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.

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.

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.

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.

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.

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.

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.

Cocaine conditioning: reversal by autoreceptor dose levels of 8-OHDPAT.

In order to investigate the contribution of serotonergic effects of cocaine to Pavlovian conditioning of cocaine locomotor stimulant effects, two experiments were conducted in which groups of rats (N=10) received cocaine treatments (10 mg/kg) paired or unpaired to placement in an open-field environment. Initially, a cocaine conditioned locomotion stimulant effect was established. Next, additional Coc-P and Coc-UP pairings were carried out in conjunction with pretreatment injections of the 5-HT1A agonist, 8-OHDPAT (0.01, 0.025 and 0.05 mg/kg) or saline. In experiment 1, the Coc-P group which received the saline pretreatment again exhibited conditioning but in the 8-OHDPAT pretreatment Coc-P group conditioning was eliminated. In the second experiment, the protocol of the first experiment was repeated but expanded in the post-conditioning phase to include an 8-OHDPAT plus the 5-HT1A antagonist pretreatment Coc-P group. As in the first experiment, the 8-OHDPAT pretreatment Coc-P group did not exhibit a cocaine conditioned locomotion stimulant effect; whereas, the saline pretreatment Coc-P and the 8-OHDPAT plus WAY-100635 pretreatment Coc-P groups did exhibit the cocaine conditioned locomotion stimulant effect. These findings are consistent with an important role for serotonin in the maintenance of cocaine Pavlovian conditioned effects.

The expression of locomotor sensitization to apomorphine is dependent on time interval between injection and testing.

This study examined the onset of locomotor sensitization induced by apomorphine as a function of the temporal delay between drug injection and testing. In experiment 1, rats received three daily administrations of 2.0 mg/kg apomorphine or vehicle either immediately (0 min) or 20 min before being placed into the test environment for 20 min test sessions. Apomorphine given immediately before testing induced a stimulant effect during the first session and sensitization by the second session. However, when testing was delayed 20 min, apomorphine induced stimulant effects only after the third injection. In experiment 2, separate groups received a single 2.0 (mg/kg) apomorphine/vehicle injection immediately before being placed into the test environment for 60 min. In this experiment, apomorphine induced a stimulant effect at 0-20 and 20-40 min. However, the 20-40 interval increase in locomotion was relative to the low level of activity in the vehicle group and was not greater than the 0-20 min locomotion of the vehicle group. Thus, sensitization depends both on peak drug concentration and habituation state of the control group. The variable post-injection delays could be a useful method to study sensitization because it can avoid ceiling effects and changing baselines in the control groups.

Serotonin and psychostimulant addiction: focus on 5-HT1A-receptors.

Serotonin(1A)-receptors (5-HT(1A)-Rs) are important components of the 5-HT system in the brain. As somatodendritic autoreceptors they control the activity of 5-HT neurons, and, as postsynaptic receptors, the activity in terminal areas. Cocaine (COC), amphetamine (AMPH), methamphetamine (METH) and 3,4-methylenedioxymethamphetamine ("Ecstasy", MDMA) are psychostimulant drugs that can lead to addiction-related behavior in humans and in animals. At the neurochemical level, these psychostimulant drugs interact with monoamine transporters and increase extracellular 5-HT, dopamine and noradrenalin activity in the brain. The increase in 5-HT, which, in addition to dopamine, is a core mechanism of action for drug addiction, hyperactivates 5-HT(1A)-Rs. Here, we first review the role of the various 5-HT(1A)-R populations in spontaneous behavior to provide a background to elucidate the contribution of the 5-HT(1A)-Rs to the organization of psychostimulant-induced addiction behavior. The progress achieved in this field shows the fundamental contribution of brain 5-HT(1A)-Rs to virtually all behaviors associated with psychostimulant addiction. Importantly, the contribution of pre- and postsynaptic 5-HT(1A)-Rs can be dissociated and frequently act in opposite directions. We conclude that 5-HT(1A)-autoreceptors mainly facilitate psychostimulant addiction-related behaviors by a limitation of the 5-HT response in terminal areas. Postsynaptic 5-HT(1A)-Rs, in contrast, predominantly inhibit the expression of various addiction-related behaviors directly. In addition, they may also influence the local 5-HT response by feedback mechanisms. The reviewed findings do not only show a crucial role of 5-HT(1A)-Rs in the control of brain 5-HT activity and spontaneous behavior, but also their complex role in the regulation of the psychostimulant-induced 5-HT response and subsequent addiction-related behaviors.

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.

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.

Cocaine conditioned behavior: a cocaine memory trace or an anti-habituation effect.

Whether cocaine locomotor conditioning represents a cocaine positive effect; i.e., a Pavlovian cocaine conditioned response; or, a cocaine negative effect; i.e., interference with habituation to the test environment, is a subject of some controversy. Three separate experiments were conducted to compare the behavior (locomotion and grooming) of separate groups of rats given 1, 9 or 14 cocaine (10 mg/kg) treatments paired/unpaired with placement into an open-field arena. The behavior of the cocaine groups on subsequent saline tests were compared with the habituation rates of saline treated rats. After one cocaine pairing with the test environment, the subsequent behavior of the cocaine paired group on saline tests was similar to a non-habituated control group. In the two experiments with repeated cocaine pairings to the test environment, the subsequent behavior of the cocaine treated groups did not parallel that of the non-habituated saline control groups. These results were not explicable in terms of cocaine anti-habituation effects. It is suggested that cocaine contextual cues paired with cocaine treatment can activate cocaine memory traces which with subsequent cocaine treatments are reinforced and strengthened. In this way repeated cocaine use can forge conditioned stimulus connections to the cocaine behavioral response that are highly resistant to extinction.

Cocaine effects on behavioral responding to a novel object placed in a familiar environment.

It is well established that cocaine stimulant effects are potentiated in a novel environment. The relationship between cocaine and novel stimuli, however, remains poorly understood. In this study, we examined the effects of different dose levels of cocaine (5.0, 10.0 and 20.0 mg/kg) administered to separate groups of rats (N=10) on attentional behavior to a small novel object stimulus placed within a central zone (CZ) of a familiar open-field environment. This method has been used to assess attentional function in young animals, brain damaged animals and drug treated animals. In previous studies, we have shown that attention to a novel object stimulus can be quantified by an animal's contact time with the object. Following a series of pre-exposures to the test environment without the novel object, we found that cocaine in a brief 10 min test session with the novel object present produced a dose related decrease in mean contact time with the novel object. In contrast caffeine (5.0, 10.0 and 20.0 mg/kg), which induced a locomotor stimulant effect equivalent to cocaine, did not impair novel object contact time. Correlational analyses indicated absence of significant negative correlation coefficients of locomotor activity and contact time with the novel object. These considerations indicate that the observed cocaine impairment of attention to the novel stimulus is not attributable to hyperactivity per-se. Furthermore, cocaine, but not caffeine, induced a dose related decrease in the duration of spontaneous grooming. Thus, cocaine appears to diminish an animal's overall capability to maintain a behavioral process (i.e., investigate a novel object stimulus and/or engage in spontaneous bodily directed activity such as grooming). Altogether, the findings obtained in the present study indicate that cocaine impairs an animal's ability to sustain attention to stimuli and suggest a behavioral state analogous to an attention deficit disorder.

Effects on spontaneous and cocaine-induced behavior of pharmacological inhibition of noradrenergic and serotonergic systems.

Cocaine-induced increases in dopamine (DA) contribute importantly to cocaine effects on behavior but, the role of concomitant increases in norepinephrine (NE) and serotonin (5-HT) is less well understood. In order to selectively block the increases in NE and 5-HT evoked by cocaine, autoreceptor preferring low doses (0.01, 0.025 and 0.05 mg/kg) of the a2 agonist, Clonidine or the 5-HT1A agonist, 8-OHDPAT were given as pretreatments 20 min prior to saline or cocaine (10.0 mg/kg) in separate groups of rats (N=10). With pharmacological stimulation of NE and 5-HT autoreceptors, release of these neurotransmitters would be suppressed and, therefore, less available for re-uptake blockade by cocaine. With increasing dose levels, Clonidine had marked inhibitory effects on spontaneous and cocaine-induced locomotion, grooming and rearing. 8-OHDPAT pretreatment also suppressed spontaneous locomotion, grooming and rearing; but, in contrast, did not reduce the cocaine locomotor stimulant effects. 8-OHDPAT, however, did suppress central zone entry and rearing in cocaine treated rats. Using ex vivo methods, we found that 8-OHDPAT selectively reduced 5-HT metabolism in the medial frontal cortex (MFC) and subcortical limbic brain. Clonidine selectively reduced NE metabolism in the MFC, but decreased both DA and 5-HT metabolism in the subcortical limbic brain without affecting NE metabolism. This diverse and broad spectrum of Clonidine effects upon neurotransmitters and behavior is striking and points-up the important, complex and integrative role of NE in brain function. While both Clonidine and 8-OHDPAT can substantially attenuate a number of cocaine behavioral effects, these inhibitory effects appear to be secondary to reductions in the behavioral baseline rather than reversals of cocaine effects.

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.

Intracellular 5-HT 2C-receptor dephosphorylation: a new target for treating drug addiction.

The 5-hydroxytryptamine (5-HT)(2C) receptor has received considerable attention as a target for treating drug addiction. 5-HT(2C)-receptor agonism, however, also induces side-effects. In this article, we review recent findings regarding the involvement of 5-HT(2C) receptors in behaviours related to drug addiction in animals. It was recently shown that 5-HT(2C)-receptor agonist effects can be induced intracellularly using the protein peptide Tat-3L4F, which prevents 5-HT(2C)-receptor dephosphorylation induced by phosphatase and tensin homologue deleted on chromosome 10. The most promising finding is that Tat-3L4F can selectively reduce the potency of addictive drugs by reducing mesolimbic dopamine transmission without eliciting the side-effects of 5-HT(2C)-receptor agonist treatment, thus highlighting its potential use as a strategy to treat drug addiction in humans.

7-OH-DPAT effects on latent inhibition: low dose facilitation but high dose blockade: implications for dopamine receptor involvement in attentional processes.

7-OH-DPAT is a dopamine D2/D3 agonist, which at low doses acts preferentially on D3 receptors but at high doses it acts on D2 and D3 receptors. The present study investigated the contribution of D3 and D2 receptors on latent inhibition (LI) by using two dose levels of 7-OH-DPAT: a low dose, 0.1 mg/kg (D3 receptor activation) and a high dose, 1.0 mg/kg, (D2/D3 receptor activation) in a conditioned emotional response (CER) paradigm. The LI Protocols included CS pre-exposure (10 or 40 CS alone trials), CER induction and a non-drug CER test phase. Additionally, the drug effects upon CER acquisition without LI were assessed using the same treatments and test environment pre-exposure protocols but without the tone CS. The effects of 7-OH-DPAT on crossing, rearing and grooming were also measured in an open field 1 day after the CER test phase. The results showed that the low dose 7-OH-DPAT treatment potentiated LI at 10 but not at 40 CS pre-exposures. The high dose 7-OH-DPAT treatment blocked LI at both the 10 and 40 stimulus pre-exposures; and it also induced hyperactivity. Thus, D3 stimulation induced by a low dose of 7-OH-DPAT can facilitate LI but these effects are contingent upon and are specific to the number of stimulus presentations. Altogether, these findings indicate that D3 stimulation can enhance attentional processes, but D2 stimulation can impair attentional processes.