AP-7 into the nucleus accumbens disrupts acquisition but does not affect consolidation in a passive avoidance task

The effect of the blockade of N-methyl-D-aspartic acid (NMDA)-type glutamatergic receptors in the nucleus accumbens septi (Acc) during different phases of a passive avoidance task (step-through paradigm, two chambers) of learning was studied in male rats which had been bilaterally cannulated into the Acc. Animals were trained with a punishment procedure (3 s shock of 1 mA) to avoid one of the chambers. The rats received either saline or (+/-)2-amino-7-phosphonoheptanoic acid (AP-7) solution (1 microg/1 microl) 10 min before training (pretraining schedule) or immediately after the shock (posttraining schedule). In the test phase, the animals were placed back into the white chamber after 1 and 8 days later. In this moment, rats stayed there for 1 min, after which the time elapsed between the removal of the door to the introduction into the dark chamber of the head (Latency 1) and body (Latency 2) and fecal boli expelled were recorded. In the pretraining injection schedule, the drug treatment significantly reduced Latency 2 (P<.05) and fecal boli (P<0.01) on Day 1, and all parameters on Day 8 (P<.05). The posttraining injection schedule did not modify behavior. We conclude that a preshock NMDA-glutamatergic blockade of the Acc leads to cognitive disturbances during acquisition and a decrease in anxiety levels, but that the consolidation of a learned task is not affected by postshock administration.     

Effects of cholinergic system of dorsal hippocampus of rats on MK-801 induced anxiolytic-like behavior

Rationale: Some investigations have shown that the glutamate receptors play a critical role in cognitive processes such as learning and anxiety. Objectives: The possible involvement of the cholinergic system of the dorsal hippocampus in the anxiolytic-like response induced by MK-801, NMDA receptor antagonist, was investigated in the present study. Methods: Male Wistar rats were used in the elevated plus maze apparatus to test the parameters: open arm time (%OAT), open arm entries (%OAE), close arm time (%CAT), close arm entries (%CAE) and other exploratory behaviors (locomotor activity, grooming, rearing and defecation) of anxiety-like response. Results: The data indicated that intra-CA1 administration of MK-801 increased %OAT (2 μg/rat) and %OAE (1 and 2 μg/rat) while decreased %CAT and %CAE and did not alter other exploratory behaviors, indicating an anxiolytic-like effect. Moreover, intra-hippocampal injections of mecamylamine, a cholinergic receptor antagonists (2 μg/rat) and scopolamine (4 μg/rat), by themselves, 5 min before testing, increased %OAT and %OAE but decreased %CAT and %CAE and did not alter locomotor activity and other exploratory behaviors, suggesting an anxiolytic-like effect. On the other hand, intra-CA1 co-administration of an ineffective dose of scopolamine (3 μg/rat), but not mecamylamine (1 μg/rat), with an ineffective dose of MK-801 (0.5 μg/rat) increased %OAT and %OAE and decreased %CAT and %CAE. The data may indicate the possible involvement of the cholinergic system of the CA1 in the anxiolytic-like response induced by MK-801.     

Role of ventral hippocampal NMDA receptors in anxiolytic-like effect of morphine

The possible role of ventral hippocampal N-methyl-d-aspartate (NMDA) receptors on morphine-induced anxiolytic-like behavior in an elevated plus maze (EPM) task was investigated in the present study. Adult male mice (7 per group) with cannulas aimed at the ventral hippocampus (VH) received NMDA or a competitive NMDA receptor antagonist D-AP5 with or without morphine and 30 min later were subjected to an EPM task. Intraperitoneal injection (i.p.) of morphine (3-9 mg/kg) increased the percentage of open arm time (%OAT) and open arm entries (%OAE), which suggested an anxiolytic-like effect. Intra-VH microinjection of NMDA (0.5-1 μg/mouse) with an ineffective dose of morphine (3 mg/kg, i.p.) significantly increased %OAT and %OAE. However, microinjections of the same doses of NMDA into the VH in the absence of morphine had no effect on %OAT and %OAE. Intra-VH microinjection of D-AP5 (0.5-2 μg/mouse) decreased the anxiolytic-like effect of morphine, while intra-VH microinjection of the same doses of D-AP5 alone increased %OAT and %OAE, which indicated an anxiolytic response. Furthermore, intra-VH microinjection of D-AP5 reversed the effect of NMDA response to the administration of a lower morphine dose as seen in the EPM task. It should be noted that intra-VH microinjection of D-AP5 plus NMDA, 5 min before morphine increased locomotor activity, while other treatments had no effect on this parameter. The results suggest that VH-NMDA receptors participate in the mediation of morphine-induced anxiolytic-like behavior.     

Alteration in sensitivity of ionotropic glutamate receptors and tachykinin receptors in spinal cord contribute to development and maintenance of nerve injury-evoked neuropathic pain

Allodynia or hyperalgesia induced by peripheral nerve injury may be involved in changes in the sensitivity of neurotransmitters at the spinal cord level. In order to clarify the functional role of neurotransmitters in peripheral nerve injury, we used rats with nerve injury induced by chronic constriction of the sciatic nerve (CCI rat model) and estimated the effects of the intrathecal injection of drugs known to affect glutamate and tachykinin receptors. In sham-operated rats, the NMDA receptor agonist NMDA and AMPA-kinate receptor agonist RS-(5)-bromowillardin reduced withdrawal latency. The non-competitive NMDA receptor antagonist MK-801, competitive NMDA receptor antagonist AP-5 and AMPA-kinate receptor antagonist NBQX increased withdrawal latency. Substance P (SP) increased the withdrawal latency but only transitorily. The NK1 receptor antagonist RP67580 increased withdrawal latency, but the NK2 receptor antagonist SR48968 did not show an effect. In CCI rats, RS-(5)-bromowillardin reduced withdrawal latency, but NMDA did not show an effect. NBQX increased withdrawal latency, while MK-801 and AP-5 showed little or no effect. SP reduced withdrawal latency, and both RP67580 and SR48968 increased it. These results indicate that the alteration in sensitivity of ionotropic glutamate receptors and tachykinin receptors in the spinal cord contribute to development and maintenance of nerve injury-evoked neuropathic pain.     

Melanocortin receptors mediate leptin effects on feeding and body weight but not adipose apoptosis

The melanocortin (MC) system is a known downstream mediator of leptin signaling in the brain; thus, activation of MC receptors by melanotan II (MTII), a MC3/4 receptor agonist, was hypothesized to increase adipose apoptosis, a phenomenon seen after leptin treatments. To test this hypothesis, male Sprague-Dawley rats received pretreatments of intracerebroventricular injections of artificial cerebrospinal fluid (aCSF, 5 microl) or SHU9119 (1.0 nmol/5 microl), an MC3/4 receptor antagonist. One hour later, aCSF (5 microl), leptin (10 microg/5 microl), or MTII (0.1 nmol/5 microl) was injected intracerebroventricularly in the aCSF-pretreated groups, and either leptin (10 microg/5 microl) or MTII (0.1 nmol/5 microl) was injected intracerebroventricularly in SHU9119-pretreated groups. Each pair of treatments was given once daily for four successive days. Body weight (BW), food intake (FI), and body temperature (BT) were measured daily at 4- and 24-h intervals. SHU9119 completely prevented the decrease in FI and BW caused by either MTII or leptin. Muscle mass remained unchanged regardless of treatment, but both leptin and MTII significantly reduced mass of inguinal (iWAT), retroperitoneal (rWAT), and epididymal (eWAT) white adipose tissues (P<.05). SHU9119 prevented the decrease in mass of intrascapular brown fat, iWAT, and rWAT (P<.05). Leptin, but not MTII, increased DNA fragmentation in eWAT (P<.05), but SHU9119 pretreatment had no effect on leptin-induced apoptosis. Thus, although the MC receptors in the brain are involved in mediating actions of leptin on FI, fat mass, and BW, leptin-induced adipose apoptosis is regulated independently of MC receptors.     

Cholecystokinin and GABA interaction in the dorsal hippocampus of rats in the elevated plus-maze test of anxiety

In the present study, we have investigated the effects and interaction of CCK and GABAergic systems in the dorsal hippocampus of rats using the elevated plus-maze test of anxiety. Bilateral injection of different doses of CCK(8s) (0.01, 0.05 and 0.1 microg/rat) into the dorsal hippocampus (intra-CA1) decreased percentage of open arm time (%OAT) and open arm entries (%OAE) that are representative of anxiogenic-like behavior. The bilateral injection of three doses of LY225910, a selective CCK2 receptor antagonist (0.01, 0.1 and 0.5 microg/rat) produced significant anxiolytic behavior. Although muscimol (GABA(A+)) (0.1, 0.5 and 1 microg/rat, intra-CA1) produced dose dependent increase in %OAT and a slight increase in %OAE, bicuculline (GABA(A-)), (1, 2 and 4 microg/rat, intra-CA1) failed to change the anxiety profile. Both muscimol (0.1 microg/rat) and bicuculline (1 microg/rat), when co-administered with LY225910, reversed the effect of latter drug on anxiety but when co-administered with CCK8s (0.05 microg/rat) showed no effect on anxiety profile. In conclusion, it seems that both CCK and GABAergic systems not only play a part in the modulation of anxiety in the dorsal hippocampus of rats but also have demonstrated a complex interaction as well.     

Further evidence that histamine in hippocampus affects the exploratory behavior in the rat

The effect of histamine (HA) and 3-methyl-histamine (3-MHA) in the hippocampus on hole-board behavior was studied. Male rats were microinjected stereotaxically into the hippocampus with 1 μl of saline solution containing 9, 45 or 90 nMol of HA or 3-MHA. Five min later, all rats were tested for 5 min in a hole-board and locomotor, rearing, grooming and head-dipping activities were measured by direct observation. HA inhibited rearing and grooming at all the doses used but it affected locomotor activity only at 45 and 90 nMol doses. There was no effect on head-dipping behavior. 3-MHA instead increased locomotor and head-dipping activities at all the doses used and it did not change rearing and grooming. The present results give a further support for a physiological participation of HA in the hippocampus.     

A comparative study of the effects of morphine in the dorsal periaqueductal gray and nucleus accumbens of rats submitted to the elevated plus-maze test

We studied the effects of morphine injected either systemically or into the dorsal periaqueductal gray (DPAG) or nucleus accumbens (NA) using conventional and ethological analyses of behavior of rats submitted to the elevated plus-maze test with transparent walls. Intraperitoneal morphine (0.1 mg/kg and 0.3 mg/kg) increased both standard and ethological measures, expressing general exploratory activity such as total arm entries, end-exploration, scanning, head-dipping, and rearing. Morphine 10 (7.6 μg/μl) and 30 nmol (23 μg/μl) injected into nucleus accumbens produced similar effects, which were blocked by i.p. naltrexone (2.0 mg/kg), an opioid antagonist with good affinity for μ-opioid receptors. Morphine injected into the DPAG produced either antiaversive (10 nmol) or aversive effects (30 nmol), which respectively reduced and increased entries and time spent in the open arms and behaviors associated with risk assessment (peeping out, stretched attend postures, and flat back approach). The proaversive effects were inhibited by i.p. norbinaltorphimine (2.0 mg/kg), a selective inhibitor for κ-opioid receptors. These findings support the contention that at least some of the motivational effects of morphine may be due to activation of opioid mechanisms in nucleus accumbens, and DPAG has neural substrates for antiaversive and aversive effects of morphine. Moreover, on the basis of previous and present data obtained in this laboratory, it is suggested that stimulation of μ-opioid receptors inhibits and stimulation of κ-receptors activates the neural substrate of aversion in the DPAG. On the other hand, the increase in exploratory behavior due to interaction of morphine with μ-opioid receptors in the nucleus accumbens may be due to the stimulation of the interface between neural substrates of motivation and motor output in this structure. Received: 24 August 1998 / Accepted: 11 June 1999     

NMDA and non-NMDA receptors may play distinct roles in timing mechanisms and transmission in the feline respiratory network.

1. Activation of N-methyl-D-aspartate (NMDA) glutamate receptors in the brainstem network of respiratory neurones is required to terminate inspiration in the absence of lung afferents, but it is not required in the inspiratory motor act of lung inflation. In the present study we examined the involvement of non-NMDA ionotropic glutamate receptors in these two mechanisms in the adult mammal. 2. Adult cats were either decerebrated or anaesthetized with sodium pentobarbitone, paralysed and ventilated. Inspiratory motor output was recorded from the phrenic nerve and central respiratory activity from neurones in the bulbar ventral respiratory group. 3. In decerebrate vagotomized cats, ionophoretic application of 2,3-dihydroxy-6-nitro-7-sulphamoylbenzo(F)quinoxaline (NBQX) onto single respiratory neurones decreased their spontaneous discharge rate and abolished the excitatory effect of exogenously applied (RS) alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) but not NMDA. 4. In these animals, intravenous infusion (12 mg kg-1) of the non-NMDA receptor blockers GYKI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylene-dioxy-5-H-2,3-benzodi aze pine) or NBQX: (1) decreased (in 10/15 cats) or abolished (in 5/15 cats) the inspiratory-related discharge of the phrenic nerve; (2) did not prolong the inspiratory phase; (3) reduced or abolished the spontaneous discharge of respiratory neurones; and (4) profoundly decreased the excitatory effects of AMPA but not NMDA ionophoresed onto these neurones. When both the phrenic nerve and the recorded respiratory neurone were silenced, neuronal excitation by ionophoretic application of NMDA first revealed a subthreshold respiratory modulation without lengthening of the inspiratory phase, then respiratory modulation became undetectable. 5. Additional blockade of NMDA receptors by a small dose (0.15 mg kg-1) of dizocilpine (MK-801), abolished the phrenic nerve activity which persisted after NBQX (apnoea), but the discharge or the subthreshold modulation of the bulbar respiratory neurones showed a lengthening of the inspiratory phase (apneusis). 6. Elevation of FA,CO2 increased or re-established phrenic nerve discharges after blockade of non-NMDA receptors or of both NMDA and non-NMDA receptors. 7. Small doses of NBQX or GYKI 52466 induced apnoea in five of five cats anaesthetized with sodium pentobarbitone. 8. In decerebrate animals with intact vagi, GYKI 52466 and NBQX depressed the Hering-Breuer expiratory-lengthening reflex. 9. The results suggest that: (1) there is a specialization of different classes of glutamate receptors participating in timing mechanisms and transmission within the mammalian respiratory network. Neural transmission predominantly involves activation of non-NMDA receptors, acting in synergy with NMDA receptors.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacological characterization of high-fat feeding induced by opioid stimulation of the ventral striatum

Nucleus accumbens mu-opioid stimulation causes marked increases in the intake of highly palatable foods, such as a high-fat diet. However, to date there has been little examination of how other striatal neurotransmitters may mediate opioid-driven feeding of palatable foodstuffs. In the current study, free feeding rats with bilateral cannulae aimed at the nucleus accumbens received intra-accumbens pretreatment with antagonists for dopamine D-1 (SCH23390; 0 microg or 1 microg/0.5 microl/side), dopamine D-2 (raclopride; 0 microg or 2.0 microg/0.5 microl/side), AMPA (LY293558; 0 microg, 0.01 microg or 0.10 microg/0.5 microl/side), muscarinic (scopolamine 0 microg, 0.1, 1.0, or 10 microg/0.5 microl/side) or nicotinic (mecamylamine; 0 microg, 10 microg/0.5 microl/side) receptors, immediately prior to infusions of the mu-receptor agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO; 0.25 microg/0.5 microl) or vehicle. The effects of these pretreatments on 2 hr fat intake was compared to pretreatment with a general opioid antagonist (naltrexone; 0 microg or 20 microg/0.5 microl/side). DAMGO-induced feeding was unaffected by prior antagonism of dopamine, glutamate, or nicotinic receptors. As expected, naltrexone infusions blocked DAMGO-elicited fat intake. Antagonism of muscarinic acetylcholine receptors reduced feeding in both the DAMGO and vehicle-treated conditions. In an additional experiment, cholinergic receptor stimulation alone did not affect intake of the fat diet, suggesting that nucleus accumbens cholinergic stimulation is insufficient to alter feeding of a highly palatable food. These data suggest that the feeding effects caused by striatal opioid stimulation are independent from or downstream to the actions of dopamine and glutamate signaling, and provide novel insight into the role of striatal acetylcholine on feeding behaviors.     

Infusion of neurotoxic doses of N-methyl-D-aspartate into the lateral hypothalamus in rats produces stomach erosions, hyperthermia, and a disruption in eating behavior

The present study examined whether damage to intrinsic lateral hypothalamic (LH) neurons induced by microinfusions of N-methyl-D-aspartate (NMDA) would produce effects similar to those seen after electrolytic LH lesions. In Experiment 1, rats receiving electrolytic (1.2 mA anodal current, 10 s) LH lesions displayed motor impairments, whereas those receiving NMDA (20 microg/microl) infusions did not. Both electrolytic lesions and NMDA infusions were associated with eating deficits, hyperthermia, and gastric erosion formation 24 hr after surgery. In Experiment 2, either 20 microg/microl or 10 microg/microl NMDA destroyed LH cells and produced dose-dependent gastric mucosal erosions as well as similar increases in body temperature. These results indicate that an alteration in the acute activity of intrinsic LH neurons plays a role in the production of gastric mucosal injury and hyperthermia and lend support to other studies implicating a role of LH neurons in eating behavior.     

Knockdown of spinal cord postsynaptic density protein-95 prevents the development of morphine tolerance in rats

The activation of spinal cord N-methyl-D-aspartate (NMDA) receptors and subsequent intracellular cascades play a pivotal role in the development of opioid tolerance. Postsynaptic density protein-95 (PSD-95), a molecular scaffolding protein, assembles a specific set of signaling proteins around NMDA receptors at neuronal synapses. The current study investigated the possible involvement of PSD-95 in the development of opioid tolerance. Opioid tolerance was induced by intrathecal injection of morphine sulfate (20 microg/10 microl) twice a day for 4 consecutive days. Co-administration of morphine twice daily and PSD-95 antisense oligodeoxynucleotide (50 microg/10 microl) once daily for 4 days not only markedly reduced the PSD-95 expression and its binding to NMDA receptors in spinal cord but also significantly prevented the development of morphine tolerance. In contrast, co-administration of morphine twice daily and PSD-95 missense oligodeoxynucleotide (50 microg/10 microl) once daily for 4 days did not produce these effects. The PSD-95 antisense oligodeoxynucleotide at the doses we used did not affect baseline response to noxious thermal stimulation or locomotor function.The present study indicates that the deficiency of spinal cord PSD-95 attenuates the development of opioid tolerance. These results suggest that PSD-95 might be involved in the central mechanisms of opioid tolerance and provide a possible new target for prevention of development of opioid tolerance.     

Role of glutamatergic receptors located in the nucleus raphe magnus on antinociceptive effect of morphine microinjected into the nucleus cuneiformis of rat

Neurons in the nucleus cuneiformis (CnF), located just ventrolateral to the periaqueductal gray, project to medullary nucleus raphe magnus (NRM), which is a key medullary relay for descending pain modulation and is critically involved in opioid-induced analgesia. Previous studies have shown that antinociceptive response of CnF-microinjected morphine can be modulated by the specific subtypes of glutamatergic receptors within the CnF. In this study, we evaluated the role of NMDA and kainate/AMPA receptors that are widely distributed within the NRM on morphine-induced antinociception elicited from the CnF. Hundred and five male Wistar rats weighing 250-300 g were used. Morphine (10, 20 and 40 microg) and NMDA receptor antagonist, MK-801 (10 microg) or kainate/AMPA receptor antagonist, DNQX (0.5 microg) in 0.5 microl saline were stereotaxically microinjected into the CnF and NRM, respectively. The latency of tail-flick response was measured at set intervals (2, 7, 12, 17, 22, 27 min after microinjection) by using an automated tail-flick analgesiometer. The results showed that morphine microinjection into the CnF dose-dependently causes increase in tail-flick latency (TFL). MK-801 microinjected into the NRM, just 1 min before morphine injection into the CnF, significantly attenuated antinociceptive effects of morphine. On the other hand, DNQX microinjected into the NRM, significantly increased TFL after local application of morphine into the CnF. We suggest that morphine related antinociceptive effect elicited from the CnF is mediated, in part, by NMDA receptor at the level of the NRM whereas kainite/AMPA receptor has a net inhibitory influence at the same pathway.     

The role of kainic acid/AMPA and metabotropic glutamate receptors in the regulation of opioid mRNA expression and the onset of pain-related behavior following excitotoxic spinal cord injury.

Intraspinal injection of quisqualic acid, a mixed kainic acid/2-amino-3(3-hydroxy-5-methylisoxazol-4-yl)propionic acid and metabotropic glutamate receptor agonist, produces an excitotoxic injury that leads to the onset of both spontaneous and evoked pain behavior as well as changes in spinal and cortical expression of opioid peptide mRNA, preprodynorphin and preproenkephalin. What characteristics of the quisqualic acid-induced injury are attributable to activation of each receptor subtype is unknown. This study attempted to define the role of activation of the kainic acid/2-amino-3(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and metabotropic glutamate receptor subtypes in the regulation of opioid peptide expression and the onset of spontaneous and evoked pain-related behavior following excitotoxic spinal cord injury by comparing quisqualic acid-induced changes with those created by co-injection of quisqualic acid and the kainic acid/AMPA antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline, (NBQX) or the metabotropic antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA). Therefore, 42 male Long-Evans adult rats were divided into seven treatment groups and received intraspinal microinjections of saline (sham), 0.5% dimethylsulphoxide (sham), quisqualic acid (1.2 microl, 125 mM), NBQX (1.2 microl, 60 microM), AIDA (1.2 microl, 250 microM), quisqualic acid/NBQX (1.2 microl, 125 mM/60 microM), or quisqualic acid/AIDA (1.2 microl, 125 mM/250 microM) directed at spinal levels thoracic 12-lumbar 2. Behavioral observations of spontaneous and evoked pain responses were completed following surgery. After a 10-day survival period, animals were killed and brain and spinal cord tissues were removed and processed for histologic analysis and in situ hybridization. Both AIDA and NBQX affected the quisqualic acid-induced total lesion volume but only AIDA caused a decrease in the percent tissue damage at the lesion epicenter. Preprodynorphin and preproenkephalin expression is increased in both spinal and cortical areas in quisqualic acid-injected animals versus sham-, NBQX or AIDA-injected animals. NBQX did not affect quisqualic acid-induced spinal or cortical expression of preprodynorphin or preproenkephalin except for a significant decrease in preproenkephalin expression in the spinal cord. In contrast, AIDA significantly decreases quisqualic acid-induced preprodynorphin and preproenkephalin expression within the spinal cord and cortex. AIDA, but not NBQX, significantly reduced the frequency of, and delayed the onset of, quisqualic acid-induced spontaneous pain-related behavior.From these data we suggest that both the kainic acid/AMPA and metabotropic glutamate receptor subtypes are involved in the induction of the excitotoxic cascade responsible for quisqualic acid-induced neuronal damage and changes in opioid peptide mRNA expression, while metabotropic glutamate receptors may play a more significant role in the onset of post-injury pain-related behavior.     

Behavioural role of dopamine D1 receptors in the reserpine-treated mouse

The effects of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF 38393) (D1 agonist) on the motor behaviour of mice rendered hypokinetic with reserpine, were studied in the absence and presence of additional treatment with N-n-propyl-N-phenylethyl-p(3-hydroxyphenyl)ethylamine hydrochloride (RU 24213), lisuride (D2 agonists) or apomorphine (mixed D1/D2 agonist). Three hours after reserpine (5 mg/kg) stimulating dopamine D2 receptors evoked slow, ponderous walking and head-down sniffing. SKF 38393 (1.5-15 mg/kg) had no direct effect of its own, but greatly amplified the D2 response, giving more fluent locomotion, rearing and grooming. The facilitatory action of SKF 38393 was inhibited by the D1 antagonist (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin l -7-ol (SCH 23390) (0.05 mg/kg), whereas D2-mediated responses were sensitive both to SCH 23390 and the D2 antagonist metoclopramide (0.5 mg/kg). Mice treated with reserpine for 24 h became more sensitive to the motor stimulant actions of all four agonists. SKF 38393 now promoted rapid locomotion, rearing and grooming directly. The effects of D2 stimulation were weak by comparison and often antagonistic (not synergistic) with those of the D1 agonist. Both sets of agonists were now attenuated only by their respective antagonists. Reserpine caused pronounced falls in the concentrations of dopamine, 5-hydroxytryptamine and noradrenaline in the striatum, olfactory tubercle and cerebral cortex, with correspondingly elevated metabolite levels. These results indicate that D1 and D2 agonists at doses that are relatively ineffective at stimulating behaviour when given in isolation 3 h after reserpine, interact when given together to partially restore locomotion, rearing and grooming. This interaction is not apparent 24 h post-reserpine, a time at which D1 and D2 agonists produce significant effects of their own.     

Hippocampal-prefrontocortical circuits: PKA inhibition in the prefrontal cortex impairs delayed nonmatching in the radial maze in rats

Recent findings implicate the prefrontal cortex (PFC) and, in particular, frontocortical dopamine acting at D1-like receptors, in working memory. However, the mechanisms underlying this function of dopamine remain unknown. The present studies evaluated the hypothesis that dopamine contributes to working memory through its action on the 2nd messenger cyclic 3',5'-adenosine monophosphate (cAMP) and cAMP-dependent protein kinase (PKA). Thus, rats were trained to perform random foraging or delayed (30 min) nonmatching-to-position (delayed win-shift) tasks on the radial maze. With hippocampal output to the frontal cortex disconnected by injecting lidocaine (20 microg/0.5 microl) unilaterally into the ventral subiculum, contralateral frontocortical injections of lidocaine (20 microg/0.5 microl) or the D1-like dopamine receptor antagonist SCH 23390 (0.5 microg/0.5 microl) impaired delayed win-shift but not random foraging, replicating previous findings. In similarly disconnected rats, frontocortical injections of the PKA inhibitor Rp-cAMPS (5.0 and 10.0, but not 1.0, microg/0.5 microl) selectively impaired delayed nonmatching-to-position. Results suggest that activation of the cAMP-PKA pathway by dopamine acting at D1-like receptors in the frontal cortex is necessary for working memory.     

Excitatory amino acid modulation of lordosis in the rat.

Microinfusion of the excitatory amino acid agonist N-methyl-D-aspartate (NMDA) into the mediobasal hypothalamus (MBH) significantly reduced lordosis in estrogen plus progesterone-treated female rats at 10 min post-infusion with recovery to pretest values by 30 min (P less than .05; Wilcoxon). Microinfusion of the specific NMDA antagonist D,L2-amino-5-phosphonopentoic acid (AP-5) into the same sites was without effect on lordosis responding of fully receptive females. There was also a significant increase in the number of females vocalizing to mounts by males after infusion of NMDA but not after infusion of AP-5 into the MBH. When NMDA was infused into the preoptic area (POA) there was no effect on lordosis responding of full receptive females, but AP-5 infusion resulted in a significant inhibition of lordosis at 10 min post-infusion. There was no difference between groups in percentage of females vocalizing after drug infusion into the POA. These results suggest that increased excitatory amino acid activity in the MBH and decreased excitatory amino acid activity in the POA inhibits lordosis behavior.     

Spatial learning and performance in the radial arm maze is impaired after N-methyl-D-aspartate (NMDA) receptor blockade in striatal subregions.

These experiments addressed the role of striatal N-methyl-D-aspartate (NMDA) receptors in spatial behavior in the radial arm maze. Rats treated with the NMDA antagonist D-2-amino-5-phosphonopentanoic acid (AP-5) in the nucleus accumbens core, medial caudate, and posterior caudate were all significantly impaired in acquiring the correct spatial responses. In contrast, rats infused with AP-5 in the nucleus accumbens shell showed little impairment. When rats in all groups had learned the maze and were performing at similar levels, AP-5 had relatively little effect except in the posterior caudate group, where errors and trial times were again increased. These findings demonstrate the importance of NMDA receptor-dependent activity within the accumbens and caudate in spatial learning and performance. The neural processes necessary for adaptive spatial learning in complex environments may recruit multiple cortical systems having specialized functions, which in turn are integrated in widespread striatal regions.     

NBQX (6-nitro-sulfamoyl-benzo-quinoxaline-dione) and CPP (3-carboxy-piperazin-propyl phosphonic acid) potentiate dopamine agonist induced rotations in substantia nigra lesioned rats.

Degeneration of dopaminergic nigrostriatal neurons in primate models of Parkinson's disease (PD) leads to an overactivity of excitatory glutamatergic projections from the subthalamic nucleus (STN) to the output nuclei of the basal ganglia resulting in rigidity and akinesia. The selective alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonist 6-nitro-sulfamoyl-benzo-quinoxaline-dione (NBQX) and the competitive N-methyl-D-aspartate (NMDA) antagonist 3-carboxy-piperazin-propyl phosphonic acid (CPP) ameliorate parkinsonian symptomatology when co-administered with threshold doses of L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets and induce rotations in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra (SN). Here we report that in the 6-OHDA-lesioned rat NBQX and CPP induce contralateral rotations when combined with threshold doses of the direct dopamine agonists lisuride or apomorphine. AMPA antagonists and competitive NMDA antagonists may therefore be suitable as adjuvants for the treatment of PD.     

The role of non-N-methyl-D-aspartate ionotropic glutamate receptors in the spinal transmission of nociception in normal animals and animals with carrageenan inflammation.

The role of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainate receptors in spinal nociceptive transmission in both normal animals and animals with carrageenan inflammation was investigated using the AMPA/kainate receptor antagonist 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione (NBQX) and the selective GluR5 kainate receptor antagonist LY382884 [3S,4aR,6S,8aR-6-(4-carboxyphenyl)methyl-1,2,3,4,4a,5,6,7,8, 8a-deca-hydroisoquinoline-3-carboxylic acid]. In normal animals, spinal administration of 100 microg of LY382884 produced a significant inhibition of both the C-fibre-evoked response and post-discharge of dorsal horn neurons, with the wind-up of the neurons being reduced by both 50 and 100 microg of LY382884. The spinal actions of LY382884 were enhanced following 3 h of carrageenan inflammation, such that doses of 20 microg and above were able to produce significant inhibitions of the noxious-evoked response of the neurons. Spinal administration of NBQX in normal animals (5-50 microg) inhibited the C-fibre-evoked response of the dorsal horn neurons, but only 50 microg of NBQX was able to inhibit the wind-up and post-discharge of the neurons. Following 3 h of carrageenan inflammation, the ability of NBQX to inhibit the wind-up and post-discharge of the neurons was markedly enhanced. These data suggest that both AMPA and kainate GluR5 receptors play an enhanced role in spinal nociceptive processing following the development of peripheral inflammation, as antagonists at both receptors are more effective against nociceptive responses, including wind-up under these inflammatory conditions.