Amphetamine lowers brain stimulation reward (BSR) threshold in alcohol-preferring (P) and non-preferring (NP) rats: Regulation by D? and D? receptors in the nucleus accumbens.

Differences in the mesolimbic dopamine (DA) pathway that regulates alcohol preference may also increase sensitivity to the reinforcing effects of other drugs of abuse. In the present study, the curve-shift (rate-frequency) paradigm was used to quantify the interaction of amphetamine with the rewarding effects of lateral hypothalamic brain stimulation reward (BSR) in alcohol-preferring (P) and -nonpreferring (NP) rats. The role of D? and D? DA receptors of the nucleus accumbens (NAcc) in mediating the reward-potentiating effects of amphetamine was also determined. Animals were tested with randomly administered amphetamine (0.25, 0.75, 1.25 mg/kg ip), DA-receptor antagonists (SCH 23390 [2.0 μg, 5.0 μg]; eticlopride [2.0 μg, 5.0 μg]), or a combination of the 2 (SCH 23390 [2.0 μg, 5.0 μg] + 0.75 mg/kg amphetamine; eticlopride [2.0 μg, 5.0 μg] + 0.75 mg/kg amphetamine). Amphetamine produced comparable dose-related leftward shifts in the rate-frequency function for both P and NP rats, with a greater than 60% reduction observed in BSR threshold. On intervening days, baseline threshold was unaltered between tests and similar between rat lines. Unilateral infusion in the NAcc of either the D? or D? receptor antagonist produced rightward shifts in the rate-frequency function of amphetamine, completely reversing-attenuating its reward-enhancing effects. The results demonstrate that amphetamine produces similar threshold-lowering effects in both P and NP rats and that the reward-potentiating effects of amphetamine do not correlate with alcohol preference under the conditions of the present study. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopamine receptor antagonists in the nucleus accumbens attenuate analgesia induced by ventral tegmental area substance P or morphine and by nucleus accumbens amphetamine

In the present study, we examined the effects of dopamine (DA) receptor antagonists infused into the nucleus accumbens septi (NAS) on analgesia induced by intra-ventral tegmental area (VTA) infusions of the substance P (SP) analog, DiMe-C7 or morphine and intra-NAS infusions of amphetamine. Rats received intra-NAS infusions of either the mixed DA receptor antagonist flupenthixol (1.5 or 3.0 microg/0.5 microl/side; DiMe-C7 only), the DA D1/D5 receptor antagonist SCH 23390 (0.1 microg/0.5 microl/side; DiMe-C7 only) or the DA D2-type receptor antagonist raclopride (1.0, 3.0 or 5.0 microg/0.5 microl/side). Ten minutes later, rats received intra-VTA infusions of DiMe-C7 (3.0 microg/0.5 microl/side) or morphine (3.0 microg/0.5 microl/side) or intra-NAS infusions of amphetamine (2.5 microg/0.5 microl/side). Animals were then administered the formalin test for tonic pain. Intra-NAS raclopride prevented analgesia induced by intra-VTA DiMe-C7, intra-VTA morphine and intra-NAS amphetamine. Similarly, intra-NAS flupenthixol or SCH 23390 attenuated the analgesia induced by intra-VTA DiMe-C7. These findings suggest that tonic pain is inhibited, at least in part, by enhanced DA released from terminals of mesolimbic neurons. Furthermore, the evidence that SP and opioids in the VTA mediate stress-induced analgesia suggests that the pain-suppression system involving the activation of mesolimbic DA neurons is naturally triggered by exposure to stress, pain or both.     

Lack of evidence for an involvement of nucleus accumbens dopamine D1 receptors in the initiation of heroin self-administration in the rat

The involvement of dopamine D1 receptor systems in the reinforcing properties of opiate reward was studied by examining the effect of the dopamine D1 antagonist SCH23390 on the initiation of heroin self-administration in rats. The D1 antagonist was administered daily systemically or locally in the nucleus accumbens (NAC), after which the animals were allowed to self-administer heroin (IV) in a 3-h session for 5 consecutive days. Systemic treatment with SCH23390 (0.17 and 0.5 mg.kg-1) significantly decreased heroin intake during initiation of heroin self-administration, while a dose of 0.06 mg.kg-1 was not effective. Local administration of SCH23390 (0.5 and 2.5 micrograms/site) in the NAC did not affect heroin intake. Both systemic and intra-accumbal administration of SCH23390 dose dependently decreased motor behavior measured in a small open field. The attenuation of heroin intake during initiation of heroin self-administration by blockade of dopamine D1 receptor systems may be due to a decrease in the reinforcing effects of heroin or more likely to a reduction in non-reinforcement-related behavior. The dopamine D1 receptors present in the NAC are probably not involved in opiate reward.     

Drugs acting upon the cyclic adenosine monophosphate/protein kinase A signalling pathway modulate memory consolidation when given late after training into rat hippocampus but not amygdala

Rats implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus or in the amygdala were trained in one-trial step-down inhibitory (passive) avoidance using a 0.4 mA footshock. At various times after training (0, 1.5, 3, 6 or 9 h for animals implanted in the hippocampus; 0 or 3 h for those implanted in the amygdala), they received infusions of 8-Br-cAMP (cyclic adenosine monophosphate) (1.25 micrograms/side), SKF38393 (7.5 micrograms/side), SCH23390 (0.5 microgram/side), norepinephrine ClH (0.3 microgram/side), timolol ClH (0.3 microgram/side), 8-HO-DPAT (2.5 micrograms/side), NAN-190 (2.5 micrograms/side), forskolin (0.5 microgram/side) or KT5720 (0.5 microgram/side). Rats were tested for retention 24 h after training. SKF38393 is an agonist and SCH23390 an antagonist at dopamine D1 receptors, timolol is a beta-adrenoceptor antagonist, 8-HO-DPAT is an agonist and NAN-190 an antagonist at 5HT1A receptors, forskolin enhances adenylyl cyclase, and KT5720 inhibits protein kinase A. When given into the hippocampus 0 h post-training, norepinephrine enhanced memory and KT5720 was amnestic. When given 1.5 h after training, all treatments were ineffective. When given 3 or 6 h post-training, 8-Br-cAMP, forskolin, SKF 38393, noradrenaline and NAN-190 caused memory facilitation, and KT5720, SCH23390, timolol and 8-HO-DPAT caused retrograde amnesia. At 9 h from training, all treatments were again ineffective. When given into the amygdala 0 or 3 h post-training all treatments were ineffective, except for noradrenaline at 0 h, which caused retrograde facilitation. The data agree with the suggestion that in the hippocampus, but not the amygdala, a cAMP/protein kinase A pathway is involved in memory consolidation at 3 and 6 h from training, and that this is regulated by D1, beta, and 5HT1A receptors. This correlates with a previous report of increased cAMP levels, protein kinase A activity and P-CREB levels at 3-6 h from training in rat hippocampus in this task. This may be taken to suggest that the hippocampus, but not the amygdala, is involved in the long-term storage of step-down inhibitory avoidance in the rat.     

Differential involvement of cortical receptor mechanisms in working, short-term and long-term memory

Rats received, through bilaterally implanted indwelling cannulae, 0.5 microliter infusions of 6-cyano-7-nitroquinoxaline2,3-dione (CNQX) (0.5 microgram), D-2-amino-5-phophono pentanoic acid (AP5) (5.0 micrograms), muscimol (0.5 microgram), scopolamine (2.0 micrograms), SCH23390 (2.5 micrograms), saline or a vehicle into the CA1 region of the hippocampus, or into the antero-lateral prefrontal (PRE), posterior parietal (PP) and entorhinal cortex (EC). The infusions were given 6 min prior to one-trial step-down inhibitory avoidance training in order to measure their effect on working memory (WM), or immediately post-training in order to measure their effect on short-term (STM) and long-term memory (LTM), 1.5 and 24 h later, respectively. WM was inhibited by CNQX or muscimol given into any of the cortical areas, by SCH23390 given into CA1, PRE or PP, and by scopolamine given into PRE or EC. STM was unaffected by any of the treatments given into PRE, and was inhibited by CNQX or muscimol given into CA1, PP and EC and by scopolamine given into PP, and enhanced by SCH given into CA1. LTM was inhibited by CNQX, muscimol, scopolamine or SCH23390 given into PRE, by scopolamine given into PP, by SCH23390 given into the entorhinal cortex, and by AP5, CNQX, muscimol or scopolamine given into CA1. The results indicate a differential involvement of the various neurotransmitter systems in the three types of memory in the various brain areas, and a separation of the mechanisms and of the regions involved in each. In addition, some of the findings suggested links between WM and LTM processing in PRE, between WM and STM processing in EC and PP, and between all three types of memory in CA1.     

Effects of cortical and striatal dopamine D1 receptor blockade on cued versus noncued behavioral responses.

Various lines of evidence suggest that disruptions in brain dopamine (DA) transmission produce behavioral impairments that can be overcome by salient response-eliciting environmental stimuli. We examined here whether D1 receptor blockade within striatal or frontal cortical DA target regions would differentially affect head entry responses elicited by an auditory cue compared with those occurring during noncued intertrial intervals. Rats received 2 drug-free 28-trial daily sessions in which an auditory cue was immediately followed by food delivery. On the following day, separate groups of rats received bilateral infusions of D1 antagonist SCH23390 to the dorsomedial striatum (DMS), nucleus accumbens (NAcc) core, or the medial prefrontal cortex (mPFC). SCH23390 infused into the DMS and NAcc core suppressed noncued head entries but had no effect on head entries in response to the auditory cue. SCH23390 infused to the mPFC did not reduce either cued or noncued approach responses. Systemic administration of the drug, in contrast, reduced the frequency of both cued and noncued approaches. The results are consistent with the notion that has emerged from the Parkinson's literature that reduced DA transmission produces behavioral suppression that can be overcome by salient environmental response elicitors, and extends this notion by showing that D1 receptor transmission within the striatum strongly suppresses noncued responses while leaving the identical behavior intact when cued by an environmental stimulus. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Laryngeal tuberculosis and laryngeal cancer

The primary objective of this study was to determine whether the development of behavioral sensitization to the putative dopamine D3 receptor agonist 7-OH-DPAT could be prevented by either selective D1-type or D2-type dopamine receptor antagonists. In three experiments, male Wistar rats (250-350 g) were given seven to nine injections (at 48-h intervals) of 7-OH-DPAT (1.0 mg/kg, SC) or vehicle in combination with the D2-type dopamine antagonist eticlopride (0.3 mg/kg, SC), the D1-type dopamine antagonist SCH 23390 (0.1 or 0.2 mg/kg, SC), or vehicle. After the injections, the rats were tested for locomotor activity in photocell arenas for 2 h. In the first two experiments, after seven injections, all rats were tested for activity following vehicle injections to test for possible conditioning effects. In each experiment, after the last pre-exposure session, all rats were given a challenge injection of 7-OH-DPAT (1.0 mg/kg, SC) and tested for activity. Major findings were as follows: a) 7-OH-DPAT treatments produced a progressively greater increase in locomotor activity with repeated treatment; b) concurrent treatment with eticlopride or SCH 23390 (0.1 and 0.2 mg/kg) blocked the acute locomotor-activating effects of 7-OH-DPAT across days; c) eticlopride, but not SCH 23390, completely blocked the development of behavioral sensitization to 7-OH-DPAT. Although the low dose of SCH 23390 (0.1 mg/kg) produced a partial attenuation of sensitization, the higher dose (0.2 mg/kg) of SCH 23390 appeared to augment, rather than block, sensitization to 7-OH-DPAT; d) rats previously treated with SCH 23390 (0.2 mg/kg, but not 0.1 mg/kg) without 7-OH-DPAT displayed a hyperactive response to the 7-OH-DPAT challenge injection; and e) after vehicle injections, rats previously given 7-OH-DPAT, SCH 23390, or eticlopride either alone or in combination were more active than vehicle control rats. These findings suggest that the neurochemical mechanisms mediating the development of behavioral sensitization to 7-OH-DPAT may differ from those of other dopamine D2-type agonists such as quinpirole or bromocriptine. Moreover, these results demonstrate that hyperactivity responses following vehicle injections in drug-pretreated animals do not necessarily reflect conditioning mechanisms.     

Spontaneous and drug-stimulated locomotor activity after the administration of pertussis toxin into the ventral tegmental area

Pertussis toxin (PTX) injected into the ventral tegmental area (VTA) produces an enhanced locomotor response to amphetamine. In the present study, we have evaluated the role of dopamine receptors on spontaneous locomotor activity and the enhanced locomotor response to dopaminergic agonists after the administration of PTX into the VTA. PTX injected into the VTA of rats produced a delayed increase in spontaneous locomotor activity with a latency of 4 d. This activity was markedly increased by day 6 and remained elevated for at least 28 d after PTX treatment. This increased spontaneous locomotor activity of PTX-treated animals was antagonized by the administration of the D1 receptor antagonist SCH23390 (0.03 and 0.1 mg/kg sc), but not by the D2 receptor antagonist eticlopride (0.1 and 0.3 mg/kg sc). After adaptation to the locomotor cages, the animals showed a markedly enhanced motor response to amphetamine (0.5 mg/kg ip) and apomorphine (5 mg/kg sc). The heightened locomotor responses to these dopaminergic agonists could be elicited for at least 2 mo after PTX administration. The enhanced response to amphetamine was antagonized by the administration of SCH23390 (0.03 and 0.1 mg/kg sc), but not by eticlopride (0.1 mg/kg). The increased response to apomorphine in PTX-treated animals was inhibited by SCH23390 (0.1 mg/kg sc) and partially inhibited by eticlopride (0.1 mg/kg sc). Both of these antagonists inhibited the spontaneous and the drug-induced locomotor responses in vehicle-treated control animals. These results suggest that the administration of PTX into the VTA leads to an increase in spontaneous and drug-induced locomotor activity in which D1 receptors seem to play an important role.     

Systemic morphine-induced Fos protein in the rat striatum and nucleus accumbens is regulated by mu opioid receptors in the substantia nigra and ventral tegmental area

To characterize how systemic morphine induces Fos protein in dorsomedial striatum and nucleus accumbens (NAc), we examined the role of receptors in striatum, substantia nigra (SN), and ventral tegmental area (VTA). Morphine injected into medial SN or into VTA of awake rats induced Fos in neurons in ipsilateral dorsomedial striatum and NAc. Morphine injected into lateral SN induced Fos in dorsolateral striatum and globus pallidus. The morphine infusions produced contralateral turning that was most prominent after lateral SN injections. Intranigral injections of [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO), a mu opioid receptor agonist, and of bicuculline, a GABAA receptor antagonist, induced Fos in ipsilateral striatum. Fos induction in dorsomedial striatum produced by systemic administration of morphine was blocked by (1) SN and VTA injections of the mu1 opioid antagonist naloxonazine and (2) striatal injections of either MK 801, an NMDA glutamate receptor antagonist, or SCH 23390, a D1 dopamine receptor antagonist. Fos induction in dorsomedial striatum and NAc after systemic administration of morphine seems to be mediated by dopamine neurons in medial SN and VTA that project to medial striatum and NAc, respectively. Systemic morphine is proposed to act on mu opioid receptors located on GABAergic interneurons in medial SN and VTA. Inhibition of these GABA interneurons disinhibits medial SN and VTA dopamine neurons, producing dopamine release in medial striatum and NAc. This activates D1 dopamine receptors and coupled with the coactivation of NMDA receptors possibly from cortical glutamate input induces Fos in striatal and NAc neurons. The modulation of target gene expression by Fos could influence addictive behavioral responses to opiates.     

Assessing patients'' priorities and perceptions of the quality of health care: the development of the QUOTE-Rheumatic-Patients instrument

BACKGROUND: Stress can exacerbate a number of psychiatric disorders, many of which are associated with prefrontal cortical (PFC) cognitive deficits. Biochemical studies demonstrate that mild stress preferentially increases dopamine turnover in the PFC. Our study examined the effects of acute, mild stress exposure on higher cognitive function in monkeys and the role of dopaminergic mechanisms in the stress response. METHODS: The effects of loud (105-dB) noise stress were examined on a spatial working memory task (delayed response) dependent on the PFC, and on a reference memory task with similar motor and motivational demands (visual pattern discrimination) dependent on the inferior temporal cortex. The role of dopamine mechanisms was tested by challenging the stress response with agents that decrease dopamine receptor stimulation. RESULTS: Exposure to noise stress significantly impaired delayed-response performance. Stress did not impair performance on "0-second" delay control trials and did not alter visual pattern discrimination performance, which is consistent with impaired PFC cognitive function rather than nonspecific changes in performance. Stress-induced deficits in delayed-response performance were ameliorated by pretreatment with drugs that block dopamine receptors (haloperidol, SCH 23390) or reduce stress-induced PFC dopamine turnover in rodents (clonidine, naloxone hydrochloride). CONCLUSIONS: These results indicate that stress impairs PFC cognitive function through a hyperdopaminergic mechanism. Stress may take the PFC "off-line" to allow more habitual responses mediated by posterior cortical and subcortical structures to regulate behavior. This mechanism may have survival value, but may often be maladaptive in human society, contributing to the vulnerability of the PFC in many neuropsychiatric disorders.     

Interaction of CRH and energy balance in the modulation of brain stimulation reward.

The rewarding effect produced by electrical stimulation of some lateral hypothalamic sites is modulated by chronic food restriction and weight loss. The sensitivity of the rewarding effect to restriction predicts the modulation of brain stimulation reward (BSR) by the adiposity hormone, leptin. The present study examined the effect of corticotropin-releasing hormone (CRH) on the rewarding effect of stimulating restriction-sensitive and restriction-insensitive sites. Chronic food restriction reduced frequency thresholds for BSR in half of the subjects but had no effect in the others. CRH increased thresholds only in subjects in which the rewarding effect was insensitive to restriction. In contrast, frequency thresholds remained stable in nearly all rats with restriction-sensitive stimulation sites. These findings provide further evidence that sensitivity to food restriction is an important factor in determining the influence of hormones and neuropeptides on brain reward circuitry. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mesencephalic microinjections of neurotensin-(1-13) and its C-terminal fragment, neurotensin-(8-13), potentiate brain stimulation reward

Using the curve shift method, we assessed the effects of ventromedial mesencephalic tegmental (VMT) microinjections of an equimolar concentration of neurotensin-(1-13) (NT-(1-13)) and of its C-terminal fragment, neurotensin-(8-13) (NT-(8-13)), on operant responding for rewarding electrical stimulation of the caudal mesencephalic central gray. The effects of NT-(1-13) and NT-(8-13) on brain stimulation reward (BSR) were also compared to those of systemically administered quinpirole (0.1 and 0.2 mg/kg, s.c.), a direct dopamine agonist, and GBR-12909 (10 and 20 mg/kg, i.p.), a selective dopamine uptake blocker. At the concentration injected, NT-(8-13) was as effective as NT-(1-13) at facilitating BSR, producing significant leftward shifts of the function relating the rate of responding to the stimulation frequency (R/F function); neither form of the peptide was effective when injected in regions dorsal to the VMT. Similarly, GBR-12909 produced a parallel leftward shift of the R/F function, but, unlike NT-(1-13), also significantly increased the asymptotic rates of responding. In contrast, the high dose of quinpirole produced non-parallel leftward shifts of the R/F function and suppressed the asymptote. The similarity between the effects of neurotensin and GBR-12909 on one hand, and the differences between those of neurotensin and quinpirole on the other, suggest that activation VMT neurotensin receptors potentiate BSR by enhancing increases in dopamine neurotransmission that are contingent upon operant responding or rewarding brain stimulation, or both.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reward-specific blockade of morphine's effect on brain-stimulation reward by pimozide but not SCH 23390.

To test the hypothesis that dopamine plays an important role in the rewarding effects of abuse opioids, the authors compared the ability of the specific dopamine D? antagonist, SCH 23390, and the D? antagonist, pimozide, to block the threshold-lowering effect of morphine on brain-stimulation reward. Pimozide, at doses that did not alter the threshold, reversed morphine's threshold-lowering effect. Although SCH 23390 also reversed morphine's effect, in contrast to pimozide, it did so only at doses that significantly raised the threshold. Thus to the extent that brain-stimulation reward is a model of drug-induced euphoria, these data suggest that D? receptors are more specifically involved than are D? receptors in mediating the rewarding effects of morphine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neuropeptide FF in the VTA blocks the analgesic effects of both intra-VTA morphine and exposure to stress

Experiments were designed to examine the analgesic effects induced by selective tachykinin receptor agonists microinfused into either the ventral tegmental area (VTA) or nucleus accumbens septi (NAS). Rats were tested in the formalin test for tonic pain following an injection of 0.05 ml of 2.5% formalin into one hind paw immediately after bilateral intra-VTA infusions of either the NK-1 agonist, GR-73632 (0.005, 0.05 or 0.5 nmol/side), the NK-3 agonist, senktide (0.005, 0.5 or 1.5 nmol/side), or saline. Two weeks later, the saline-treated rats were assessed in the tail-flick test for phasic pain after infusions of the tachykinin agonists. Tail-flick latencies were recorded following immersion of the tail in 55 degrees C hot water at 10 min intervals for 1 h immediately after intra-VTA infusions of either GR-73632 (0.5 nmol/side), senktide (1.5 nmol/side) or saline. In a second group of rats, the same effects were studied after infusions into the nucleus accumbens (NAS) of GR-73632 (0.005, 0.5 or 1.5 nmol/side), senktide (0.005, 0.5 or 1.5 nmol/side), or saline. In both the VTA and NAS, the NK-1 and the NK-3 agonists caused significant analgesia in the formalin test, although the NK-1 agonist appeared to be more effective. Naltrexone (2.0 mg/kg) pretreatment failed to reverse the analgesic effects in the formalin test induced by intra-VTA infusions of the substance P (SP) analog, DiMe-C7 (3.0 microg/side), GR-73632 (0.5 nmol/side), or senktide (1.5 nmol/side). Neither compound given at either site was effective in the tail-flick test. These findings suggest that SP-dopamine (DA) interactions within the mesolimbic DA system play an important role in the inhibition of tonic pain. Furthermore, they support our earlier ideas that activation of midbrain DA systems by SP might play a role in stress- and/or pain-induced analgesia.     

Late and prolonged post-training memory modulation in entorhinal and parietal cortex by drugs acting on the cAMP/protein kinase A signalling pathway

Rats implanted bilaterally with cannulae in the entorhinal or posterior parietal cortex or in the amygdaloid nucleus were trained in one-trial step-down inhibitory (passive) avoidance using a 0.3 mA footshock. At 0, 3, 6 or 9 h after training, they received localized 0.5 microliter infusions into these areas of a vehicle, or of 8-Br-cAMP, forskolin (adenylyl cyclase activator), KT5720 (protein kinase A inhibitor), SKF38393 (dopamine D1 receptor agonist), SCH23390 (D1 antagonist), norepinephrine hydrochloride, timolol hydrochloride (beta blocker), 8-HO-DPAT (5-HT1A receptor agonist) or NAN-190 (5-HT1A antagonist) dissolved in 20% dimethylsulfoxide (DMSO) in saline (vehicle). Rats were tested for retention 24 h after training. 8-Br-cAMP, forskolin, SKF 38393 and norepinephrine caused memory facilitation and KT5720, SCH23390, timolol and 8-HO-DPAT caused retrograde amnesia when given into the entorhinal cortex 0, 3 or 6 h but not 9 h after training. When given into the posterior parietal cortex 0, 3 or 6 but not 9 h after training, KT5720 was amnestic. When given into this structure 3 or 6 h but not 0 or 9 h after training 8-Br-cAMP, forskolin and norepinephrine caused memory facilitation and KT5720, SCH23390 and timolol caused retrograde amnesia. All treatments given into the amygdala 0, 3 or 6 h after training were ineffective except for norepinephrine given at 0 h, which caused facilitation. The data point to a role of cAMP/protein kinase A-dependent mechanisms in memory formation in the entorhinal and parietal cortex, but not the amygdala, from 0 to 6 h after training, and to a strong modulation of these mechanisms by dopaminergic D1, beta-noradrenergic and 5-HT1A receptors. The lack of effect of NAN-190 but not 8-HO-DPAT in both cortical regions suggests that 5-HT1A receptors do not play a physiological role but can be activated pharmacologically. The fact that SCH23390 was amnestic but SKF38393 had no effect when given into the parietal cortex suggests that D1 receptors may play a maintenance rather than a stimulant role in this area.     

NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine

The present study was performed to assess the role of excitatory amino acid and dopamine receptors on associative functions of the prefrontal cortex (PFC) of the rat. Spatial delayed alternation was used as a PFC-sensitive cognitive task. In addition, in vivo microdialysis was used to assess the release of dopamine in the PFC. The noncompetitive NMDA antagonists ketamine (10-30 mg/kg) and MK-801 (0.1 and 0.5 mg/kg) dose-dependently impaired the spatial delayed alternation performance compared with the saline-treated control group. Administration of the dopamine antagonists raclopride (0.1 and 0.5 mg/kg), SCH-23390 (0.1 mg/kg), or haloperidol (0.1 mg/kg) was without a significant effect. However, haloperidol and raclopride (but not SCH-23390) reversed the disruptive effect of 30 mg/kg ketamine on spatial delayed alternation performance. Microdialysis studies revealed that this dose of ketamine preferentially increased the release of dopamine in the PFC compared with the striatum. These findings indicate that attenuation of glutamatergic neurotransmission at the NMDA receptor impairs PFC-dependent cognitive functions. Furthermore, activation of dopamine neurotransmission contributes, at least in part, to this impairment.     

Clozapine, haloperidol, and the D4 antagonist PNU-101387G: in vivo effects on mesocortical, mesolimbic, and nigrostriatal dopamine and serotonin release

With in vivo microvoltammetry, the dopamine (DA) receptor antagonists, clozapine (D4/D2), haloperidol (D2) and the selective D4 antagonist, PNU-101387G, were evaluated for their effects on DA and serotonin (5-HT) release within A10 neuronal terminal fields [mesocortical, prefrontal cortex (PFC), mesolimbic, nucleus accumbens, (NAcc)] and within A9 neuronal terminal fields [nigrostriatal, caudate putamen (CPU)], in chloral hydrate anesthetized rats. Clozapine, which also has 5-HT2 receptor antagonist properties, significantly (p < 0.001) increased DA release within A10 terminal fields, PFC and NAcc; DA release was not increased by clozapine within A9 terminals, CPU. Serotonin release was significantly (p < 0.001) increased by clozapine within A10 and A9 terminal fields. Haloperidol significantly (p < 0.001) increased DA release within PFC, dramatically and significantly (p < 0.001) increased DA release within CPU, but not within NAcc; haloperidol had a small but statistically significant (p < 0.05) increase on 5-HT release within PFC [only at the highest dose studied (2.5 mg/kg)] and within CPU [only at the lowest dose studied 1.0 mg/kg) (p < 0.05)]. The selective D4 antagonist, PNU-101387G dramatically and significantly (p < 0.001) increased DA release within PFC, modestly, but significantly (p < 0.001) increased DA release within CPU, did not alter DA release within NAcc at the lowest dose studied (1.0 mg/kg) and significantly (p < 0.05) decreased DA release within NAcc at the highest dose studied (1.0 mg/kg). The selective D4 antagonist did not affect 5-HT release within either A10 or A9 terminal fields. The present data are discussed in terms of the neurochemistry, antipsychotic activity, and side effect profiles of clozapine and haloperidol, in order to provide comparative profiles for a selective D4 antagonist, PNU-101387G.     

Glutamatergic regulation of basal and stimulus-activated dopamine release in the prefrontal cortex

The present study was undertaken to determine whether basal and stimulus-activated dopamine release in the prefrontal cortex (PFC) is regulated by glutamatergic afferents to the PFC or the ventral tegmental area (VTA), the primary source of dopamine neurons that innervate the rodent PFC. In awake rats, blockade of NMDA or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors in the VTA, or blockade of AMPA receptors in the PFC, profoundly reduced dopamine release in the PFC, suggesting that the basal output of dopamine neurons projecting to the PFC is under a tonic excitatory control of NMDA and AMPA receptors in the VTA, and AMPA receptors in the PFC. Consistent with previous reports, blockade of cortical NMDA receptors increased dopamine release, suggesting that NMDA receptors in the PFC exert a tonic inhibitory control on dopamine release. Blockade of NMDA or AMPA receptors in the VTA as well as blockade of AMPA receptors in the PFC reduced the dopaminergic response to mild handling, suggesting that activation of glutamate neurotransmission also regulates stimulus-induced increase of dopamine release in the PFC. In the context of brain disorders that may involve cortical dopamine dysfunction, the present findings suggest that abnormal basal or stimulus-activated dopamine neurotransmission in the PFC may be secondary to glutamatergic dysregulation.     

Impairment in a discrimination reversal task after D1 receptor blockade in the pigeon "prefrontal cortex".

Dopamine (DA) is known to modulate cognitive functions of the prefrontal cortex (PFC) of mammals, especially via D1 receptor mechanisms. Like the PFC, the neostriatum caudolaterale (NCL) of birds is characterized by dopaminergic input, and NCL and PFC lesions cause similar deficits. The significance of DA it a color discrimination reversal was assessed by evaluating the effects of bilateral infusions of the D1 receptor antagonist SCH 23390 into the NCL of pigeons (Columba livia). Reversal deficits were qualitatively similar to those in mammals. At a low dose, perseveration occurred predominantly to the incorrect stimulus. Higher doses caused additional spatial perseveration. The data demonstrate, for the first time, that D1 receptor mechanisms in the NCL of pigeons contribute substantially to its function in cognitive processes. Thus, the avian NCL and mammalian PFC could represent functionally equivalent neural networks under control of the DA system. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Invasion depth diagnosis of depressed type early colorectal cancers by combined use of videoendoscopy and chromoendoscopy

The activation of rat mesocortical dopaminergic (DA) neurons evoked by the electrical stimulation of the ventral tegmental area (VTA) induces a marked inhibition of the spontaneous activity of prefrontocortical cells. In the present study, it was first shown that systemic administration of either clozapine (a mixed antagonist of D1, D2, and alpha1-adrenergic receptors) (3-5 mg/kg, i.v.), prazosin (an alpha1-adrenergic antagonist) (0.2 mg/kg, i.v.), or sulpiride (a D2 antagonist) (30 mg/kg, i.v.), but not SCH 23390 (a D1 antagonist) (0.2 mg/kg, i.v.), reversed this cortical inhibition. Second, it was found that following the systemic administration of prazosin, the VTA-induced cortical inhibition reappeared when either SCH 23390 or sulpiride was applied by iontophoresis into the prefrontal cortex. Third, it was seen that, whereas haloperidol (0.2 mg/kg, i.v.), a D2 antagonist which also blocks alpha1-adrenergic receptors, failed to reverse the VTA-induced inhibition, the systemic administration of haloperidol plus SCH 23390 (0.2 mg/kg, i.v.) blocked this inhibition. Finally, it was verified that the cortical inhibitions obtained following treatments with either "prazosin plus sulpiride" or "prazosin plus SCH 23390" were blocked by a superimposed administration of either SCH 23390 or sulpiride, respectively. These data indicate that complex interactions between cortical D2, D1, and alpha1-adrenergic receptors are involved in the regulation of the activity of prefrontocortical cells innervated by the VTA neurons. They confirm that the physiological stimulation of cortical alpha1-adrenergic receptors hampers the functional activity of cortical D1 receptors and suggest that the stimulations of cortical D1 and D2 receptors exert mutual inhibition on each other's transmission.