Sodium pentobarbital: sensory and associative effects in classical conditioning of the rabbit nictitating membrane response

Four experiments were conducted to determine the effects of sodium pentobarbital (0, 3, 9, and 15 mg/kg) on the acquisition of the rabbit's classically conditioned nictitating membrane response (NMR) and to determine the locus of the drug's effects on sensory, motor, associative, and nonassociative processes. In experiment 1, classical conditioning of the NMR was accomplished by pairing tone and light conditioned stimuli (CSs) with paraorbital shock as the unconditioned stimulus (US). The experiment revealed that pentobarbital retarded the acquisition of conditioned responses (CRs) to both tone and light CSs. Experiment 2, employing unpaired CS, UCS presentations, indicated small but significant drug effects on NMR base rate and nonassociative NMRs to the CS. Experiment 3 revealed no significant drug effect on the psychophysical functions relating UCS intensity to UCR frequency or amplitude, nor on the UCS intensity threshold for eliciting UCRs. On the other hand, in experiment 4, the drug significantly impaired CR frequency over an extended range of CS intensities and raised CS intensity threshold. It was concluded that pentobarbital's attenuation of CS intensity also operated to impair CR acquisition.     

Effects of morphine and LSD on the classically conditioned nictitating membrane response

Two experiments were carried out to determine the effects of LSD and morphine on the unconditioned nictitating membrane response of the rabbit elicited by 5 intensities of a 100 msec puff of air directed at the cornea, and on the acquisition of conditioned responses to a tone and light conditioned stimulus using the air-puff as an unconditioned stimulus. In Experiment 1, LSD tartrate (0.013 mg/kg) had no effect of the frequency, amplitude, magnitude or latency of the unconditioned response. However, LSD significantly enhanced the rate of acquisition of conditioned responses to both tone and light conditioned stimuli. In Experiment 2, morphine sulfate (5 mg/kg) had no effect on the frequency, amplitude, magnitude or latency of the unconditioned response, but significantly retarded the acquisition of conditioned responses to both tone and light conditioned stimuli. The results indicated that the enhancement of acquisition produced by LSD and the retardation of acquisition produced by morphine were not due to effects of the drugs on either the sensory processing of the air-puff unconditioned stimulus or on the motoric expression of the unconditioned response.     

Sensory and associative effects of morphine and naloxone in classical conditioning of the rabbit nictitating membrane response

In Experiment I, classical conditioning of the rabbit's nictitating membrane response was accomplished by the pairing of tone and light conditioned stimuli with a shock unconditioned stimulus applied to the paraorbital region of the head. Morphine (5 mg/kg) significantly retarded the acquisition of conditioned responses to both conditioned stimuli. Moreover, morphine had no effect on nonassociative responding (baseline responding or responding to tone and light stimuli) or on the latency and amplitude of the unconditioned response elicited by shock during the explicitly unpaired presentations of tone, light and shock stimuli. The retardant effect of morphine on acquisition of conditioned responses was blocked by naloxone (1 mg/kg). In Experiment II, morphine (0.2–10 mg/kg) had no effect on the intensity threshold of the shock unconditioned stimulus for elicitation of unconditioned responses or on the latencies of the elicited responses. However, morphine (5 and 10 mg/kg) did produce a small but significant decrease in the amplitude of unconditioned responses elicited by the two highest shock intensities employed (3 and 4 mA). This latter effect of morphine was completely blocked by naloxone (1 mg/kg). In Experiment III, morphine (5 mg/kg) blocked the sensory processing of a tone conditioned stimulus, in previously trained animals, as measured by a significant (24 dB) elevation in the intensity threshold of the conditioned stimulus for elicitation of conditioned responses and an increase in the latency of the elicited response. Naloxone (1 mg/kg) completely blocked the effects of morphine on the sensory processing of the tone-conditioned stimulus. The retardant effect of morphine on the acquisition of conditioned responses appears to be primarily due to an action on opioid receptors that produces a decrease in the sensory processing of the conditioned stimulus.     

Absence of central cholinergic deficits in ApoE knockout mice

 ApolipoproteinE (ApoE) genotype has recently been identified as a major risk factor for Alzheimer’s disease (AD) but the mechanism(s) by which ApoE isoforms influence this disease remain unclear. Recent studies suggest that mice deficient in ApoE may exhibit impaired central cholinergic function. Since this neurotransmitter system has traditionally been associated with the pathogenesis of AD, we have further investigated the impact of ApoE gene deletion on this system. Female ApoE knockout (ko) mice, age 12 months, were compared with wild type littermate controls using a range of behavioural, biochemical and histochemical techniques. Pre-treatment with the cholinomimetic, donepezil (E2020; 2.5–5 mg kg^–1 IP), produced significant hypothermia and induction of tremor in both wild type and ApoE ko mice. The magnitude of change did not significantly differ between the groups. Cognitive testing in the Morris water maze revealed that both wild type and ApoE ko mice could learn the location of a hidden escape platform with similar rates of acquisition and accuracy. Similarly, the behaviour of both genotypes proved indistinguishable in a Y-maze spontaneous alternation procedure. The protocols used for both cognitive tests were then shown to be sensitive to the disruptive effects of scopolamine (but not scopolamine methyl bromide). Following behavioural testing, choline acetyltransferase (ChAT) activity was measured in the hippocampus, frontal and entorhinal cortex and striatum. In each case there was no difference between the genotypes. In addition, coronal sections of striatum and anterior hippocampal regions of ApoE ko and wild type mice showed similar patterns of acetylcholinesterase (AChE) staining, with no qualitative or obvious quantitative difference. Finally, analysis of plasma cholesterol levels confirmed ApoE genotype. In conclusion, using a combination of behavioural, histochemical and biochemical measurements, we have failed to detect any significant differences in central cholinergic activity between wild type and ApoE ko mice. Received: 24 October 1996 / Final version: 16 December 1996     

Inhibitory effects of α,β-methylene ATP on nerve-mediated contractions of the nictitating membrane in reserpinised cats

Residual responses of the cat nictitating membrane to nerve stimulation were obtained after reserpine pretreatment (40% of controls), in spite of a pronounced reduction in noradrenaline content. The putative ATP-receptor desensitising agent α,β-methylene ATP (α,β-MATP), administered intraarterially through the lingual artery produced a contraction of the nictitating membrane and subsequently inhibited the residual responses evoked by sympathetic nerve stimulation in reserpinised cats. These doses of α,β-MATP did not modify the contractions evoked by exogenous noradrenaline (i.a.) but antagonized the contractions of the nictitating membrane elicited by β,γ-methylene ATP, which is an agonist at P2 receptors. These results are compatible with a co-transmitter role for ATP in the neurally mediated contractile responses of the nictitating membrane following depletion of endogenous noradrenaline stores by pretreatment with reserpine.     

Effects of paraquat on mitochondrial electron transport system and catecholamine contents in rat brain

 The effects of paraquat on rat brain were studied. Activities of complex I (NADH: ubiquinone oxidoreductase) in mitochondrial electron transport system, lipid peroxidation and the amount of catecholamines in rat brain were measured after acute paraquat exposure. Complex I activities were significantly lower and lipid peroxides were higher in the brains of a paraquat-treated group than in those of a control group. Lipid peroxide in rat serum, however, did not increase after paraquat exposure. A study of the time dependency of paraquat effects disclosed that mitochondrial complex I activities in rat brain as well as those in rat lung and liver gradually decreased prior to the appearance of respiratory dysfunction. As compared to controls, the dopamine in rat striatum was significantly lower in the paraquat-treated group. These results suggest that paraquat after crossing the blood-brain barrier might be reduced to the radical in rat brain, which may damage the brain tissue, especially dopaminergic neurons in striatum. We therefore propose that cerebral damage should be taken into consideration on paraquat exposure. Patients may therefore need to be followed up after exposure to high doses of paraquat. Received: 19 June 1995/Accepted: 18 January 1996     

Manipulations of mu-opioid and nicotinic cholinergic receptors in the pontine tegmental region alter cocaine self-administration in rats

Rationale: The pedunculopontine tegmental nucleus (PPTg) has been implicated in drug reward, particularly in the development of dependence. However, little is known of the receptor systems within this nucleus which might be involved. Furthermore, some research suggests that the PPTg may also be part of the neuronal circuitry involved in established drug-taking behavior. Objective: The objective of these experiments was to examine the role of mu-opioid and nicotinic cholinergic mechanisms in the PPTg in cocaine self-administration. Methods: Microinfusions of mu-opioid and nicotinic receptor selective compounds were made into the PPTg of rats trained to self-administer cocaine intravenously, in the vicinity of cholinergic cells which are known to project to the midbrain dopamine neurons of the ventral tegmental area (VTA). Results: The mu-opioid selective agonist DAMGO, tested at doses of 0, 0.05 and 0.5 μg, produced a dose-related reduction in the number of cocaine infusions obtained during the 1-h self-administration sessions. The mu-selective antagonist CTOP (0–2 μg) and nicotine (0–10 μg) did not produce significant changes in cocaine self-administration. Microinfusions of the nicotinic antagonist dihydro-β-erythroidine (0–30 μg) produced a small but significant increase in cocaine-maintained responding. Conclusions: These data show that mu-opioid mechanisms in the PPTg can influence cocaine self-administration markedly. Moreover, the data demonstrate that PPTg circuitry can influence drug reward in already-established drug-reinforced behavior, as well as during the development of dependence (as shown by previous research). Received: 30 November 1998 / Final version: 25 March 1999     

Activation of the mesocorticolimbic dopaminergic system by stimulation of muscarinic cholinergic receptors in the ventral tegmental area

Objective: To investigate the function of muscarinic receptors in the ventral tegmental area in vivo, the release of endogenous monoamines was simultaneously measured in the somatodendritic (ventral tegmental area) and terminal (frontal cortex and nucleus accumbens) regions of the mesocorticolimbic dopaminergic system in rats, using dual probe microdialysis. Methods: Rats were implanted with dual microdialysis probes ipsilaterally into the ventral tegmental area (VTA) and nucleus accumbens (NAC) or frontal cortex (FC). Results: Intrategmental infusion of the muscarinic agonist oxotremorine M (OXO M, 0.1 and 1 mM) increased extracellular levels of dopamine and serotonin, but not noradrenaline, in the VTA to a maximum of 200% over baseline in both urethane-anaesthetized and unanaesthetized rats. In freely moving animals, this effect was accompanied by strong motor agitation. Both VTA dopamine and serotonin levels dropped to 60% or less of baseline when the perfusion medium was replaced by a calcium-free medium containing OXO M. In the NAC and FC, a similar increase in extracellular dopamine, but not serotonin and noradrenaline, was observed during OXO M infusion in the VTA. The removal of calcium during OXO M infusion in the VTA did not cause a decrease in NAC dopamine levels. Activation of serotonin and dopamine release by OXO M in the VTA and FC was dramatically reduced or prevented by the co-infusion of the muscarinic antagonist N-methylscopolamine (0.1 mM). Conclusion: These data demonstrate that VTA dopamine cells possess functional muscarinic receptors whose activation stimulates the release of dopamine in the VTA, NAC and FC. These results also suggest that muscarinic receptors may modulate the synaptic release of serotonin in the VTA. Received: 12 February 1999 / Final version: 6 July 1999     

Impairment of memory and plasma flunitrazepam levels

 The 5-HT_2A/2C receptor antagonist, ritanserin, was reported to retard the acquisition of conditioned responses (CRs) during classical conditioning of the rabbit’s nictitating membrane (NM) response. The present study compared the effects of ritanserin on acquisition of CRs to a tone conditioned stimulus (CS) with that of the 5-HT_2A/2C receptor antagonist, LY-53,857 and the 5-HT_2A selective antagonist, MDL-11,939. All three drugs were injected at equimolar doses of 0.067, 0.67 and 6.7 μmol/kg, SC, 1 h before behavioral testing. Ritanserin and MDL-11,939 retarded CR acquisition to a tone CS, while LY-53,857 had no effect. Control experiments demonstrated that ritanserin (1 μmol/kg), MDL-11,939 (1 μmol/kg) and LY-53,857 (2 μmol/kg) had no effect on baseline responding or non-associative responding to the CS. However, both ritanserin and MDL-11,939 impaired the performance of the unconditioned NM reflex, as measured by a decrease in UR amplitudes on US alone trials, while LY-53,857 had no effect. In previously trained animals, ritanserin robustly impaired the performance of CRs, as measured by a reduced ability of the CS to elicit CRs, while the effects of LY-53,857 and MDL-11,939 were marginal. The retardation of associative learning produced by ritanserin and MDL-11,939 may have been due, at least in part, to their impairment of the NM reflex arc. Since MDL-11,939 is a highly selective 5-HT_2A antagonist, the retardation of learning and impairment of UR amplitudes produced by MDL-11,939 and ritanserin may have been due to blockade of the 5-HT_2A receptor. The ability of ritanserin and MDL-11,939 to produce effects on learning and performance that were opposite to that of 5-HT_2A/2C agonists suggests that they may be acting as inverse agonists at that receptor. These results stress the importance of the serotonergic system for optimal associative learning and motor function. Received: 22 May 1997 / Final version: 3 December 1997     

Augmented depression and reduced excitability of the central nervous system (CNS) by cadmium in the rat

Reports indicating that low doses of cadmium caused vasodilation, but that larger quantities elicited a pressor response, apparently mediated by a CNS reflex, prompted an examination of cadmium-induced changes in CNS responsiveness and activity. Rats were injected intraperitoneally with either 2 mg/kg or 4 mg/kg of CdCl2 solution, after which the CNS was either depressed by pentobarbital or excited by strychnine at different dose levels. Cadmium treatment, administered before pentobarbital, decreased the time required for sleep induction and prolonged sleep duration at doses of either 20 mg/kg or 30 mg/kg: at 40 mg/kg only induction was affected and at 60 mg/kg neither was influenced. At a dosage of 60 micrograms/kg, strychnine caused convulsions in all control animals, but in none pretreated with CdCl2. When either 75 or 120 micrograms/kg of strychnine was used, cadmium at either dosage failed to prevent convulsions, although the onset was delayed and duration curtailed. The rapidity with which Cd modified CNS activity indicated that the effect can not depend upon cadmium-induced synthesis of metallothionine, but represents a direct effect of Cd on the CNS. Cadmium treatment did not substantially improve the survival of rats that convulsed when treated with strychnine.     

Associative and non-associative fentanyl tolerance in the rat: evaluation of cross tolerance with mu-and kappa-specific opioids

Rationale: Associative tolerance to the analgesic effects of morphine is most pronounced when morphine is paired with a distinctive context at a long inter-dose interval (IDI). In contrast, morphine administered at a short IDI promotes the development of non-associative tolerance and disrupts the acquisition of associative tolerance. The impact of IDI on the development of associative tolerance to opioids other than morphine has not been investigated previously. Objectives: This research examined associative and non-associative tolerance to the analgesic effects of fentanyl in rats. Cross tolerance for these two forms of tolerance with morphine (mu- receptor agonist) and U50,488H (kappa-receptor agonist) analgesia was also investigated. Methods: Animals were given eight fentanyl injections (0.10 mg/kg) paired or unpaired with a distinctive context at either a 3-h (short) or 96-h (long) IDI. Subjects were then tested for tolerance in the distinctive context using the tail-flick procedure and dose–response curve methodology. Results: At the short IDI, animals developed non-associative tolerance to fentanyl that was receptor specific, i.e., cross tolerant with morphine analgesia but not with U50,488H analgesia. At the long IDI, fentanyl-tested animals displayed tolerance that appeared to be controlled primarily by associative processes. This associative form of tolerance was also receptor specific, displaying cross tolerance with morphine but not with U50,488H. Conclusions: The impact of IDI on the development of non- associative and associative fentanyl tolerance is consistent with findings obtained with morphine showing that conditions conducive to the development of non-associative tolerance disrupt the acquisition of associative tolerance. The cross-tolerance data, however, did not parallel previous research examining the cross-tolerance profiles of associative and non-associative morphine tolerance. Received: 26 April 1999 / Final version: 5 October 1999     

Release and actions of adenosine in the central nervous system

Adenosine is released from active neurons into the extracellular fluid at a concentration of about 1mol/l. Neither the precise cellular origin nor the biochemical form of release has been firmly established, though the nucleotide is probably released partly directly, as a result of raised intracellular levels, and partly as nucleotides, which are subsequently hydrolysed. Once in the extracellular medium, adenosine markedly inhibits the release of excitatory neurotransmitters and modulatory peptides and has direct inhibitory effects on postsynaptic excitability via A₁ receptors. A population of A₂ receptors may mediate depolarization and enhanced transmitter release. Adenosine also modulates neuronal sensitivity to acetylcholine and catecholarnines, all these effects probably contributing to the behavioural changes observed in conscious animals. As a result of their many actions, adenosine analogues are being intensively investigated for use as anticonvulsant, anxiolytic, and neuroprotective agents.     

Long-term haloperidol administration enhances and short-term administration attenuates the behavioral effects of cocaine in a place conditioning procedure

 Many behavioral effects of cocaine are attenuated by dopamine (DA) receptor antagonists. Yet, long-term DA antagonist administration enhances neuronal responsiveness to DA in several pathways, including the mesolimbic system. This study compared the effects of short-term versus long-term administration of the DA antagonist, haloperidol, on cocaine place conditioning. In the short-term study, rats were maintained on haloperidol or vehicle for the 10 days of place conditioning. Place conditioning to moderate doses of cocaine (10–15 mg/kg) was attenuated significantly, consistent with the dopaminergic actions of haloperidol and cocaine. In the second study, rats were administered haloperidol after place conditioning which had no effect on the expression of this behavior. Finally, rats were maintained on haloperidol for 30 days prior to and throughout place conditioning and testing which resulted in significant place conditioning at low cocaine doses (2.5–7.5 mg/kg). Because these cocaine doses do not support place conditioning in vehicle-maintained rats, these data suggest that long-term haloperidol administration enhances the sensitivity to these behavioral effects in contrast to the attenuation seen with short-term haloperidol administration. These results have wide-ranging implications for cocaine abuse treatment, particularly among schizophrenic populations. Received: 6 April 1996 / Final version: 29 June 1996     

Effects of test conditions on the outcome of place conditioning with morphine and naltrexone in mice

 Drug administration during test trials can increase the expression of place conditioning, offering an opportunity to determine the specificity of this enhanced response. Prior to training, Swiss-Webster mice spent similar durations in each of the distinctive compartments of a two-compartment box during three 900-s tests. During a 4-day conditioning period, daily injections of morphine (5–20 mg/kg, SC) or vehicle were differentially paired with one of two compartments of the box using an unbiased place conditioning procedure. Post-conditioning tests were conducted 2 and 3 days after the last conditioning day. Mice pre-treated during post-conditioning tests with vehicle did not show significant preference for the morphine-paired compartment when conditioned with morphine. Pretreatment with morphine (2.5–30 mg/kg, SC) led to a dose-dependent increase in time spent in the morphine-paired compartment. Post-conditioning tests in other groups of mice were conducted with heroin (0.1–3 mg/kg), fentanyl (0.01–0.3 mg/kg), cocaine (10–30 mg/kg) and pentobarbital (10–30 mg/kg), and results suggested that none of the tested drugs facilitated the expression of the morphine-conditioned place preference. In another experiment, naltrexone (0.1–10 mg/kg, SC) was administered as the conditioning drug. When tested with naltrexone (0.1–10 mg/kg), there was a dose-dependent avoidance of the naltrexone-paired compartment. Overall, the present data indicated that: (1) failure to exhibit place preference or place aversion when tested in a drug-free state does not imply the failure of conditioning procedure; and (2) effects of the morphine cue reinstatement during the post-conditioning tests appeared to be related to the unique pharmacological profile of the morphine stimulus. Received: 28 November 1997 / Final version: 23 July 1998     

慢性肾功能衰竭患者使用第三代头孢菌素致中枢神经系统不良反应病例分析

目的分析第3代头孢菌素对慢性肾功能衰竭患者的中枢神经系统造成的不良反应情况,并研究其相应的临床防治对策。方法在我院内科住院患者中,随机选取接受过第3代头孢菌素治疗的慢性肾功能衰竭患者79例,统计其中枢神经系统的不良反应情况,以及相应的对症治疗措施,分析、评价患者的临床治疗效果。结果 77例患者在服药约1周时,出现不同程度的注意力减退、容易疲劳、嗜睡、记忆力下降、呆滞、妄想、幻听、幻视、烦躁不安、意识障碍、认知能力异常等中枢神经系统一般不良反应;4例患者在服药约1~2周时,表现出中枢神经系统肾性脑病的严重不良反应。经过及时抢救和对症治疗后,其临床症状均明显减退或痊愈。结论第3代头孢菌素能够引起慢性肾功能衰竭患者中枢神经系统的不良反应,因此,在治疗期间需严格控制药量,不可长期大剂量应用,在发现不良反应症状后应立即停止用药,并给予相应的对症治疗。对于用药时间过长而引起的严重中枢性肾性脑病患者应积极抢救,必要时行血液透析治疗以确保患者的生命安全。     

Picrotoxin in the medial prefrontal cortex impairs sensorimotor gating in rats: reversal by haloperidol

  Rationale: Neuropathological data indicate a GABAergic dysfunction in the prefrontal cortex and hippocampus of schizophrenics. On this basis, the construct validity of an animal model of schizophrenia was tested. Objective: This study assessed prepulse inhibition (PPI) of startle in rats after injections of the GABA antagonist picrotoxin into the prefrontal cortex and the ventral hippocampus. It was also tested if reductions in PPI are reversed by the dopamine antagonist haloperidol. PPI is a measure of sensorimotor gating and is impaired in schizophrenia patients. The hypothesis underlying this study was that blockade of prefrontocortical and hippocampal GABA receptors disrupts PPI in a dopamine- dependent way. This hypothesis was based on neuropathological data from schizophrenics indicating a loss of GABAergic neurons in the prefrontal cortex and hippocampus and on the observation that PPI is reduced in schizophrenics. Methods: Picrotoxin (0, 5, 10 ng/0.5 μl) was infused through chronically indwelling cannulae into the medial prefrontal cortex (mPFC), into the lateral prefrontal cortex and into the ventral hippocampus. The effect on PPI was measured directly after picrotoxin infusion. The neuroleptic compound haloperidol (0.1 mg/kg) was administered intraperitoneally 30 min before testing. Results: Picrotoxin in the mPFC dose-dependently reduced PPI and this effect was antagonized by systemic pretreatment with the dopamine antagonist haloperidol. No significant effects on PPI were observed after picrotoxin infusions into the lateral prefrontal cortex or into the ventral hippocampus. Conclusions: These findings indicate that acute blockade of GABA receptors in the mPFC impairs sensorimotor gating in a dopamine-dependent manner. Since PPI in rats has been shown to possess face, predictive, and construct validity as an animal model for some psychotic symptoms, we discuss the potential relevance of our findings for the pathophysiology of schizophrenia. Received: 16 August 1998 / Final version: 25 January 1999     

Effects of physostigmine,scopolamine, and mecamylamine on the sleeping time induced by ketamine in the rat

Male Sprague-Dawley rats weighing 116–241 g were injected i.p. with ketamine hydrochloride, 80 mg per kilo of body weight. Immediately after loss of righting reflex, scopolamine, physostigmine, and mecamylamine were administered i.p. to different groups of rats. Control animals received sterile saline by the same route. The ketamine-induced sleeping time was significantly prolonged by physostigmine and scopolamine, but not by mecamylamine. After the delayed injection of physostigmine, the ketamine sleeping time was longer. These results, although too preliminary for a mechanistic interpretation, suggest that multiple neurotransmitter systems, probably including the cholinergic system, are involved in the mechanism of action of ketamine-induced narcosis.     

Context-specific morphine tolerance on the paw-pressure and tail-shock vocalization tests: evidence of associative tolerance without conditioned compensatory responding

Rationale: Demonstrations of associative tolerance to the analgesic effects of morphine, not confounded by practice or novelty effects, have been restricted to the tail-flick and flinch-jump tests. Objectives: Experiment 1 investigated whether associative tolerance would be found on two other nociceptive assessment methods: the paw-pressure withdrawal and tail-shock vocalization thresholds. Experiment 2 tested the hypothesis that conditioned compensatory behavioral responses are the substrate of associative morphine tolerance in the paw-pressure, tail-shock, and tail-flick tests. Methods: Rats were given eight morphine injections (20 mg/kg, i.p.) explicitly paired or unpaired with a distinctive context. Control animals were given saline injections over the course of conditioning. Animals were then tested after morphine (experiment 1) or placebo injections (experiment 2) in the context. Results: There was evidence of context-specific tolerance across both testing methods, with a rightward shift of dose–response curves of paired relative to unpaired animals. No evidence of conditioned compensatory responding was found on any of the three testing methods. Conclusions: The data indicated that, although Pavlovian processes can play a major role in tolerance acquisition, there was little support for the thesis that the conditioned tolerance response is a behavioral effect that is opposite in direction to the direct effects of the drug. Received: 22 December 1998 / Final version: 22 March 1999     

Hyperlocomotion and increased dopamine efflux in the rat nucleus accumbens evoked by electrical stimulation of the ventral subiculum: role of ionotropic glutamate and dopamine D1 receptors

Rationale and objectives: The role of glutamatergic afferents from the hippocampus in the modulation of dopamine (DA) efflux in the nucleus accumbens (NAcc) and concomitant increases in locomotor activity was examined following brief high-frequency electrical stimulation of the ventral subiculum (vSub). Reverse dialysis of ionotropic glutamate receptor (iGluR) antagonists into the NAcc identified the relative contributions of N-methyl-d-aspartate (NMDA) and non-NMDA glutamate receptors in the modulation of DA efflux, whereas microinjection of these compounds or selective DA D₁ or D₂ receptor antagonists were used to analyze the roles of glutamatergic and DA receptors in the stimulation-induced hyperlocomotion. Methods and results: Electrical stimulation of the vSub at 20 Hz (10 s, 300 μA) induced a significant increase in (1) DA levels in the NAcc (≈30% from pre-stimulation DA levels) and (2) locomotor activity (≈400%). The evoked DA release was completely blocked by reverse dialysis of a selective non-NMDA antagonist DNQX (10 μM and 100 μM), whereas only a high dose of the NMDA antagonist AP-V (100 μM) was effective. The increased motor activity, however, was only slightly attenuated by reverse dialysis of these drugs. Bilateral intra-NAcc injection of DNQX (1 μg/0.5 μl) blocked the increased motor activity induced by vSub stimulation relative to saline treatment. In contrast, bilateral intra-NAcc injection of AP-V (1 μg/ 0.5 μl) alone caused a significant increase in locomotor activity. The increased motor activity induced by vSub stimulation appears to be mediated through the DA D₁ receptor, as systemic administration of the D₁ antagonist SCH 23390 (0.25 mg/kg and 1 mg/kg), but not the D₂ antagonist sulpiride (2 mg/kg and 10 mg/kg) blocked these effects. Conclusions: These data indicate an important role for hippocampal glutamatergic afferents in modulating the release of DA through iGluR on DA-receptive neurons in the NAcc and possibly on output neurons to the ventral tegmental area, which subsequently elicits a prolonged increase in locomotor behavior. The role of this circuit in mediating context-dependent behavioral sensitization to repeated administration of psychostimulants is discussed. Received: 13 October 1999 / Accepted: 21 December 1999     

Enhancement of the acoustic startle response in rats by the dopamine D1 receptor agonist SKF 82958

  Rationale: The present series of experiments was conducted in order to assess the nature of dopaminergic modulation of the acoustic startle response using agonists and antagonists specific for dopamine D₁ and D₂ receptors. Objectives: The objective of the present study was to demonstrate an enhancement of the acoustic startle response by dopamine D₁ receptor agonists and to characterize this effect pharmacologically in terms of dose-response and selective antagonism at both the dopamine D₁ and D₂ receptor using a varied range of startle-eliciting intensities. Methods: Male Sprague-Dawley rats were injected subcutaneously with the dopamine D₁ receptor agonist SKF 82958 (0, 0.01, 0.1, 1, or 3 mg/kg) or SKF 81297 (3 mg/kg) and their startle response was measured across a range of startle-eliciting intensities. For testing with the dopamine D₁ or D₂ receptor antagonists, animals received injections of either SCH 23390 (0.01 and 0.1 mg/kg) or raclopride (0.1 and 1 mg/kg) 10 min before the challenge with SKF 82958 (1 mg/kg). Results: Systemic administration of SKF 82958 produced a marked enhancement of startle over a wide range of startle intensities. This effect was dose-dependent, with a dose of 1 mg/kg producing the maximal amount of startle enhancement at each intensity. SKF 81297 (3 mg/kg) also produced a robust enhancement of startle. Pretreatment with SCH 23390 produced a dose-dependent blockade of the enhancement of startle by SKF 82958. Pretreatment with raclopride blocked the enhancement of startle by SKF 82958 at the low intensities and attenuated the enhancement at the high intensities. Conclusions: These data suggest that dopamine D₁ receptor agonists enhance the acoustic startle response. Furthermore, this effect is dependent on a cooperative type of D₁/D₂ receptor interaction whereby D₂ receptor activation is necessary for the full expression of the D₁ receptor-mediated enhancement of startle. Received: 10 October 1998 / Final version: 11 January 1999