Δ<Superscript>9</Superscript>-THC administered into the medial prefrontal cortex disrupts the spatial working memory

Rationale Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) disrupts working memory. The prefrontal cortex (PFC) is involved in the processing of working memory, and its medial portion (mPFC) is part of a brain reward circuit as constituted by the mesocorticolimbic dopaminergic system.Objective This study examined the involvement of the mPFC in the effects of Δ⁹-THC on spatial working memory.Methods Ten male Wistar rats well-trained in a radial arm maze and with bilateral cannula implanted in the mPFC received Δ⁹-THC intracortically (Δ⁹-THC IC) at doses of 0 (VEH), 32, 100 or 180 μg, 5 min before a 5-s or a 1-h delayed task in order to measure a short- or long-term spatial working memory, respectively. By contrast, 11 other animals received Δ⁹-THC intraperitoneally (Δ⁹-THC IP) at doses of 0 (VEH), 0.32, 1 or 1.8 mg/kg, 30 min before a 5-s or a 1-h delayed task. Additionally, after a 15-day washout, the effect of an IP or IC pre-exposure of Δ⁹-THC was examined by repeating both dose–effect curves in a crossover order for the routes of administration.Results Δ⁹-THC IP produced significantly larger number of errors at doses of 0.32 or 1 mg/kg as compared to VEH in the 1-h post-delay performance. Δ⁹-THC 100 μg IC also produced significantly larger number of errors as compared to VEH and also to the other doses (32 or 180 μg) IC in the 1-h post-delay performance. Previous exposure to Δ⁹-THC IP or IC did not significantly affect the disruptive effect of this cannabinoid.Conclusions Δ⁹-THC administered directly in the mPFC impaired 1-h delayed task in the radial arm maze in a manner similar to that observed for its systemic administration, suggesting that the mPFC is involved in the disruptive effects of Δ⁹-THC on spatial working memory.     

Effect of different tryptophan sources on amino acids availability to the brain and mood in healthy volunteers

Rationale Pyrilamine, a selective histamine H₁ antagonist, impaired spatial memory, and decreased hippocampal theta activity during a radial maze task. Objective We investigated the ameliorative effects of glutamatergic drugs on pyrilamine-induced spatial memory deficit and the decrease in hippocampal theta activity in rats. Materials and methods Drug effects were measured using an eight-arm radial maze with four arms baited. Hippocampal theta rhythm during the radial maze task was also recorded with a polygraph system using a telemetric technique. Results Intraperitoneal injection of pyrilamine (35 mg/kg) resulted in impaired reference and working memory in the radial maze task and a decrease in the amplitude and power of hippocampal theta waves. The working memory deficit and the decrease in hippocampal theta power were antagonized by intrahippocampal injection of d-cycloserine (1 μg/side), spermidine (10 μg/side), spermine (10 μg/side), aniracetam (1 μg/side), and 1-(1,3-benzodioxol-5-ylcarbonyl) piperidine (1-BCP) (1 μg/side), but not concanavalin A. Conclusion These results clearly indicate that H₁ antagonist-induced working memory deficit, and the decrease in hippocampal theta activity was closely associated with hippocampal glutamatergic neurotransmission mediated by N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.     

Dissociation of the effects of ethanol on memory, anxiety, and motor behavior in mice tested in the plus-maze discriminative avoidance task

Rationale Several studies have shown the amnestic effects of ethanol (ETOH). However, while memory tasks in rodents can be markedly influenced by anxiety-like behavior and motor function, ETOH induces anxiolysis and different effects on locomotion, depending on the dose. Objective Verify the effects of ETOH in mice tested in the plus-maze discriminative avoidance task (PMDAT) concomitantly evaluating memory, anxiety-like behavior, and motor behavior. Methods ETOH acutely or repeatedly treated mice were submitted to the training session in a modified elevated plus-maze with two open and two enclosed arms, aversive stimuli in one of the enclosed arms, and tested 24 h later without aversive stimuli. Learning/memory, locomotion, and anxiety-related behavior were evaluated by aversive arm exploration, number of entries in all the arms and open arms exploration, respectively. Results Acute ETOH: (1) either increased (1.2–1.8 g/kg) or decreased (3.0 g/kg) locomotion; (2) decreased anxiety levels (1.2–3.0 g/kg); and (3) induced learning deficits (1.2–3.0 g/kg) and memory deficits (0.3–3.0 g/kg). After repeated treatment, sensitization and tolerance to hyperlocomotion and anxiolysis induced by 1.8 g/kg ETOH were observed, respectively, and tolerance to the amnestic effect of 0.6 (but not 1.8) g/kg ETOH occurred. Conclusion Neither the anxiolytic nor the locomotor effects of ETOH seem to be related to its amnestic effect in the PMDAT. Additionally, data give support to the effectiveness of the PMDAT in simultaneously evaluating learning, memory, anxiety-like behavior, and motor activity by different parameters. Possible relationships between the behavioral alterations found are discussed.     

Effects of clonidine in the locus coeruleus on prefrontal- and hippocampal-dependent measures of attention and memory in the rat

Rationale The locus coeruleus (LC) is the source of norepinephrine (NE) in the prefrontal cortex (PFC) and hippocampus and may influence cognitive functions of these areas. Chronic effects of LC-NE lesions do not correspond consistently with acute effects of systemic or intracortical injections of adrenergic agents. Objective These studies aim to manipulate LC activity pharmacologically and study acute effects on measures of attention and memory that depend on the PFC and hippocampus. Methods Rats were trained to criterion for one of three tasks: visuospatial reaction time (VSRT), a measure of attention sensitive to PFC lesions, delayed matching trained with retractable levers (DM-RL), and delayed nonmatching trained in radial mazes (DNM-RM), measures of spatial working memory sensitive to PFC and hippocampal lesions, respectively. LC activity was manipulated with bilateral 0.5-μl injections of the alpha-2 agonist clonidine (0, 1.1, 4.5, and 18 nmol). Results Clonidine produced significant dose-dependent impairments of VSRT, affecting choice response time at the 18-nmol dose and choice accuracy at the 4.5- and 18-nmol doses. Clonidine had no effect on DMRL or DNM-RM at any of the doses tested. Conclusions Reversible reduction of LC-NE activity by clonidine impaired measures of visuospatial attention sensitive to PFC lesions but were insufficient to affect PFC- or hippocampal-dependent measures of spatial working memory. These results are consistent with reports that LC-NE lesions produce chronic deficits in attention with little or no effect on measures of working memory.     

Mesocortical dopamine modulation of executive functions: beyond working memory

Rationale Dopamine (DA) neurotransmission in the prefrontal cortex (PFC) is known to play an essential role in mediating executive functions such as the working memory. DA exerts these effects by acting on D₁ receptors because blockade or stimulation of these receptors in the PFC can impair performance on delayed response tasks. However, comparatively less is known about dopaminergic mechanisms that mediate other executive functions regulated by the PFC. Furthermore, the functional importance of other DA receptor subtypes that reside on PFC neurons (D₂ and D₄) is unclear.Objectives This review will summarize previous findings and previously unpublished data addressing the contribution of PFC DA to higher-order cognition. We will compare the DA receptor mechanisms, which regulate executive functions such as working memory, behavioral flexibility, and decision-making.Results and conclusions Whereas PFC D₁ receptor activity is of primary importance in working memory, D₁ and D₂ receptors act in a cooperative manner to facilitate behavioral flexibility. We note that the principle of the “inverted U-shaped” function of D₁ receptor activity mediating working memory does not necessarily apply to other PFC functions. DA in different subregions of the PFC also mediates decision-making assessed with delay discounting or effort-based procedures, and we report that D₁, D₂, and D₄ receptors in the medial PFC contribute to decision-making when animals must bias the direction of behavior to avoid aversive stimuli, assessed with a conditioned punishment procedure. Thus, mesocortical DA modulation of distinct executive functions is subserved by dissociable profiles of DA receptor activity in the PFC.     

Effects of scopolamine on learning and memory in monkeys

The effects of scopolamine were evaluated in monkeys responding under operant procedures designed to evaluate drug effects on learning and memory. In one procedure, responding was maintained by food presentation under a multiple schedule. One component of the multiple schedule was a repeated-acquisition task in which the discriminative stimuli for left- and right-key responses changed each session (learning). In the other component, the discriminative stimuli for responses were the same each session (performance). In both components of the multiple schedule, scopolamine produced dose-related decreases in responding; there was little evidence of differential rate-decreasing effects between components. Percent errors in learning were increased in a dose-related manner, whereas percent errors in performance were generally unaffected except at high doses, which also produced substantial decreases in response rate. These results suggest that acquisition is more sensitive to the disruptive effects of scopolamine than is performance. The second procedure utilized repeated acquisition and delayed performance as a technique to study the effects of scopolamine on memory. In this procedure, each session was divided into three phases: acquisition, delay and performance. After a 24-h delay, scopolamine had little or no effect on retention, accuracy or rate of responding. In contrast, after a 60-min delay, scopolamine decreased retention in a dose-related manner. These data suggest that scopolamine produces a greater disruptive effect on short (60-min) versus long (24-h) delays.     

Effects of the adenosine A2A antagonist istradefylline on cognitive performance in rats with a 6-OHDA lesion in prefrontal cortex

Rationale

Altered cognitive function is a common feature of both the early and later stages of Parkinson’s disease (PD) that involves alterations in cortical dopamine content. Adenosine A_2A antagonists, such as istradefylline, improve motor function in PD, but their effect on cognitive impairment has not been determined.

Objective

The present study investigated whether impairment of working memory due to the loss of dopaminergic input into the prefrontal cortex (PFC) is reversed by administration of istradefylline. We also evaluated whether A_2A antagonist administration modulates dopamine levels in the PFC.

Methods

Bilateral lesions of the dopaminergic input to the PFC were produced in rats using 6-hydroxydopamine (6-OHDA). Cognitive performance was evaluated using an object recognition task and delayed alternation task. The effects of istradefylline, donepezil and methamphetamine on cognitive performance were examined. In addition, the effect of istradefylline on extracellular dopamine levels in the PFC was studied.

Results

PFC dopamine levels and cognitive performance were significantly reduced by 6-OHDA lesioning. Istradefylline, donepezil and methamphetamine improved cognitive performance of PFC-lesioned rats. Istradefylline increased dopamine levels in the PFC in both normal and PFC-lesioned rats.

Conclusions

PFC dopaminergic input plays an important role in working memory performance. Blockade of A_2A receptors using istradefylline reverses the changes in cognitive function, and this may be due to an increase in PFC dopamine content. Adenosine A_2A receptor antagonists not only improve motor performance in PD but may also lead to improved cognition.     

Ethanol induced delayed cellular protection in mouse cardiac myocytes: role of inducible nitric oxide synthase

This study has examined the hypotheses that, firstly, the ethanol induces delayed cellular protection in mouse cardiac myocytes against subsequent sustained simulated ischemia (SI). Secondly, the delayed cyto-protective effect induced by the ethanol depends more on time than the dose in mouse cardiac myocytes. Finally, ethanol-induced delayed cellular protection in mouse cardiac myocytes is mediated through inducible nitric oxide synthase (iNOS). Accordingly, we planned the following groups of BALB/c mouse cultured cardiac myocytes in our study: (a) SI, (b) 5 mM ethanol (ETOH)/15 min + SI, (c) 5 mM ETOH/30 min + SI, (d) 10 mM ETOH/15 min + SI, (e) 10 mM ETOH/30 min + SI, (f) 25 mM ETOH/15 min + SI, (g) 25 mM ETOH/30 min + SI, (h) 25 mM ETOH/60 min + SI, (i) 50 mM ETOH/15 min + SI, (j) 50 mM ETOH/30 min + SI, (k) 50 mM ETOH/60 min + SI, (l) 250 mM ETOH/15 min + SI and (m) 250 mM ETOH/30 min + SI. Another set of experiments we designed with iNOS-/- and its wild-type (iNOS+/+) mice cardiac myocytes as follows: SI, 5 mM ETOH/30 min + SI, 10 mM ETOH/30 min + SI, 25 mM ETOH/30 min + SI, 50 mM ETOH/30 min + SI and 250 mM ETOH/30 min + SI. Cellular injury was measured by the release of creatinine kinase (CK, U/l) into the medium. BALB/c mouse cardiac myocytes subjected to SI demonstrated significant increase in CK release as compared to the ethanol-treated cells. Ethanol-induced delayed cellular protection resulted in a significant (p < 0.001) attenuation in the cellular injury as indicated by reduction in the release of CK (U/l) from 9.25 +/- 0.52 to 5.16 +/- 0.44 (5 mM ETOH/30 min), from 7.50 +/- 0.43 (10 mM ETOH/15 min) to 4.16 +/- 0.64 (10 mM ETOH/30 min), from 5.91 +/- 0.41 (25 mM ETOH/15 min) to 2.50 +/- 0.58 (25 mM ETOH/30 min) and to 2.25 +/- 0.37 (25 mM ETOH/60 min), from 5.41 +/- 0.28 (50 mM ETOH/15 min) to 1.66 +/- 0.56(50 mM ETOH/30 min) and to 1.25 +/- 0.30 (50 mM ETOH/60 min), and from 5.25 +/- 0.21(250 mM ETOH/15 min) to 1.66 +/- 0.51(250 mM ETOH/30 min). Reduction in CK release from ethanol-treated iNOS-/-mouse cardiac myocytes was insignificant (p > 0.05) compared to non-treated wild-type (iNOS+/+) mouse cardiac myocytes subjected to SI alone. Our data suggest that ethanol induces delayed cellular protection in mouse cardiac myocytes against sustained simulated ischemia. Further, ethanol-induced delayed cellular protection depends more on time than the dose. Furthermore, ethanol-induced delayed cellular protection is dependent on iNOS.     

Prefrontal Cortical GABA Modulation of Spatial Reference and Working Memory

Background:

Dysfunction in prefrontal cortex (PFC) GABA transmission has been proposed to contribute to cognitive dysfunction in schizophrenia, yet how this system regulates different cognitive and mnemonic functions remains unclear.

Methods:

We assessed the effects of pharmacological reduction of GABA_A signaling in the medial PFC of rats on spatial reference/working memory using different versions of the radial-arm maze task. We used a massed-trials procedure to probe how PFC GABA regulates susceptibility to proactive interference. Male rats were well-trained to retrieve food from the same 4 arms of an 8-arm maze, receiving 5 trials/day (1–2min intervals).

Results:

Infusions of the GABA_A receptor antagonist bicuculline (12.5–50ng) markedly increased working and reference memory errors and response latencies. Similar treatments also impaired short-term memory on an 8-baited arm task. These effects did not appear to be due to increased susceptibility to proactive interference. In contrast, PFC inactivation via infusion of GABA agonists baclofen/muscimol did not affect reference/working memory. In comparison to the pronounced effects on the 8-arm maze tasks, PFC GABA_A antagonism only causes a slight and transient decrease in accuracy on a 2-arm spatial discrimination.

Conclusions:

These findings demonstrate that prefrontal GABA hypofunction severely disrupts spatial reference and short-term memory and that disinhibition of the PFC can, in some instances, perturb memory processes not normally dependent on the frontal lobes. Moreover, these impairments closely resemble those observed in schizophrenic patients, suggesting that perturbation in PFC GABA signaling may contribute to these types of cognitive deficits associated with the disorder.     

The Effect of Midazolam and Propranolol on Fear Memory Reconsolidation in Ethanol-Withdrawn Rats: Influence of D-Cycloserine

Background:

Withdrawal from chronic ethanol facilitates the formation of contextual fear memory and delays the onset to extinction, with its retrieval promoting an increase in ethanol consumption. Consequently, manipulations aimed to reduce these aversive memories, may be beneficial in the treatment of alcohol discontinuation symptoms. Related to this, pharmacological memory reconsolidation blockade has received greater attention due to its therapeutic potential.

Methods:

Here, we examined the effect of post-reactivation amnestic treatments such as Midazolam (MDZ, 3 mg/kg i.p) and Propranolol (PROP, 5 mg/kg i.p) on contextual fear memory reconsolidation in ethanol- withdrawn (ETOH) rats. Next, we examined whether the activation of N-methyl-D-aspartate (NMDA) receptors induced by d-cycloserine (DCS, 5 mg/kg i.p., a NMDA partial agonist) before memory reactivation can facilitate the disruptive effect of PROP and MDZ on fear memory in ETOH rats.

Results:

We observed a resistance to the disruptive effect of both MDZ and PROP following memory reactivation. Although intra-basolateral amygdala (BLA; 1.25 ug/side) and systemic PROP administration attenuated fear memory in DCS pre-treated ETOH rats, DCS/MDZ treatment did not affect memory in these animals. Finally, a decrease of both total and surface protein expression of the α1 GABAA receptor (GABAA-R) subunit in BLA was found in the ETOH rats.

Conclusions:

Ethanol withdrawal facilitated the formation of fear memory resistant to labilization post-reactivation. DCS administration promoted the disruptive effect of PROP on memory reconsolidation in ETOH rats. The resistance to MDZ’s disruptive effect on fear memory reconsolidation may be, at least in part, associated with changes in the GABAA-R composition induced by chronic ethanol administration/withdrawal.     

Differential effects of scopolamine on working and reference memory of rats in the radial maze

Anticholinergics have often been found to impair choice accuracy in the radial maze. Some researchers have suggested that this indicates involvement of cholinergically innervated structures in cognitive mapping while others argue that these structures mediate working memory. However, most results are open to either interpretation since the baiting method did not allow a distinction between reference and working memory errors. To further test these hypotheses this study examined the effects of systemic scopolamine on radial maze performance, using a 4-out-of-8 baiting procedure. Food-deprived Wistar rats were pretrained until working memory choice accuracy stabilized to a criterion of 87% or better. Scopolamine (0.1, 0.4 and 0.8 mg/kg, IP, 30 min before a session) significantly increased the number of working memory errors (re-entries into baited arms) whereas reference memory errors (entries into never baited arms) did not change significantly. Observed deficits appeared not to be attributable to a drug-induced disruption of motivational systems. Results confirm the behavioural similarities between the memorial effects of hippocampectomy and anticholinergics, and implicate cholinergically innervated structures in working memory.     

Propranolol blocks chronic risperidone treatment-induced enhancement of spatial working memory performance of rats in a delayed matching-to-place water maze task

Rationale Atypical antipsychotics improve cognitive function, including working memory, in schizophrenia. Some atypical antipsychotics have been reported to activate the locus coeruleus and induce beta-adrenoceptor antagonist sensitive c-Fos-like immunoreactivity in the prefrontal cortex. Materials and methods The present study investigated the effects of chronic treatment of rats with risperidone (1 mg kg⁻¹ day⁻¹ s.c.), clozapine (10 mg kg⁻¹ day⁻¹ s.c.), or acidified saline vehicle control for 2, 4, or 8 weeks on spatial working memory performance in a delayed matching-to-place water maze task with a 60-s inter-trial retention interval with and without acute challenge with propranolol (10 mg/kg i.p.). Results Treatment with risperidone for 8 weeks, but not 2 or 4 weeks, significantly improved working memory performance. In contrast, treatment with clozapine for up to 8 weeks did not improve working memory. Acute challenge with propranolol blocked the improvement in working memory produced by chronic treatment with risperidone, but had no significant effect on performance in saline- or clozapine-treated animals. Conclusions The delayed matching-to-place water maze task may prove valuable in the investigation of the behavioural pharmacology of the cognitive effects of antipsychotic drugs. These data suggest that beta adrenoceptors may contribute to the cognitive effects of chronic treatment with atypical antipsychotics.     

5-HT1B receptors, ventral orbitofrontal cortex, and aggressive behavior in mice

Rationale Systemic injections of 5-HT_1B receptor agonists have been shown to have specific anti-aggressive effects in aggressive individuals. One site of action for these drugs is the 5-HT_1B receptors in the ventral orbitofrontal cortex (VO PFC), an area that has been implicated in the inhibitory control of behavior and is a terminal region for 5-HT projections.Objective To assess the anti-aggressive effects of the 5-HT_1B receptor agonist CP-94,253 when microinjected into the VO PFC (0.1, 0.56, and 1.0 μg/0.2 μl) or into the infralimbic prefrontal cortex (IL PFC; 1.0 μg/0.2 μl) in separate groups of aggressive resident male mice. To confirm the 5-HT_1B receptor as the critical site of action for the anti-aggressive effects, the 5-HT_1B/D antagonist GR-127,935 was microinjected at 10.0 μg/0.2 μl into the VO PFC. After recovery from surgery, the anti-aggressive effects of microinjected CP-94,253 were studied during 5-min resident–intruder confrontations that were recorded and analyzed.Results Microinjections of CP-94,253 (0.56 and 1.0 μg/0.2 μl) dose-dependently reduced the frequency of attack bites and sideways threats. This effect was behaviorally specific because non-aggressive motor activities were not significantly altered by the drug. In the IL vmPFC or in an area lateral to the VO PFC, CP-94,253 (1.0 μg/0.2 μl) did not have significant behavioral effects.Conclusions The results highlight the 5-HT_1B receptors in the VO PFC as a particularly important site for the inhibition of species-typical aggressive behavior in male mice.     

Differential effects of chronic haloperidol and olanzapine exposure on brain cholinergic markers and spatial learning in rats

Abstract Rationale. In psychiatric patients, haloperidol (HAL) induces a number of adverse extrapyramidal and cognitive symptoms, which appear to be less problematic with olanzapine (OLZ). In animals, HAL may initiate a number of harmful effects on central nervous system neurons, including damage to cholinergic pathways – an effect that could be especially deleterious to those experiencing memory dysfunction. The identification of the neurobiological substrates of such effects in animal models may help to improve the algorithms used for proper drug selection especially for long-term neuroleptic use. Objectives. The aim of this study was to compare the effects of chronic (45-day and 90-day), continuous oral exposure to HAL with OLZ for effects on cognitive performance and cholinergic markers in rats. Methods. After chronic neuroleptic exposure (and a 4-day washout) spatial memory performance was measured in a water maze task, and choline acetyltransferase (ChAT) immunoreactivity was assessed with immunofluorescence staining. Results. In water maze experiments, HAL and OLZ (relative to vehicle) administered for 90 days (but not 45 days) significantly impaired learning performance (i.e., higher mean latencies across several trials to reach a hidden platform). HAL administered for 90 days was associated with impairment across a greater number of trials than OLZ and it also impaired probe trial performance, as indicated by a reduced number of crossings over the previous platform area (when compared with OLZ or vehicle). Both 45 days and 90 days of HAL treatment reduced ChAT staining in the cortex and hippocampus when compared with OLZ or vehicle. Conclusions. The results in the rat suggest that OLZ (relative to HAL) may be more desirable as an antipsychotic for patients suffering from memory dysfunction especially for those in which cholinergic deficits may already be present. Electronic Publication     

Influence of haloperidol and clozapine on some behavioral effects in rats

The experiments presented in the following paper aimed to investigate the influence of atypical antipsychotic clozapine (CLO, CAS 578-21-0) classified also as normothymic drug on spatial memory in rats in Morris water maze test. The study also investigated the probably occurring side effects (measuring cataleptic activity and motor coordination) following single and chronic administration of CLO compared to haloperidol (HAL, CAS 52-86-8), a conventional antipsychotic. All the tests were carried out on male Wistar rats. CLO 10 mg/kg was administered orally 30 min before the tests and HAL 0.15 mg/kg was administered orally 60 min before the tests. In the Morris test memory improvement only after chronic administration of CLO on the 7th and 14th day of treatment was observed, whereas after 14 days of HAL treatment spatial memory impairment was noted. CLO did not induce catalepsy after single as well as chronic administration, but administrated chronically induced a tendency for its occurrence. HAL evoked a strong cataleptic effect both after acute and chronic treatment. CLO had no impact on motor coordination in the chimney test except on day 14 when statistically significant impairments were observed. HAL disturbed motor coordination in rats after single as well as chronic administration. The wide and unique spectrum of receptor activity of CLO in comparison with HAL as well as some neurotransmitters' interactions may explain its usefulness in long-term therapy of bipolar affective disorder and schizoaffective disorder with co-occurred cognitive deficits.     

Chronic nicotine working and reference memory effects in the 16-arm radial maze: interactions with D1 agonist and antagonist drugs

Chronic nicotine infusion has been found in a series of studies in our laboratory to significantly improve choice accuracy of rats in the eight-arm radial maze. The current study was designed to compare the effects of chronic nicotine infusion on working and reference memory in a 16-arm radial maze. Nicotine was administered to female Sprague-Dawley rats at approximately 5 mg/kg per day SC via osmotic minipumps. Controls received saline infusions. Chronic nicotine infusion significantly lowered the number of working memory errors compared to controls, whereas the number of reference memory erros was not significantly affected. The modest nicotine-induced reduction in working memory errors was seen as a main effect over the 4 weeks of infusion, but the clearest effect was seen in weeks 3–4 of nicotine administration. For the 2 weeks after withdrawal, the nicotine effect was no longer evident. Acute D₁ challenges were given with the D₁ agonist dihydrexidine (0, 0.25, 0.5 and 1 mg/kg) and the D₁ antagonist SCH 23390 (0, 0.005, 0.015 and 0.05 μg/kg) during weeks 3–4 of chronic nicotine administration and weeks 1–2 after withdrawal from nicotine. Dihydrexidine caused a modest dose-related increase in reference memory errors but not working memory errors in the nicotine-treated, but not the control rats. The D₁ antagonist SCH 23390 caused a modest though significant decrease in reference memory errors but not working memory errors in the control, but not the nicotine-treated rats. The behavioral specificity of chronic nicotine infusion was demonstrated with selective improvement in working memory function. Pharmacological interactions were seen with chronic nicotine treatment increasing responsivity to D₁ agonist and decreasing responsivity to a D₁ antagonist with regard to reference memory. The mechanisms of this interaction are still undiscovered.     

Spatial working memory in rats: effects of monoaminergic antagonists

To assess the possible involvement of the monoaminergic neurotransmitters norepinephrine, dopamine and serotonin in the maintenance of spatial working memory rats were treated with antagonists 0 or 2 hr after completing the first 4 choices in an 8 arm maze. Haloperidol (0.25-1 mg/kg), when administered 2 hr after Choice 4, produced a small but consistent impairment in performance on retention tests given 5 hr after the first 4 choices. This deficit closely resembled natural forgetting in terms of the type of errors committed. By contrast, haloperidol in the same doses given 0 hr after Choice 4 or 3 hr before the first 4 choices did not affect retention. Likewise treatment with propranolol (10-20 mg/kg), phentolamine (5-20 mg/kg) or methysergide (5-15 mg/kg) did not impair spatial memory, regardless of when these drugs were injected within the session. Evidently dopaminergic neuronal systems are important in the maintenance of normal spatial working memory.     

Role of the simultaneous enhancement of NMDA and dopamine D1 receptor-mediated neurotransmission in the effects of clozapine on phencyclidine-induced acute increases in glutamate levels in the rat medial prefrontal cortex

Clozapine (CLZ) can improve both the positive and negative symptoms of treatment-resistant schizophrenia (TRS), which does not respond to typical antipsychotics. This suggests that elucidation of the pharmacological mechanism for CLZ could lead to further clarification of the pathophysiology of TRS. This study examined the effects of CLZ on phencyclidine (PCP)-induced hyperlocomotion and on the acute increases in glutamate levels that occur in the medial prefrontal cortex (mPFC) in order to test the hypothesis that CLZ effect is associated with the simultaneous enhancement of N-methyl-d-aspartate (NMDA) and dopamine D₁ receptor-mediated neurotransmission. CLZ effect on PCP-induced hyperlocomotion and increases in glutamate levels were examined by using behavioral rating scores and in vivo microdialysis, respectively. CLZ and haloperidol (HAL) dose-relatedly attenuated PCP-induced hyperlocomotion, and concentration-relatedly blocked PCP-induced acute increases in glutamate levels in the mPFC, with the decrease in saline-induced locomotor activity induced by CLZ being much weaker than that induced by HAL. CLZ also blocked, in a dose-related manner, acute increases in glutamate levels in the mPFC that were induced by local perfusion with a competitive NMDA receptor antagonist, CPP, in this region. Although an enhanced blocking effect of the sub-threshold concentration of NMDA perfusion on PCP-induced acute increases in glutamate levels in the mPFC was noted after co-perfusion with a dopamine D₁ receptor agonist, SKF-38393, perfusion with SKF-38393 did not reverse the CLZ blocking of PCP-induced increases in glutamate levels. Therefore, CLZ may block PCP-induced acute increases in glutamate levels in the mPFC by an enhancement of the NMDA receptor-mediated neurotransmission that is not accelerated by an enhanced dopaminergic transmission via dopamine D₁ receptors. This blocking effect may partially explain the CLZ-induced attenuation of PCP-induced hyperlocomotion.     

On the Origin of Cortical Dopamine: Is it a Co-Transmitter in Noradrenergic Neurons?

Dopamine (DA) and noradrenaline (NA) in the prefrontal cortex (PFC) modulate superior cognitive functions, and are involved in the aetiology of depressive and psychotic symptoms. Moreover, microdialysis studies in rats have shown how pharmacological treatments that induce modifications of extracellular NA in the medial PFC (mPFC), also produce parallel changes in extracellular DA.To explain the coupling of NA and DA changes, this article reviews the evidence supporting the hypothesis that extracellular DA in the cerebral cortex originates not only from dopaminergic terminals but also from noradrenergic ones, where it acts both as precursor for NA and as a co-transmitter.Accordingly, extracellular DA concentration in the occipital, parietal and cerebellar cortex was found to be much higher than expected in view of the scarce dopaminergic innervation in these areas.Systemic administration or intra-cortical perfusion of alpha(2)-adrenoceptor agonists and antagonists, consistent with their action on noradrenergic neuronal activity, produced concomitant changes not only in extracellular NA but also in DA in the mPFC, occipital and parietal cortex.Chemical modulation of the locus coeruleus by locally applied carbachol, kainate, NMDA or clonidine modified both NA and DA in the mPFC.Electrical stimulation of the locus coeruleus led to an increased efflux of both NA and DA in mPFC, parietal and occipital cortex, while in the striatum, NA efflux alone was enhanced.Atypical antipsychotics, such as clozapine and olanzapine, or antidepressants, including mirtazapine and mianserine, have been found to increase both NA and DA throughout the cerebral cortex, likely through blockade of alpha(2)-adrenoceptors. On the other hand, drugs selectively acting on dopaminergic transmission produced modest changes in extracellular DA in mPFC, and had no effect on the occipital or parietal cortex.Acute administration of morphine did not increase DA levels in the PFC (where NA is diminished), in contrast with augmented dopaminergic neuronal activity; moreover, during morphine withdrawal both DA and NA levels increased, in spite of a diminished dopaminergic activity, both increases being antagonised by clonidine but not quinpirole administration.Extensive 6-hydroxy dopamine lesion of the ventral tegmental area (VTA) decreases below 95% of control both intra- and extracellular DA and DOPAC in the nucleus accumbens, but only partially or not significantly in the mPFC and parietal cortex.The above evidence points to a common origin for NA and DA in the cerebral cortex and suggests the possible utility of noradrenergic system modulation as a target for drugs with potential clinical efficacy on cognitive functions.     

Infralimbic kappa opioid and muscarinic M1 receptor interactions in the concurrent modulation of anxiety and memory

RATIONALE: Spontaneous working memory and anxiety-like behaviour can be concurrently influenced following kappa opioid or muscarinic M1 antagonist infusions in the infralimbic (IL) area of the ventromedial prefrontal cortex (vmPFC) in CD-1 mice. Further dose-response analyses of our previous norBNI and pirenzepine data revealed significant dose x drug interactions on trial-1 and -2 anxiety-related elevated plus-maze indices. These data prompted us to evaluate the effects of simultaneous IL norBNI/pirenzepine infusions on anxiety and spontaneous working memory. OBJECTIVE: The present study sought to evaluate whether (a) our previously reported anxiogenic and working memory disruptive effects of norBNI, and anxiolytic and working memory disruptive effects of pirenzepine data could be replicated using the most effective dose (10 nmol) of each drug and (b) IL infusions of mixed kappa/M1 receptor inhibitor drugs might interactively influence these cognitive, behavioural processes. METHODS: Anxiety was evaluated in the elevated plus maze, and spontaneous alternation memory was evaluated in the Y-maze following pirenzepine, norBNI or two levels of norBNI/pirenzepine drug mix infusions in the IL vmPFC. RESULTS: Pretreatment with the M1 antagonist pirenzepine was anxiolytic in trial 1 (10 nmol) and trial 2 (no-injection) in the elevated plus maze 24 h later, and disrupted alternation performance and some aspects of attention in the Y-maze. Pretreatment with the kappa antagonist norBNI was anxiogenic in trial 1 (10 nmol) and trial 2 (no-injection) in the elevated plus maze 24 h later, and also disrupted alternation performance and some aspects of attention in the Y-maze. The norBNI-10 nmol/pirenzepine-10 nmol mixed drug infusion was somewhat anxiogenic in trial 1, exerted no carry-over effects in trial 2 in the elevated plus maze, and disrupted alternation memory and some aspects of attention in the Y-maze. The norBNI-5 nmol/pirenzepine-10 nmol drug mix had no effect on trial-1 or -2 anxiety measures in the elevated plus maze, yet also disrupted Y-maze spontaneous memory performance. CONCLUSIONS: (1) The effects of IL infusions of norBNI or pirenzepine (10 nmol/0.5 microl) alone on anxiety-like behaviour and aversive learning and memory in the elevated plus-maze replicated previously reported data. (2) Mixed M1/kappa receptor inhibition in the IL cortex exerted counteractive effects on anxiety-like behaviour and aversive learning in the elevated plus maze. (3) Mixed M1/kappa receptor inhibition appeared to exert additive disruptive effects on alternation performance and aspects of attention related to active working memory in the Y-maze.