thus, functional differences in striatal DATs between ILS and ISS mice likely contribute to the differential behavioral activation of cocaine in these two mouse strains.     

The involvement of noradrenergic transmission in the morphine-induced locomotor hyperactivity in mice withdrawn from repeated morphine treatment.

1. Our previous studies suggest that in addition to the cerebral dopaminergic systems the noradrenergic ones have a crucial role in the morphine-induced behavioural sensitization in mice. Therefore the effects of alpha2-adrenoceptor antagonist, idazoxan (1 and 3 mg kg(-1), i.p.) on morphine-induced locomotor hyperactivity as well as on morphine-induced changes in cerebral noradrenaline (NA) and striatal dopamine (DA) metabolism were studied in mice withdrawn for 3 days from 5 day repeated morphine treatment. The concentrations of NA, free 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 3-methoxytyramine (3-MT) were determined. 2. Acute morphine (10 mg kg(-1), s.c.) increased locomotor activity in control and in morphine-withdrawn mice; idazoxan alone did not alter the activity. Idazoxan pretreatment did not alter the locomotor hyperactivity induced by acute morphine in control mice but potentiated it in morphine-withdrawn mice. 3. Acute morphine elevated MOPEG less but increased DOPAC and HVA more clearly in morphine-withdrawn mice than in controls, and decreased 3-MT only in controls. Idazoxan alone did not alter the NA or DA metabolite concentrations in control mice, but elevated MOPEG as well as DOPAC in morphine-withdrawn mice. 4. In control mice idazoxan enhanced acute morphine's elevating effect on MOPEG. In withdrawn mice idazoxan counteracted the tolerance so that acute morphine elevated MOPEG in these mice to about similar level as in controls. 5. Idazoxan pretreatment abolished the HVA increasing effect of acute morphine both in control and withdrawn mice. In control mice idazoxan enhanced morphine's elevating effect on DOPAC and abolished morphine's decreasing effect on 3-MT. Idazoxan did not alter morphine's effects on DOPAC or 3-MT concentrations in withdrawn mice. 6. Our results show that in morphine-withdrawn mice idazoxan pretreatment reveals the morphine-induced locomotor sensitization. This most probably occurs by overcoming the tolerance towards the acute morphine-induced increase of cerebral NA turnover and release. It is suggested that in mice the cerebral noradrenergic in addition to the dopaminergic systems are major determinants of the behavioural sensitization to morphine.     

Behavioral sensitization to MK-801 (dizocilpine): neurochemical and electrophysiological correlates in the mesoaccumbens dopamine system

MK-801, a non-competitive antagonist at the N-methyl-D-aspartate (NMDA) subtype of central glutamate receptor, stimulates locomotor activity in rats. Administration of MK-801 (0.25mg/kg, i.p.) on four consecutive days results in progressive sensitization of its locomotor stimulatory effects. Because of the importance of dopamine (DA) systems in locomotor sensitization to other stimulants (e.g. amphetamine and cocaine), we examined the possible role of DA transmission in MK-801 sensitization. The D1 antagonist SCH 23390 was used for these experiments because of the well-established ability of D1 antagonists to block both D1- and D2-mediated unconditioned behaviors. Acute behavioral effects of MK-801 were reduced by SCH 23390 only at doses that decreased basal activity, while the expression of MK-801 sensitization was attenuated by SCH 23390 in some experiments but never completely prevented. Co-administration of SCH 23390 with MK-801 on pretreatment days did not prevent the development of sensitization. In vivo microdialysis experiments compared the effect of MK-801 on extracellular DA levels in the nucleus accumbens (NAc) on Days 1 and 4 of repeated administration. On Day 1, MK-801 produced a modest elevation of DA levels. On Day 4, only 6/17 rats in microdialysis experiments expressed sensitization; these rats, however, exhibited a more rapid rise in DA levels than Day 1 rats or non-sensitized Day 4 rats. Electrophysiological studies revealed that repeated MK-801 administration resulted in supersensitivity of D1 receptors on NAc neurons. Thus, behavioral studies support the importance of non-dopaminergic mechanisms in MK-801 sensitization, while neurochemical and electrophysiological studies suggest that MK-801 sensitization is accompanied by changes in DA transmission in the NAc similar to those observed in amphetamine- or cocaine-sensitized rats.     

Intracerebroventricular D-Pen2, D-Pen5-enkephalin administration soon after stressor imposition influences behavioral responsivity to a subsequent stressor encounter in CD-1 mice

Endogenous opioid peptide systems diminish stress-induced autonomic nervous system, neuroendocrine (hypothalamic-pituitary-adrenal axis) and behavioral responses, attenuating a collection of physiological symptoms basic to emotional and affective states. Neurogenic stressors may incite specific central changes in opioid peptide availability as well as changes in mu and delta-opioid receptor function. The present investigation evaluated the proactive influence of an intracerebroventricular injection of the opioid receptor agonist D-Pen2, D-Pen5-enkephalin (DPDPE) (0 microg, 0.005 microg, 1.0 microg or 2.5 microg) on locomotor behavior of mice following uncontrollable footshock (Shock) or novel shock chamber exposure (No Shock). It was expected that DPDPE administration following Shock on Day 1 would restore locomotor activity up to 1 week and prevent shock-associated behavior of mice encountering a brief session of footshock 18 days later. Exposure to Shock reduced horizontal locomotor and vertical locomotor (rearing) activity of mice while 2.5 microg DPDPE restored behavior. Eighteen days following Shock and DPDPE challenge, mice were exposed to either an abbreviated session of footshock (Mild Stress) or the shock chamber (Cues). Mice in the No Shock and Shock groups administered 2.5 microg DPDPE on Day 1 did not exhibit any locomotor deficits in response to Mild Stress on Day 18. Mice in the Shock group administered 0.005 microg DPDPE on Day 1, did not exhibit exaggerated rearing deficits following ensuing Mild Stressor encounter relative to mice reexposed to Cues on Day 18. Taken together, these data show that (a) footshock differentially affects rearing and locomotor activity, (b) DPDPE administration increases locomotor activity for up to 1 week following footshock and DPDPE administration, (c) reexposure to Mild Stress affects rearing and locomotor performance differently depending on previous stressor history and DPDPE dose, (d) DPDPE affords long-lasting protection to previously non-stressed mice against the deleterious effects of subsequent mild stress on locomotor activity, while a low dose of DPDE is sufficient to prevent shock-induced sensitization of rearing deficits, 18 days following original stressor and drug presentation. Finally, our investigation demonstrates that DPDPE administration alters the behavioral impact of future stressful encounters and emphasizes the importance of investigating opioid mechanisms in chronic stress disorders.     

Differences in the effects of morphine on the alpha-methyl-p-tyrosine-induced depletion of dopamine and noradrenaline in various areas of the mouse brain

The effect of morphine on the alpha-methyl-p-tyrosine (alpha MT)-induced depletion of dopamine (DA) and noradrenaline (NA) was studied in various brain areas of male NMRI mice, whose locomotor activity is clearly stimulated by morphine. Morphine (10 mg/kg) accelerated the alpha MT-induced DA depletion in the striatum and in the area "rest of forebrain + midbrain", which contains the limbic dopaminergic neurons, but did not clearly alter it in the hypothalamus. The effects were blocked by naloxone. The enhancement of the striatal DA depletion was attenuated when morphine was given after alpha MT or when morphine dose was increased to 30 mg/kg. The smallest dose of morphine to enhance the alpha MT-induced NA depletion in the forebrain + midbrain area was 3 mg/kg, and in the hypothalamus and the lower brain stem 10 mg/kg. The enhancement of the NA depletion was dose-dependent, occurred whether morphine was given before or after alpha MT, and was blocked by naloxone. Our findings suggest that morphine alters the alpha MT-induced depletion of cerebral DA in mice similarly to what has been reported to occur in rats. In contrast its effects on cerebral NA depletion in mice are clearly different from its effects in rats. The substantial activation of cerebral noradrenergic systems, especially of those in the forebrain + midbrain area, in mice could underly the fact that morphine's predominant behavioural effect in mice is stimulation of motor activity.     

Psychopharmacological investigations of a lead-induced long-term cognitive deficit in monkeys

This study investigated pharmacological manipulations of the cholinergic (ACh) and dopaminergic (DA) transmitter systems in monkeys with a long-term lead-induced cognitive deficit on delayed spatial alternation (DSA). Both ACh and DA have been found to be affected by developmental lead exposure and to be involved with performance on spatial learning and memory tasks. The lead-induced deficit in performance accuracy on DSA persisted throughout the 2 years of this experiment, which ended more than 8 years after the end of the postnatal lead exposure. Acute administration of agonists and antagonists of the ACh and DA systems did not elicit differential effects from the lead-exposed and control groups in terms of DSA per cent correct performance. The ACh antagonist, scopolamine, caused a dose-related decline in performance in both groups. Significant amelioration of the lead-induced DSA deficit was achieved by chronic treatment with the DA agonist, L-dopa. After withdrawal from L-dopa, the lead-related deficit reappeared. Improvement in performance of the lead-treated group was also seen after chronic amphetamine administration, but this effect was not significant. These data implicate DA mechanisms in the long-lasting cognitive effects of developmental lead exposure. The alleviation of the deficit with chronic administration of a DA precursor points to a possible line of treatment for the cognitive effects of developmental lead exposure.     

Effects of isatin, an endogenous MAO inhibitor, on dopamine (DA) and acetylcholine (ACh) concentrations in rats

Isatin (indole-2,3-dione), an endogenous inhibitor of monoamine oxidase (MAO), has several physiological properties for stress and anxiety. We previously identified isatin in the brain of stroke-prone spontaneously hypertensive rats (SHRSP) using gas-chromatography mass spectrometry. This study elucidated the effects of isatin on the ACh and DA levels of brain tissues in rats. Furthermore, we evaluated the effect of isatin on DA levels in a rat model of Parkinson's disease induced by Japanese encephalitis virus. Striatal ACh and DA levels significantly increased at 2 hours after isatin (50-200 mg/kg, i.p.) administration. Perfused through a microdialysis probe, isatin (10(-6)-10(-4) M) also produced a significant and concentration-dependent increase in the ACh and DA concentrations in the perfusate from the rat striatum. Furthermore, urinary isatin concentrations in patients with Parkinson's disease tend to increase according to the severity of disease. Isatin (100 mg/kg, i.p.) significantly increased striatal DA levels in a rat model of Parkinson's disease. These results suggest that urinary isatin may become a diagnostic marker for the clinical severity of Parkinson's disease and that endogenous isatin, a new biological modulator, may play a role in the regulation of the brain levels of ACh by increasing the level of DA under stress.     

PD 158771, a potential antipsychotic agent with D2/D3 partial agonist and 5-HT(1A) agonist actions. II. Preclinical behavioral effects

PD 158771 has been described in receptor binding and biochemical tests as a partial agonist at dopamine (DA) D2 and D3 receptors as well as an agonist at serotonin (5-HT)(1A) receptors. The present studies describe the profile of PD 158771 in rodent and primate behavioral tests. PD 158771 reduced spontaneous locomotor activity in mice (ED(50)=0.38 mg/kg, i.p.) and rats (ED(50) = 1.2 mg/kg, i.p. and 0.16 mg/kg, s.c.), and reduced amphetamine-stimulated locomotion in mice (ED(50) = 0.13 mg/kg, i.p.). At relatively higher doses up to 3 mg/kg, s.c. in rats, PD 158771 did not produce locomotor stimulation or induce stereotypy, indicating a lack of postsynaptic DA agonist activity. PD 158771 reduced apomorphine stimulated locomotion in rats at a dose 4.6-fold greater than those that reduced spontaneous locomotor activity, indicating weak postsynaptic DA antagonist actions; results consistent with a partial agonist profile. PD 158771 produced anxiolytic-like effects in the water-lick (Vogel) conflict test, effects possibly due to the 5-HT(1A) activity. However, PD 158771 was inactive in the water wheel behavioral despair model in rats, indicating lack of antidepressant properties. Similar to known antipsychotics, PD 158771 produced a potent and long-lasting inhibition of conditioned avoidance responding in squirrel monkeys. In contrast to standard antipsychotics, and similar to clozapine, PD 158771 did not cause catalepsy in rats at a dose 20-fold higher than the ED(50) dose for locomotor inhibition. PD 158771 also had a somewhat lower liability than haloperidol to produce extrapyramidal dysfunction in squirrel and cebus monkeys sensitized to the dystonic effects of haloperidol. The data indicate that PD 158771 is a DA partial agonist with weak intrinsic activity that selectively activates brain DA autoreceptors. PD 158771 produced behavioral effects consistent with potential antipsychotic and anxiolytic efficacy, and has an improved profile in the extrapyramidal side effect model when compared to certain currently available antipsychotic agents.     

Locomotor activity as a predictor of times and dosages for studies of nicotine's neurochemical actions

Nicotine's action on the central nervous system is complex and likely involves an interaction of neurotransmitters. To determine the time after administration of nicotine and dosage for neurochemical studies, locomotor activity of CD-1 mice was determined at 5 min intervals between 0-60 min. A low nicotine dosage (0.05 mg/kg) did not alter activity 5-15 min after drug injection, but increased activity 28% at 15-25 min post-injection. A high dosage (0.8 mg/kg) reduced total distance 62% and rearing 87% at 5-15 min; at 15-25 minutes total distance declined 56% and rearing 69%; all measures returned to control values after 30 minutes; rearing then increased at 40 min after nicotine. Pretreatment (15 min before nicotine) with mecamylamine (1.0 mg/kg), but not hexamethonium (1.0 mg/kg), prevented the depressant effect of nicotine. Dopamine (DA) and its metabolites as well as acetylcholine (ACh) synthesis were measured at the point of nicotine's maximal depressant action. Striatal levels of dihydroxyphenylacetic acid (DOPAC) were increased and ACh utilization was reduced in striatum (-25%) and cortex (-24%) 10 min after nicotine (0.8 mg/kg). Mecamylamine, while preventing the depressant effect of nicotine on locomotor activity, did not alter its effects on DA metabolism. These results demonstrate that the behavioral outcome of acute nicotine treatment is time and dose-dependent. Nicotine's depressant action appears not to be due to altered DA but may be related to changes in carbohydrate and acetylcholine metabolism.     

Alterations in striatal acetylcholine overflow by cocaine,morphine, and MK-801: relationship to locomotor output

The activity of cholinergic interneurons in the striatum appears to be modulated by a variety of different systems including dopamine, opiate, and glutamate. The purpose of this study was to characterize the effects of drugs known to act on these three systems (i.e., cocaine, morphine, and MK-801) on striatal ACh overflow with microdialysis procedures, and to determine if alterations in ACh function induced by these agents are related to changes in locomotor activity. Cocaine was found to increase striatal ACh following intraperitoneal injections of 20 and 40 mg/kg, but not 10 mg/kg. The increases in locomotor activity induced by cocaine appeared to be dose dependent, while the effects on striatal ACh were not. Injections of 0.1 mg/kg MK-801 (a non-competitive NMDA receptor antagonist) produced dramatic increases in locomotor activity while decreasing striatal ACh overflow. A lower dose (0.03 mg/kg) of MK-801 failed to alter locomotor activity or striatal ACh. Morphine produced an apparent dose-dependent elevation in striatal ACh while only the lowest dose (5 mg/kg) increased locomotor activity. These appears to be no relationship between alterations in striatal ACh and locomotor output following systemic administration of these psychoactive agents.     

Functional alteration of brain dopaminergic system in isolated aggressive mice.

The present study examined the effects of social isolation on cortical dopamine (DA) release in vivo and on brain DA receptor functions to study the possible involvement of cortical DA neurons in an antiaggressive effect of the serotonin (5-HT)1A receptor agonist (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino] propoxy]-1,3-benzodioxole HCl (MKC-242). MKC-242 and the DA receptor agonist apomorphine reduced aggressive behavior in isolated mice. MKC-242 increased cortical DA release in vivo in mice, and the effect was antagonized by the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide. The basal level of extracellular DA in the frontal cortex was higher in isolated mice than in grouped mice. MKC-242-induced and high K(+)-induced increases in the cortical DA release were less pronounced in isolated mice than in grouped mice. The effect of apomorphine on locomotor activity was more pronounced in isolated mice than in grouped mice. These findings suggest that the isolation stress enhances cortical DA release and the brain DA receptor function and reduces the responses of the dopaminergic terminals to 5-HT1A receptor stimulation and high K(+)-induced depolarization.     

Influences of diterpene sclareol glycol on some dopamine related behavior

1. The effects of the diterpene sclareol glycol (SG) of the labdane family on some dopamine (DA) related behavior (locomotor activity in mice, apomorphine-induced stereotypy in mice and rats, and haloperidol-induced catalepsy in rats) were studied. 2. The locomotion frequency of mice was significantly increased by SG (stronger effect by low and medium dose). SG antagonized the hypomotility induced by reserpine pretreatment. SG enhanced the apomorphine decreased motility (induced by small dose of apomorphine). 3. SG provoked increase of apomorphine stereotypy. The long-term SG treatment augmented the sensitivity of rats to apomorphine-induced stereotypy. 4. SG at low dose decreased haloperidol-induced catalepsy: at higher dose it increased the catalepsy. SG treatment alone did not induce catalepsy. 5. These results were discussed in the light of a possible interaction of SG with dopaminergic transmission (DA autoreceptors and postsynaptic DA receptors) at the level of the striatum and the nucleus accumbens. The interaction of SG with adenylate cyclase (stimulation of catalytic subunit) and with GABAergic transmission in realization of its effects on DA related behavior was also discussed.