A partial habituation method to test for anterograde and retrograde amnestic treatment effects: Evidence that antagonism of the NMDA receptor can induce anterograde but not retrograde amnestic effects.

BACKGROUND: A progressive decrease in spontaneous locomotion with repeated exposure to a novel environment has been assessed using both within and between-session measures. While both are well-established and reliable measurements, neither are useful alone as methods to concurrently assess treatment effects on acquisition and retention of habituation. NEW METHOD: We report a behavioral method that measures habituation by combining the within and between measurements of locomotion. We used a 30 min session divided into 6 five min blocks. In the first novel environment session activity was maximal in the first 5 min block but was reduced to a low level by the sixth block, indicative of within-session habituation. Using 8 daily sessions, we showed that this terminal block low level of activity progressed incrementally to the first block to achieve complete habituation. RESULTS/COMPARISON WITH EXISTING METHODS: Within-session activity across sessions was used to identify different stages of between session habituation. It was then possible to assess drug treatment effects from partial to complete habituation, so that treatment effects on retention of the previously acquired partial habituation, expressed as a reversion to an earlier within session habituation pattern (retrograde amnesia assessment), as well as the effects on new learning by the failure in subsequent sessions to acquire complete between-session habituation (anterograde amnesia assessment). CONCLUSIONS: The use of spontaneous motor activity to assess learning and memory effects provides the opportunity to assess direct treatment effects on behavior and motor activity in contrast to many learning and memory models.

Morphine and dopamine: Low dose apomorphine can prevent both the induction and expression of morphine locomotor sensitization and conditioning.

The disinhibition of dopamine neurons in the VTA by morphine is considered an important contributor to the reward potency of morphine. In this report, three experiments were conducted in which a low dose of apomorphine (0.05 mg/kg) was used as a pretreatment to reduce dopamine activity. Locomotor hyperactivity was used as the behavioral response to morphine (10.0 mg/kg). In the first experiment, five treatments with morphine induced the development of locomotor and conditioned hyperactivity that were prevented by apomorphine given 10 min prior to morphine. Apomorphine before either vehicle or morphine induced equivalent reductions in locomotion. In the second experiment, the apomorphine pretreatment was initiated after induction of a conditioned hyperactivity and apomorphine prevented the expression of the conditioning. To assess the effects of apomorphine on VTA and the nucleus accumbens, ERK measurements were carried out after the induction of locomotor and conditioned hyperactivity. Increased ERK activation was found and these effects were prevented by the apomorphine in both experiments. A third experiment was conducted to assess the effects of acute morphine on ERK before locomotor stimulation was induced by morphine. Acute morphine did not increase locomotion, but a robust ERK response was produced indicating that the morphine-induced ERK activation was not secondary to locomotor stimulation. ERK activation was again prevented by the apomorphine pretreatment. We suggest that contiguity between the ongoing behavioral activity and the morphine activation of the dopamine reward system incentivizes and potentiates the ongoing behavior generating equivalent behavioral sensitization and conditioned effects.

Context evoked morphine conditioned effects can be equivalent to morphine induced drug effects in terms of behavioral response and ERK activation in reward associated subcortical brain structures.

Conditioned drug cues can evoke brief drug-like responses. In this report we show that using brief test sessions, contextual cues can induce conditioned hyperlocomotion and ERK responses equivalent to morphine induced responses. To assess acute unconditioned effects, rats that received morphine (MOR-1) or vehicle (VEH-1) were immediately placed onto an arena for a 5-min locomotion recording session after which ERK was measured in the ventral tegmental area (VTA) and nucleus accumbens (NAc). There were no differences in locomotion between the groups. However, the MOR-1 group had strong ERK activation in VTA and NAc. To assess MOR-conditioned effects, a chronic phase was carried out according to a Pavlovian conditioning protocol. There were two MOR paired groups (MORP), one MOR unpaired (MOR-UP) group and two VEH groups. The treatments were administered over 5 daily five minute test sessions. The final conditioning test was on day 6, in which one of the MOR-P groups and one of the VEH groups received VEH (MOR-P/VEH-6 and VEH/VEH-6, respectively). The other MOR-P group and VEH group received MOR (MOR-P/MOR; VEH/MOR-6, respectively). The MOR-UP group received VEH (MOR-UP/VEH-6). Rats received the treatments immediately prior to a 5-minute arena test, and after the session ERK was measured. No morphine induced locomotor stimulation was observed on day 1 but on days 2 to 5, hyperlocomotion in both MOR-P groups occurred. On test day 6, the MOR-P/VEH-6 and the MOR-P/MOR-6 groups had comparable locomotor stimulant responses and similar ERK activity in the VTA and NAc. The MOR-UP group did not differ from the VEH group. We suggest that ERK activation evoked by acute morphine served as a Pavlovian unconditioned stimulus to enable the contextual cues to acquire morphine conditioned stimulus properties and increase the incentive value of the contextual cues.

A new method to study learning and memory using spontaneous locomotor activity in an open-field arena.

BACKGROUND: Reduced locomotion with repeated exposure to a novel environment is often used as a measure of the basic adaptive learning process of habituation. While this is a well-established and reliable measure of habituation, it is not useful for the investigation of neurobiological changes before and after habituation because of the uncontrolled differential activity levels in a novel versus habituated environment. In this study we report a behavioral method that uses spontaneous locomotion to measure habituation, in which the total spontaneous locomotion in an initially novel environment does not change with repeated testing but, the ratio of central to peripheral activity does change and is indicative of habituation. The test sessions are brief (5 min) and the locomotion is measured in 2 separate zones. The peripheral zone comprises 8/9 of the test arena and the central zone 1/9 of the arena. RESULTS/COMPARISON WITH EXISTING METHODS: In contrast to methods that use between-session reductions in locomotion to assess habituation, this method employs brief test sessions in which overall activity between sessions does not change, but the distribution of locomotion in the periphery versus the central zone of the arena does change. The brevity of the test session also enables us to utilize post-trial drug treatment protocols to impact memory consolidation. CONCLUSIONS: The progressive change in the central/peripheral activity ratio with repeated testing can be determined independently of total activity and provides a habituation acquisition function that permits the measurement of neurobiological changes without the complication of effects related to changes in locomotor activity per se. The present report also presents evidence that this method can be used with post-trial drug treatment protocols to study the learning and memory effects of the post-trial treatments without the use of explicit rewards and punishments.

Morphine reward effects and morphine behavioral sensitization: The adventitious association of morphine activation of brain reward effects with ongoing spontaneous activity.

The development of sensitization is one of the hallmarks of addictive drugs such as morphine. We administered morphine (10 mg/kg; MOR) to induce locomotor sensitization and ERK activation in the VTA and NAc. In the first experiment, four groups of rats received five daily 30 min sessions in an open-field, and locomotion was measured. For the first four sessions, one group received MOR pre-test (MOR-P); a second group received vehicle pre-test (MOR-UP) and MOR 30 min post-test; the remaining 2 groups received vehicle (VEH) pre-test. On the fifth session, the MOR-P, MOR-UP, and one VEH group received MOR pre-test and the remaining VEH group received VEH. Sensitization emerged in the first 5 min and progressed over to the second and third 5 min blocks only in the MOR-P group. For the second experiment, 4 groups received MOR and 4 groups VEH, and were then returned to their home cage and after 5, 15, 30 or 60 min post-injection, were euthanized for ERK measurements in VTA and NAc. ERK activation increased and peaked at 5 min post injection in the MOR group and then declined to VEH levels by 30 min. Another two groups received either MOR or VEH immediately before a 5 min arena test and ERK was measured immediately post-test. MOR had no effect on locomotion but increased ERK in the VTA and NAc. The peak ERK activation in VTA reflected activation of reward systems by morphine that reinforced locomotor behavior and with repeated treatments, induced a sensitization effect.

Morphine administered post-trial induces potent morphine conditioned effects if the context is novel but not if the context is familiar.

Morphine administered shortly after exposure to a novel environment induces potent locomotor stimulant conditioning. Environmental novelty is important as pre-exposure (PE) to a stimulus can attenuate the capacity to acquire conditioned stimulus (CS). Here, the importance of environmental novelty for the efficacy of an open-field to become a CS for elicitation of a morphine conditioned response was assessed by comparing the effects of morphine administered post-trial following a 5 min exposure to a novel environment versus a PE environment. Four groups of rats (2 vehicle and 2 morphine groups) were used. Two groups received ten daily 5 min non-drug PEs to an open-field arena and the other two groups were not pre-exposed to the environment. Subsequently, all groups received post-trial injections of either vehicle or morphine immediately after each of five daily 5 min sessions in the open-field. Importantly, on the first day of testing prior to the first post-test morphine administration, the locomotor activity of the novel and PE groups was not different. Over the 5 post-trial morphine treatments, the activity of the PE morphine group, the PE vehicle and the novel environment vehicle groups did not change and were equivalent. In contrast, in the novel environment morphine group, a conditioned hyper-activity response increased with repeated post-trial morphine treatments. For the morphine group it is suggested that the novel environment initiated a post-trial stimulus trace that occurred in temporal contiguity with the post-trial drug response and enabled the trace to become a CS for the morphine unconditioned response. In contrast, PE induced a latent inhibition effect in the PE morphine group, thus the post-trial CS trace was insufficient to become associated to the morphine response and no conditioning occurred. In addition to conventional drug induced Pavlovian delay conditioning, the findings are suggestive of drug induced Pavlovian trace conditioning.

Drugs and memory: Evidence that drug effects can become associated with contextual cues by being paired post-trial with consolidation/re-consolidation. Mini review.

An extensive literature has validated the critical importance of a brief post-trial consolidation period for the incorporation of an experience into memory. Importantly, during this active consolidation state the memory formation is vulnerable to modification. While the subsequent stabilization of the memory makes it relatively resistant to modification, conditioned drug cues that re-activate the cue drug state association can initiate a re-consolidation process and during this re-consolidation the drug-cue association again becomes briefly unstable and sensitive to modification by post-trial treatments. Although most post-trial treatments shown to interact with memory consolidation processes have been used with instrumental learning protocols, this review is focused on recent findings that indicate that psycho-stimulant drug responses induced by apomorphine and morphine during the post-trial consolidation/re-consolidation state can become incorporated into the memory process. As a consequence, these post-trial drug treatment effects can be expressed in a subsequent non-drug test as behavioral responses comparable to the drug induced responses. In fact, apomorphine and morphine when administered post-trial can induce sensitization/conditioned effects that mirror the effects generated when these same drugs are administered in the presence of contextual cues. In addition, it has been shown that apomorphine given at stimulant/inhibitory dopaminergic dose levels post-trial during re-consolidation of a conditioned drug behavior can intensify/reverse the drug conditioning previously induced by apomorphine, morphine or haloperidol. The apparent efficacy of a post-trial drug state induced by a psycho-stimulant drug during consolidation/re-consolidation to become incorporated into contextual memory points up an alternative way, in addition to Pavlovian conditioning, by which psycho-stimulant drug effects can become embedded into an engram activated by contextual cues. These findings further suggest that drug treatments can be used to counter-condition the re-consolidated conditioned addictive drug response to substantially reduce the salience and motivational significance the conditioned association induced by the addictive drug.

Post-trial low dose apomorphine prevents the development of morphine sensitization.

The development of sensitization is one of the hallmarks of addictive drugs. Consistent with this relationship many studies have demonstrated that the highly addictive opioid agonist morphine induces sensitization effects. In this study, we administered morphine (10 mg/kg) (MOR) to induce sensitization. In that sensitization is considered to involve associative processes and that dopamine activity is an important contributor to learning and memory processes, we administered a dopamine inhibitory treatment using apomorphine (0.05 mg/kg) (APO) during memory consolidation following a morphine sensitization treatment protocol. Seemingly, a decrease in dopamine activity during consolidation would impair the salience of the association of the morphine response with the contextual cues during consolidation and interfere with the development of morphine sensitization. In two separate experiments, MOR or vehicle (VEH) were administered pre-trial and either VEH or APO were administered post-trial over 5 and 10 days of treatment, respectively. In both the 5 and 10 drug treatment sessions post-trial experiments, MOR groups given VEH immediately post-trial exhibited strong sensitization effects. These sensitization effects were substantially attenuated in the MOR groups given APO immediately post-trial but not in the MOR groups given APO after a 15 min. post-trial delay. In subsequent conditioning and sensitization challenge tests, the MOR groups that had been given APO immediately post-trial exhibited diminished sensitization and conditioned responses relative to MOR groups that had received VEH or APO delayed post-trial. This MOR-APO interaction effect was unique in that it occurred post-trial so that it was only expressed in a pre-trial test in which only MOR was administered. Seemingly, the inhibitory dopamine effect of APO was incorporated into memory during the post-trial consolidation process suggesting that drug/drug interactions can occur during consolidation.

Morphine administered post-trial can induce potent conditioned morphine effects.

Morphine has substantial pro-dopamine effects and in rodents, this is expressed in behavior as increased locomotor activation. Here we administered post-trial 3 dose levels of morphine (3.0, 5.0 and 10.0 mg/kg) or vehicle either immediately or after a 15 min delay to different groups of rats following a brief (5 min) exposure to a novel test environment. Three post-trial injections were administered on three successive days. One day after the first post-trial morphine injections, the non-drug activity levels in the immediate post-trial morphine treatment groups were selectively increased compared to vehicle groups. The activity effects were potentiated with repeated immediate post-trial morphine treatments but the same morphine treatments given after a 15 min post-trial delay did not increase activity in any tests and did not differ from vehicle. Subsequently, all groups were given 5 daily non-drug test sessions as an extinction protocol. The increased activity levels in the 5.0 and 10.0 mg/kg immediate post-trial morphine groups were sustained over the five extinction sessions. Two days later all groups were given a 30 min non-drug test and the 5.0 and 10.0 immediate post-trial groups continued to exhibit a heightened level of activity relative to vehicle restricted to the initial 10 min of the test session. There were no other group differences. The findings that the locomotor stimulant effects in the immediate post-test morphine groups occurred on non-drug tests and that the same morphine treatments given 15 min post-test were without effect are consistent with a conditioned morphine effect. In that acquisition of familiarization with a new environment is a basic learning process that engages consolidation mechanisms, it is possible that the immediate post-trial morphine effects that occur concurrently with consolidation can become incorporated into this consolidation process and subsequently be expressed as a conditioned drug effect.

Medial prefrontal cortex ERK and conditioning: Evidence for the association of increased medial prefrontal cortex ERK with the presence/absence of apomorphine conditioned behavior using a unique post-trial conditioning/extinction protocol.

Increases in medial prefrontal cortex ERK have been linked to learning and memory processes. In the present study separate groups of rats initially underwent testing in an open-field paired with either 2.0 mg/kg apomorphine or vehicle injections. Subsequently, in a brief conditioning 5 min. test the paired apomorphine group manifested a conditioned hyperactivity response. The vehicle/apomorphine groups were then subdivided into two vehicle and two apomorphine subgroups matched for their activity scores in this conditioning test. Following another apomorphine/vehicle pairing in the test environment the groups received 3 additional 5 min. non-drug conditioning tests in which the groups received post-trial vehicle/apomorphine treatments. The vehicle groups received vehicle either immediately or 15 min. after the first two of the three conditioning tests and the apomorphine groups received 2.0 mg/kg either immediately or 15 min. after the first two of the three conditioning tests. In the first conditioning test both of the apomorphine groups exhibited equivalent conditioned responses. By the third test, the conditioned response of the immediate post-trial apomorphine group remained robust whereas conditioned response of the 15 min. apomorphine post-trial group was extinguished. Immediately following the third conditioning test, the animals were euthanized and ERK was measured in the medial prefrontal cortex and the nucleus accumbens. ERK was enhanced in both brain areas, selectively in the immediate apomorphine post-trial group. Increased ERK activity linked to the presence of the apomorphine conditioned response coupled with the absence of increased ERK activity following extinction of the apomorphine conditioned response suggests that ERK activity immediately following a conditioning test is an indicator of activity in brain systems with substantial dopaminergic input that are important in learning and memory. The facilitative effects of the immediate post-trial apomorphine treatment on the conditioned response are also consistent with the proposition that immediate post-trial dopaminergic drug treatments can modify the re-consolidation of conditioned behavior.

Reversal of morphine conditioned behavior by an anti-dopaminergic post-trial drug treatment during re-consolidation.

Morphine has potent pro-dopamine effects that can be manifested as hyper-locomotion and these behavioral effects can undergo conditioning and sensitization. The aim of the present study was to assess whether an inhibitory dopaminergic post-trial treatment (0.05 mg/kg apomorphine) given during re-consolidation could reduce morphine conditioning. To induce conditioned morphine hyperactivity and control for morphine exposure, a paired/unpaired Pavlovian conditioning protocol was used. The morphine paired groups received morphine in the open-field test arena and the unpaired groups received the same morphine (10 mg/kg) treatments but in a different environment. The morphine treatments were administered once per day for 5 days. With repeated treatments, the paired morphine groups developed a sensitized hyper-locomotion response whereas the unpaired morphine groups did not differ from vehicle groups. Subsequently, the paired, unpaired and vehicle groups were given four daily non-drug 5 min conditioning tests. In these conditioning tests, the paired but not the unpaired and vehicle groups exhibited a conditioned locomotor stimulant response. These groups were subdivided into matched groups and received either vehicle or 0.05 mg/kg apomorphine either during re-consolidation immediately post-test or after re-consolidation 15 min post-test. In the immediate post-trial treatment groups, the morphine conditioned response in the paired group was eliminated after only one post-trial apomorphine treatment. The same immediate 0.05 mg/kg apomorphine post-trial treatments had no effect on the unpaired morphine or vehicle groups. In the paired group that received vehicle immediately post-trial, the conditioned response remained robust and unchanged over the four conditioning tests. In the post-trial 15 min delay treatment groups, the post-trial apomorphine treatments had no effect on the morphine conditioned response. These results showed that the inhibition of dopamine activity by apomorphine during the re-consolidation of a cue activated morphine conditioned response eliminated morphine conditioned effects. In that morphine conditioned effects are important for the initiation of addiction and in triggering drug craving and relapse, this finding has potential relevance to opioid addiction treatment.

Repeated pre-trial and post-trial low and high dose apomorphine treatments induce comparable inhibitory/excitatory sensitization and conditioned drug effects.

This investigation was undertaken to compare the sensitization/conditioned effects induced by apomorphine given pre-trial versus administered immediately post-trial or 15 min post-trial. We measured the effects on locomotor activity of 5 daily apomorphine treatments induced by an inhibitory low auto-receptor dose (0.05 mg/kg) and a stimulatory high postsynaptic dose (2.0 mg/kg). Three sets of four groups were used and each set of four groups was comprised of two vehicle and two apomorphine groups (0.05/2.0 apomorphine). The only difference among the three sets of four groups was when the treatments were administered relative to placement in the novel environment. One set received the treatment pre-test, another set was injected immediately after and the third set injected 15 min after 5 min test sessions in a novel environment. The repeated pre and immediate post-test apomorphine treatments induced locomotor sensitization over the 5 days of treatment. The low dose pre and immediate post-test treatments progressively decreased locomotion and the high dose pre and immediate post-test progressively increased locomotion. Critically, the tests for the immediate post-test groups were non-drug and for both the pre-test and immediate post-test groups, sensitization effects did not occur until the second test day. To control for non-associative apomorphine effects, the same apomorphine treatments were given post-test after a 15 minute delay and were found to be equivalent to vehicle. In a subsequent conditioning test, both the pre and immediate post-test low dose apomorphine groups showed conditioned behavioral inhibition and the pre and immediate post-test high dose apomorphine groups showed conditioned behavioral stimulation. We propose that the inhibitory low dose apomorphine decreased the salience/incentive of the novel environment association and thereby decreased the behavioral response and conversely that the high dose excitatory apomorphine treatment increased the salience/incentive value of the novel environment association and potentiated the behavioral response.

Feasibility of Incremental 2-Times Weekly Hemodialysis in Incident Patients With Residual Kidney Function.

INTRODUCTION: We hypothesized that at least half of incident hemodialysis (HD) patients on 3-times weekly dialysis could safely start on an incremental, 2-times weekly HD schedule if residual kidney function (RKF) had been considered. METHODS: RKF is assessed in all our HD patients. This single-center, retrospective cohort study of incident adult HD patients, who survived ≥6 months on a 3-times weekly HD regimen and had a timed urine collection within 3 months of starting HD, assessed each patient's theoretical ability to achieve adequate urea clearance, ultrafiltration rate, and hemodynamic stability if on 2-times weekly HD. RESULTS: Of the 410 patients in the cohort, we found that 112 (27%) could have optimally and 107 (26%) could have been appropriately considered for 2-times weekly incremental HD. In general, diuretics were underutilized in >50% of subjects who had adequate RKF urea clearance. The optimal 2-times weekly patients had better potassium and phosphorus control. The correlation coefficient of calculated residual kidney urea clearance with 24-hour urine volume and with kinetic model residual kidney clearance was 0.68 and 0.99, respectively. DISCUSSION: More than 50% of incident HD patients with RKF have adequate kidney urea clearance to be considered for 2-times weekly HD. When additionally ultrafiltration volume and blood pressure stability are taken into account, more than one-fourth of the total cohort could optimally start HD in an incremental fashion.

ERK activation in the prefrontal cortex by acute apomorphine and apomorphine conditioned contextual stimuli.

The activation of extracellular signal-regulated kinase protein (ERK) has been linked to the adaptive responses to environmental changes and memory. The aim of this study was to measure ERK activation in primary dopamine projection areas namely, the prefrontal cortex and the nucleus accumbens, following a conditioned dopaminergic drug response. Initially, the effect of unconditioned apomorphine (2.0mg/kg) administration on ERK activation was measured and the results showed an increase in ERK for both brain regions. Subsequently, two experiments were conducted to assess ERK activation in these two areas following apomorphine conditioned contextual stimuli. In experiment 1, rats received 5 daily injections of 2.0mg/kg apomorphine or vehicle immediately prior to placement in an open-field. After a withdrawal period of two days, a conditioning test was conducted, in which rats received a 30min non-drug test. Immediately after completion of the test, an immunohistochemical protocol was carried out to measure ERK activation. In experiment 2, a similar test protocol was performed except that the treatments were administered 30min following open-field tests (post-trial experiment). The results showed that the repeated apomorphine treatments given prior to testing induced conditioned effects. An increase in ERK activation was seen in the prefrontal cortex but not in the nucleus accumbens. There was no conditioning response observed in the post-trial experiment and no differential ERK activation. These observations implicate the prefrontal cortex in the associative neuro-adaptive changes induced by dopaminergic stimulation.

The acquisition, extinction and spontaneous recovery of Pavlovian drug conditioning induced by post-trial dopaminergic stimulation/inhibition.

In contextual drug conditioning, the onset of the drug treatment is contiguous with the contextual cues. Evidence suggests that drug conditioning also can occur if there is a discontinuity between the onset of the drug effect and offset of the contextual cues. Here we examine whether post-trial contextual drug conditioning conforms to several Pavlovian conditioning tenets namely: acquisition, extinction and spontaneous recovery. Six groups of rats received apomorphine (0.05 or 2.0mg/kg) and vehicle immediately or after a 15min delay following a 5min non-drug exposure to an open-field during three successive days (conditioning phase). The extinction phase occurred on days 4-8, in which all post-trial treatments were vehicle injections. After 2days of non-testing, the final test was performed. The results showed that on the first test day, the activity levels of the 6 groups were statistically equivalent. On test day 2, there were marked differences in activity levels selectively between the two immediate post-trial apomorphine treatment groups. The immediate low dose apomorphine group displayed a reduction in activity and the immediate high dose group an increase in activity relative to their day 1 levels. The activity levels of both vehicle groups and both apomorphine delay groups remained equivalent to their day 1 activity levels. On test day 3, the differences in activity levels between the two immediate post-trial apomorphine groups increased but the activity levels of the vehicle groups and the 15min delay post-trial apomorphine groups remained unchanged. In the extinction phase, the conditioned activity differences between the two immediate post-trial apomorphine groups were gradually eliminated. During the final test, the activity differences between the immediate post-trial apomorphine groups were partially restored, indicative of spontaneous recovery. These findings are consistent with several basic elements of Pavlovian conditioning and are supportive of drug induced trace conditioning.

Post-trial dopaminergic modulation of conditioned catalepsy: A single apomorphine induced increase/decrease in dopaminergic activation immediately following a conditioned catalepsy response can reverse/enhance a haloperidol conditioned and sensitized catalepsy response.

Haloperidol can induce catalepsy and this drug effect can be conditioned as well as sensitized to contextual cues. We used a paired/unpaired Pavlovian conditioning protocol to establish haloperidol catalepsy conditioned and sensitized responses. Groups of rats were given 10 daily catalepsy tests following administration of vehicle (n=24) or haloperidol (1.0mg/kg) either paired (n=18) or unpaired (n=18) to testing. Subsequently, testing for conditioning was conducted and conditioning and sensitization of catalepsy were observed selectively in the paired group. Immediately following a second test for catalepsy conditioning, the groups were subdivided into 4 vehicle groups, 3 unpaired haloperidol groups and 3 paired haloperidol groups and were given one of three post-trial treatments (vehicle, 0.05mg/kg or 2.0mg/kg apomorphine). One day later the conditioned catalepsy test 3 was carried out and on the next day, a haloperidol challenge test was performed. The post-trial apomorphine treatments had major effects on the paired groups upon both conditioning and the haloperidol challenge test. The low dose apomorphine post-trial treatment enhanced both the conditioned and the haloperidol sensitized catalepsy responses. The high dose apomorphine post-trial treatment eliminated conditioned catalepsy and eliminated the initial acute catalepsy response to haloperidol that was induced in the vehicle control groups. These results demonstrate the sensitivity of conditioned drug cues to modification by increases/decreases in activity of the dopamine system in the immediate post-trial interval after a conditioning trial. This demonstration that post-trial dopaminergic drug treatments can modify conditioned drug behavior has broad implications for conditioned drug effects.

Reciprocal activation/inactivation of ERK in the amygdala and frontal cortex is correlated with the degree of novelty of an open-field environment.

RATIONALE: Phosphorylated extracellular signal-regulated kinase (ERK) has been used to identify brain areas activated by exogenous stimuli including psychostimulant drugs. OBJECTIVE: Assess the role of the amygdala in emotional responses. METHODS: Experimental manipulations were performed in which environmental familiarity was the variable. To provide the maximal degree of familiarity, ERK was measured after removal from the home cage and re-placement back into the same cage. To maximize exposure to an unfamiliar environment, ERK was measured following placement into a novel open field. To assess whether familiarity was the critical variable in the ERK response to the novel open field, ERK was also measured after either four or eight placements into the same environment. ERK quantification was carried out in the amygdala, frontal cortex, and the nucleus accumbens. RESULTS: After home cage re-placement, ERK activation was found in the frontal cortex and nucleus accumbens but was absent in the amygdala. Following placement in a novel environment, ERK activation was more prominent in the amygdala than the frontal cortex or nucleus accumbens. In contrast, with habituation to the novel environment, ERK phosphors declined markedly in the amygdala but increased in the frontal cortex and nucleus accumbens to the level observed following home cage re-placement. CONCLUSIONS: The differential responsiveness of the amygdala versus the frontal cortex and the nucleus accumbens to a novel versus a habituated environment is consistent with a reciprocal interaction between these neural systems and points to their important role in the mediation of behavioral activation to novelty and behavioral inactivation with habituation.

Neuropharmacology of light-induced locomotor activation.

Presentation of non-aversive light stimuli for several seconds was found to reliably induce locomotor activation and exploratory-like activity. Light-induced locomotor activity (LIA) can be considered a convenient simple model to study sensory-motor activation. LIA was previously shown to coincide with serotonergic and dopaminergic activation in specific cortical areas in freely moving and anesthetized animals. In the present study we explore the neuropharmacology of LIA using a receptor antagonist/agonist approach in rats. The non-selective 5-HT2-receptor antagonist ritanserin (1.5-6 mg/kg, i.p.) dose-dependently reduced LIA. Selective antagonism of either the 5-HT2A-receptor by MDL 11,939 (0.1-0.4 mg/kg, i.p.), or the 5-HT2C-receptor by SDZ SER 082 (0.125-0.5 mg/kg, i.p.), alone or in combination, had no significant influence on LIA. Also the selective 5-HT1A-receptor antagonist, WAY 100635 (0.4 mg/kg, i.p.) did not affect LIA. Neither did the preferential dopamine D2-receptor antagonist, haloperidol (0.025-0.1 mg/kg, i.p.) nor the D2/D3-receptor agonist, quinpirole (0.025-0.5 mg/kg, i.p.) affect the expression of LIA. However, blocking the glutamatergic NMDA-receptor with phencyclidine (PCP, 1.5-6 mg/kg, i.p.) dose-dependently reduced LIA. This effect was also observed with ketamine (10 mg/kg, i.p.). These findings suggest that serotonin and dopamine receptors abundantly expressed in the cortex do not mediate light-stimulus triggered locomotor activity. PCP and ketamine effects, however, suggest an important role of NMDA receptors in LIA.