Opioid regulation of spinal cord plasticity: evidence the kappa-2 opioid receptor agonist GR89696 inhibits learning within the rat spinal cord

Spinal cord neurons can support a simple form of instrumental learning. In this paradigm, rats completely transected at the second thoracic vertebra learn to minimize shock exposure by maintaining a hindlimb in a flexed position. Prior exposure to uncontrollable shock (shock independent of leg position) disrupts this learning. This learning deficit lasts for at least 24h and depends on the NMDA receptor. Intrathecal application of an opioid antagonist blocks the expression, but not the induction, of the learning deficit. A comparison of selective opioid antagonists implicated the kappa-opioid receptor. The present experiments further explore how opioids affect spinal instrumental learning using selective opioid agonists. Male Sprague-Dawley rats were given an intrathecal injection (30 nmol) of a kappa-1 (U69593), a kappa-2 (GR89696), a mu (DAMGO), or a delta opioid receptor agonist (DPDPE) 10 min prior to instrumental testing. Only the kappa-2 opioid receptor agonist GR89696 inhibited acquisition (Experiment 1). GR89696 inhibited learning in a dose-dependent fashion (Experiment 2), but had no effect on instrumental performance in previously trained subjects (Experiment 3). Pretreatment with an opioid antagonist (naltrexone) blocked the GR89696-induced learning deficit (Experiment 4). Administration of GR89696 did not produce a lasting impairment (Experiment 5) and a moderate dose of GR89696 (6 nmol) reduced the adverse consequences of uncontrollable nociceptive stimulation (Experiment 6). The results suggest that a kappa-2 opioid agonist inhibits neural modifications within the spinal cord.     

Opioid receptors mediate direct predictive fear learning: evidence from one-trial blocking

Pavlovian fear learning depends on predictive error, so that fear learning occurs when the actual outcome of a conditioning trial exceeds the expected outcome. Previous research has shown that opioid receptors, including μ-opioid receptors in the ventrolateral quadrant of the midbrain periaqueductal gray (vlPAG), mediate such predictive fear learning. Four experiments reported here used a within-subject one-trial blocking design to study whether opioid receptors mediate a direct or indirect action of predictive error on Pavlovian association formation. In Stage I, rats were trained to fear conditioned stimulus (CS) A by pairing it with shock. In Stage II, CSA and CSB were co-presented once and co-terminated with shock. Two novel stimuli, CSC and CSD, were also co-presented once and co-terminated with shock in Stage II. The results showed one-trial blocking of fear learning (Experiment 1) as well as one-trial unblocking of fear learning when Stage II training employed a higher intensity footshock than was used in Stage I (Experiment 2). Systemic administrations of the opioid receptor antagonist naloxone (Experiment 3) or intra-vlPAG administrations of the selective μ-opioid receptor antagonist CTAP (Experiment 4) prior to Stage II training prevented one-trial blocking. These results show that opioid receptors mediate the direct actions of predictive error on Pavlovian association formation.     

Opiate antagonists and long-term analgesic reaction induced by inescapable shock in rats

Five experiments examined the influence of opiate antagonists on both the short-term analgesic reaction resulting 30 min after exposure to inescapable shock and the long-term analgesic reaction resulting after reexposure to shock 24 hr after inescapable shock exposure. Experiment 1 showed that the long-term analgesic reaction could be reduced by administration of naltrexone prior to exposure to inescapable tail shock. Experiment 2 showed that the reduction in the long-term analgesic reaction produced by naltrexone was dose-dependent. Experiment 3 showed that the long-term analgesic reaction could also be reduced by administration of naltrexone prior to reexposure to shock. Experiment 4 showed that the long-term analgesic reaction could be reduced by administration of large dose of naloxone prior to reexposure to shock. Experiment 5 showed that the short-term analgesic reaction was reduced by naltrexone administered prior to inescapable shock. Some implications of these results for the biochemical substrates of both learned helplessness and stress-induced analgesia are discussed.     

Defeat-induced hypoalgesia in the rat: effects of conditioned odors, naltrexone, and extinction

In Experiment 1, male rats were either defeated as a colony intruder by alpha conspecifics or had no defeat experience, and 24 hr later they were given a paw injection of formalin prior to observational tests with or without alpha-colony odors. The combination of defeat and tests with these odors produced conditioned hypoalgesia (i.e., a suppression in paw licking) and freezing. In Experiment 2, defeated rats were given either an injection of naltrexone or saline prior to defeat and 24 hr later prior to testing. An injection of naltrexone prior to defeat increased freezing during defeat and later testing. In contrast, naltrexone during testing did not affect freezing but significantly reduced hypoalgesia. In Experiment 3, a 12-hr exposure session with alpha-colony odors extinguished hypoalgesia in previously defeated rats. These findings are discussed in terms of associative, opioid/nonopioid, and adaptive evolutionary processes.     

Analgesic and opioid involvement in the shock-elicited activity and escape deficits produced by inescapable shock

Three experiments examined the involvement of analgesic processes and endogenous opioids in the production of the shuttlebox escape acquisition and unconditioned activity deficits which follow exposure to inescapable shock. Experiment 1 found that the opiate antagonist naltrexone administered before the inescapable shock session interfered with the shuttlebox escape acquisition deficit which would normally follow. Experiment 2 found naltrexone to completely prevent the unconditioned activity deficit. The final experiment revealed that dexamethasone, a synthetic glucocorticoid which abolishes the analgesia produced by inescapable shock, reversed the activity deficit. These results indicate that endogenous opioids may be involved in the production of both the escape acquisition and activity deficits. They also suggest that the analgesia produced by these opioids may participate in the mediation of the activity deficit, even though analgesia is not involved in producing the shuttlebox acquisition deficit.     

Differential involvement of M1-type and M4-type muscarinic cholinergic receptors in the dorsomedial striatum in task switching

Previous experiments have demonstrated that the rat dorsomedial striatum is one brain area that plays a crucial role in learning when conditions require a shift in strategies. Further evidence indicates that muscarinic cholinergic receptors in this brain area support adaptations in behavioral responses. Unknown is whether specific muscarinic receptor subtypes in the dorsomedial striatum contribute to a flexible shift in response patterns. The present experiments investigated whether blockade of M1-type and/or M4-type cholinergic receptors in the dorsomedial striatum underlie place reversal learning. Experiment 1 investigated the effects of the M1-type muscarinic cholinergic antagonist, muscarinic-toxin 7 (MT-7) infused into the dorsomedial striatum in place acquisition and reversal learning. Experiment 2 investigated the effects of the M4-type muscarinic cholinergic antagonist, muscarinic-toxin 3 (MT-3) injected into the dorsomedial striatum in place acquisition and reversal learning. All testing occurred in a modified cross-maze across two consecutive sessions. Bilateral injections of MT-7 into the dorsomedial striatum at 1 or 2 microg, but not 0.05 microg impaired place reversal learning. Analysis of the errors revealed that MT-7 at 1 and 2 microg significantly increased regressive errors, but not perseverative errors. An injection of MT-7 2 microg into the dorsomedial striatum prior to place acquisition did not affect learning. Experiment 2 revealed that dorsomedial striatal injections of MT-3 (0.05, 1 or 2 microg) did not affect place acquisition or reversal learning. The findings suggest that activation of M1-type muscarinic cholinergic receptors in the dorsomedial striatum, but not M4-type muscarinic cholinergic receptors facilitate the flexible shifting of response patterns by maintaining or learning a new choice pattern once selected.     

东莨菪碱对吗啡诱导的大鼠行为敏感化的影响

药物重复处理导致的行为敏感化与成瘾过程密切相关。本实验检验东莨菪碱对吗啡诱导的大鼠行为敏感化发展和转化的影响。实验一动物分为3组,分别进行生理盐水（对照组）、吗啡（10mg/kg,吗啡组）、吗啡（10mg/kg）＋东莨菪碱（3mg/kg,吗啡-东莨菪碱组）前处理,36小时腹腔注射4次（第1~2天）。自然戒断7天（第3~9天）。第10天,所有动物均使用吗啡（4mg/kg）激发,记录动物的自发活动量;第24天,吗啡组和吗啡-东莨菪碱组动物重复第10天的操作。实验二动物分为3组,分别接受生理盐水（对照组）、吗啡（10mg/kg,吗啡组）、吗啡（10mg/kg,吗啡-东莨菪碱组）处理,36小时腹腔注射4次（第1~3天）;间隔12小时后,3组动物分别接受生理盐水、生理盐水和东莨菪碱（3mg/kg）处理,仍为36小时腹腔注射4次（第3 ~5天）。第6~9天不进行药物处理。第10天和第17天,分别使用吗啡（4mg/kg）激发,记录动物的活动量。记录时间均为两小时(10分钟为一个记录单元)。结果表明,东莨菪碱能够抑制吗啡诱导的行为敏感化的发展,一定程度上也能够延缓行为敏感化的转化但没有阻断这种转化     

Noradrenergic receptor blockade of the NTS attenuates the mnemonic effects of epinephrine in an appetitive light-dark discrimination learning task

These experiments examined the contribution of noradrenergic neurons in the nucleus of the solitary tract (NTS) in mediating the memory-facilitating effects of epinephrine. In Experiment 1, saline or 0.05 or 0.1 mg/kg of epinephrine was given intraperitoneally (ip) to rats after the second day of training in a light-dark Y-maze discrimination task. On a 20-trial retention test given 2 and 7 days later, the 0.1 mg/kg epinephrine group made significantly more correct responses than controls and required fewer trials to reach criterion. In Experiment 2, phosphate-buffered saline or the noradrenergic antagonist dl-propranolol (0.3 or 1.0 microg/0.5 microl) was infused into the NTS prior to an ip injection of saline or 0.1 mg/kg of epinephrine. The memory-enhancing effects of epinephrine were attenuated by the infusion of 0.3 microg/0.5 microl of dl-propranolol into the NTS. These findings indicate an involvement of NTS noradrenergic neurons in mediating the effects of peripheral epinephrine on memory storage processes.     

Immunization of opioid analgesia: Effects of prior escapable shock on subsequent shock-induced and morphine-induced antinociception

In Experiment 1, it was shown that experience with escapable foot shock 4 hr prior to a session of 80 inescapable tail shocks prevented the occurrence of an analgesic response normally observed immediately following the tail shock. It has been suggested by J. W. Grau, R. L. Hyson, S. F. Maier, J. Madden, and J. D. Barchas (Science, 1981, 213, 1409–1411) that the analgesia that occurs following this number of inescapable tail shocks is mediated by endogenous opioid systems. To further explore the influence of escapable shock on opiate-mediated analgesia, Experiment 2 examined the effects of prior escapable shock on the long-term analgesia reaction that occurs upon brief exposure to shock 20 hr after morphine administration. Rats were given escapable shock, inescapable shock, or no shock 4 hr prior to a morphine injection. Twenty hours following the injection, all subjects received 5 brief foot shocks and were then immediately given tail-flick analgesia tests. Subjects which received inescapable shock or no shock prior to the morphine injection displayed a significant analgesic response. However, subjects which received escapable shock prior to morphine were not analgesic following brief exposure to shock. Thus, escapable shock seems to directly influence the activation of opioid analgesia systems.     

Associative vs topographical accounts of the immediate shock-freezing deficit in rats: Implications for the response selection rules governing species-specific defensive reactions

Rats were placed in a novel chamber and were given a single shock, either immediately upon placement in the chamber or after a 2-m delay. During a postshock observation period, delayed shock animals froze while immediate shock rats did not (Experiments 1–5). Additionally, delayed shock animals showed an elevation in defecation, relative to unshocked controls, while immediate shock animals did not (Experiment 1). Freezing and elevated defecation were first found with a 9-s delay between placement and shock, and both responses increased linearly with increasing delays up to at least 81 s (Experiment 2). Immediate shock rats did not show escape-related behaviors when potential escape routes were available (Experiments 3–4). A 2-m preexposure to the chamber, that was separated in time from shock, did not alleviate the immediate shock deficit (Experiments 4–5). The immediate shock deficit was also apparent in a test given 24 h after shock receipt (Experiment 6). If immediate shock rats were later given delayed shock they began to freeze but showed no carryover effects of their prior shock experience (Experiment 6). It was concluded that the immediate shock deficit reflects a deficit in association formation between contextual stimuli and shock rather than a difference in defensive behavioral topography. It also appears that freezing is the dominant conditional response to shock-associated stimuli even though freezing is not unconditionally elicited by the shock itself.     

The impairment of retention induced by pentylenetetrazol in mice may be mediated by a release of opioid peptides in the brain

Pentylenetetrazol (PTZ, 45 mg/kg, ip) impaired retention of a one-trial step-through inhibitory avoidance task when injected into male Swiss mice 10 min after training, as indicated by retention performance 48 h later. The amnestic effect of PTZ was prevented by naltrexone (0.01 or 0.10 mg/kg, ip) administered after training, but prior to PTZ-treatment. On the contrary, neither naltrexone methyl bromide (0.01, 0.10, or 10.0 mg/kg, ip), a quaternarium analog of naltrexone, nor MR2266 (0.01 or 0.10 mg/kg, ip), a putative kappa opiate receptor antagonist, modified the behavioral effects of PTZ. On the other hand, the body seizures produced by PTZ were unaffected by any of the three opiate receptor antagonists that were given before the convulsant. Taken together, these results suggest that the effects of PTZ on retention are mediated, at least in part, by opioid peptides of central origin, and rules out a possible participation of opioid peptides derived from prodynorphin-precursor molecule. Administration of beta-endorphin (0.01 or 0.10 microgram/kg, ip) 10 min prior to testing attenuate the retrograde amnesia caused by PTZ. The effect of beta-endorphin was prevented by the simultaneous administration of naltrexone (0.10 mg/kg, ip) prior to testing. Naltrexone has no effect of its own upon retrieval. These results suggest that the impairment of retention induced by PTZ is probably due, at least in part, to a release of opioid peptides in the brain during the post-training period. PTZ given after training do not affect consolidation or memory storage, as mice thus treated may retrieve the learned information when they are submitted to an appropriate neurohumoral and/or hormonal state in the test session, that is, beta-endorphin injection. Therefore, the action of PTZ would be primarily at the level of the mechanism that make stored information available for late retrieval.     

Involvement of central cholinergic mechanisms in the effects of oxytocin and an oxytocin receptor antagonist on retention performance in mice

Oxytocin (OT, 0.10 microg/kg, sc) impaired retention of a one-trial step-through inhibitory avoidance task when injected into male Swiss mice 10 min after training, as indicated by retention performance 48 h later. In contrast, the immediate post-training administration of the putative oxytocin receptor antagonist d(CH(2))(5)[Tyr(Me)(2), Thr(4), Thy-NH(9)(2)] OVT (AOT, 0.30 microg/kg, sc) significantly enhanced retention performance. Neither OT nor AOT affected response latencies in mice not given footshock on the training trial, and neither the impairing effects of OT nor the enhancing effects of AOT were seen when the training-treatment interval was 180 min, suggesting that both treatments influenced memory storage. The effects of OT (0.10 microg/kg, sc) on retention were prevented by AOT (0.03 microg/kg, sc) given immediately after training, but 10 min prior to OT treatment. The central acting anticholinesterase physostigmine (35, 70, or 150 microg/kg, i.p.), but not its quaternary analogue neostigmine (150 microg/kg, i.p.), reversed the impairment of retention performance induced by OT, whereas low subeffective doses of the centrally active muscarinic cholinergic antagonist atropine (0.5 mg/kg, i.p.) or the central acting nicotinic cholinergic antagonist mecamylamine (5 mg/kg, i.p.), but not methylatropine (0.5 mg/kg, i.p.) or hexamethonium (5 mg/kg, i.p.) prevented the enhancement of retention performance caused by AOT. We suggest that oxytocin negatively modulates the activity of central cholinergic mechanisms during the posttraining period that follows an aversively motivated learning experience, leading to an impairment of retention performance of the inhibitory avoidance response.     

Activation of nociceptin opioid peptide (NOP) receptor impairs contextual fear learning in mice through glutamatergic mechanisms

The present study investigated whether the selective nociceptin opioid peptide (NOP) receptor agonist, Ro64-6198, impairs acquisition of fear conditioning through glutamatergic mechanisms. Systemic administration of Ro64-6198 (0.3 and 1 mg/kg) or the non-competitive NMDA receptor antagonist, MK-801 (0.03 and 0.1 mg/kg) prior to conditioning severely impaired contextual but not cued fear learning in C57BL/6N mice. When administered together at sub-effective doses, Ro64-6198 (0.5 mg/kg) and MK-801 (0.05 mg/kg), synergistically impaired contextual fear learning, but left cued fear learning intact. We next used the immediate shock deficit paradigm (ISD) to examine the effects of Ro64-6198 and MK-801 on contextual memory formation in the absence of the foot-shock. As expected, naive mice that were shocked briefly after being placed in the training chamber displayed no contextual fear conditioning. This learning deficit was elevated by prior exposure of mice to the training context. Furthermore, administration of Ro64-6198 and MK-801, either separately at amnesic doses (1 mg/kg and 0.1 mg/kg, respectively) or concomitantly at sub-effective doses (0.5 mg/kg and 0.05 mg/kg, respectively) significantly reduced the facilitating effects of context preexposure. These findings demonstrate the existence of functional antagonism between NOP and NMDA receptors that predominantly contributes to modulation of conditioned fear learning which involves spatial-processing demands.     

Exposure to inescapable shock produces both activity and associative deficits in the rat

Interference with shuttle-box escape learning following exposure to inescapable shock is often difficult to obtain in rats. The first experiment investigated the role of shock intensity during escape training in the apparent fragility of the effect. Experiment 1A demonstrated that the magnitude of the interference effect was systematically related to shock intensity during shuttle-box testing. At .6 mA, a robust effect was obtained, whereas at .8 mA and 1.0, little or no deficit in the escape performance of inescapably shocked rats was observed. Experiment 1B demonstrated that the deficit observed in Experiment 1A depended upon whether or not rats could control shock offset. Experiment 2 suggested that preshock may suppress activity and that higher shock levels may overcome this deficit. Experiment 3 tested this as the sole cause of the escape deficit by requiring an escape response which exceeded the level of activity readily elicited by a 1.0-mA shock in both restrained and preshocked rats. In such a task, preshocked rats performed more poorly than did restrained controls. These results are consistent with the possibility that inescapable shock may, in addition to reducing activity, produce an associative deficit. Experiment 4 more clearly demonstrated that inescapable shock produces deficits in performance which cannot be expleined by activity deficits and which appear to be associative in nature. It was shown that inescapable shock interfered with the acquisition of signaled punishment suppression but not CER suppression. The theoretical implications of these data for explanations of the manner in which prior exposure to inescapable shock interferes with escape learning were discussed.     

Opioid modulation of Fos protein expression and olfactory circuitry plays a pivotal role in what neonates remember

Paradoxically, fear conditioning (odor-0.5 mA shock) yields a learned odor preference in the neonate, presumably due to a unique learning and memory circuit that does not include apparent amygdala participation. Post-training opioid antagonism with naltrexone (NTX) blocks consolidation of this odor preference and instead yields memory of a learned odor aversion. Here we characterize the neural circuitry underlying this switch during memory consolidation. Experiment 1 assessed post-training opioid modulation of Fos protein expression within olfactory circuitry (olfactory bulb, piriform cortex, amygdala). Odor-shock conditioning with no post-training treatment (odor preference) induced significant changes in Fos protein expression in the granule cell layer of the olfactory bulb and anterior piriform cortex. Post-training opioid receptor antagonism (odor aversion) prevented the learning-induced changes in the anterior piriform cortex and also induced significant changes in Fos protein expression in the central nucleus of the amygdala. Experiment 2 assessed intra-amygdala opioid modulation of neonate memory consolidation. Post-training infusion of NTX within the amygdala permitted consolidation of an odor aversion, while vehicle-infused pups continued to demonstrate an odor preference. Overall, results demonstrate that opioids modulate memory consolidation in the neonate via modulating Fos protein expression in olfactory circuitry. Furthermore, these results suggest that opioids are instrumental in suppressing neonate fear behavior via modulating the amygdala.     

The hippocampal dentate gyrus is essential for generating contextual memories of fear and drug-induced reward

The hippocampus is believed to play a role in processing information relative to the context in which emotionally salient experiences occur but evidence on the specific contribution of the hippocampal dentate gyrus (DG) to these processes is limited. Here, we have used two classical behavioral paradigms to study the participation of the dorsal DG in context-conditioned reward and context-conditioned fear. Rats received intra-hippocampal vehicle or colchicine injections (4 microg/microl solution; 0.2 microl injections at 10 sites) that damaged the DG but spared other hippocampal subfields. In the first experiment, we used a place conditioning procedure pairing cocaine exposure (20 mg/kg, i.p.) with a specific context and vehicle treatment with another. While rats with sham lesions exhibited preference for the cocaine-paired context following conditioning, rats with lesions of the DG showed no evidence of cocaine-induced place preference. In the second experiment, rats with sham or colchicine lesions received a foot shock in a given context and conditioned freezing was measured upon reexposure to the shock-paired context (2, 24, 48 and 96 h after conditioning). Rats with sham lesions exhibited high levels of conditioned freezing when exposed to the conditioning context but rats with lesions of the DG showed impaired conditioning, behaving as controls that had experienced shock in a different context. These observations indicate that the integrity of the DG is essential for establishing a coherent representation of the context to which emotional experiences, either hedonic or aversive, are bound.     

Pharmacological evidence of a central effect of naltrexone, morphine, and beta-endorphin and a peripheral effect of met- and leu-enkephalin on retention of an inhibitory response in mice

Immediate post-training administration of the central acting opioid receptor antagonist naltrexone (0.01-1.00 mg/kg) facilitated 48-h retention of a one-trial inhibitory avoidance task. An inverted-U dose-response curve was obtained. In this dose range naltrexone did not significantly affect response latencies of mice not given a footshock during the training. However, higher doses of naltrexone (3.0 and 10.0 mg/kg) increased latencies of both shocked and unshocked mice. The peripheral-acting opioid receptor blocker, naltrexone methyl bromide (MR 2263) (0.01-10.00 mg/kg), did not significantly influence retention latencies of either shocked or unshocked mice. Further, MR 2263 (0.1, 1.0, or 10.0 mg/kg) did not block the retention impairment produced by concurrently administered morphine (3.0 mg/kg) or beta-endorphin (0.1 microgram/kg). These findings indicate that the effect of these agonists on memory are not due to a peripheral influence. However, MR 2263 does prevent the memory-impairing effect of both metenkephalin (1.0 microgram/kg) and leu-enkephalin (0.3 microgram/kg) on retention. Those results suggest that enkephalins affect retention through influences initiated peripherally. Thus, different sites and mechanisms of action for beta-endorphin and the enkephalins are proposed.     

Open field habituation learning is improved by nicotine and attenuated by mecamylamine administered posttrial into the nucleus accumbens

Using the paradigm of habituation learning in the open field, we tested the effects of unilateral microinjections of the agonist nicotine (8.0, 40.0, and 80.0 microg) and the nicotine receptor antagonist mecamylamine (0.1, 1.0, 10.0 microg) into the core of the nucleus accumbens. When injected posttrial, that is, immediately after the first exposure to the open field, nicotine dose-dependently enhanced behavioral habituation during the test on the following day, indicating a facilitation of memory, whereas mecamylamine impaired habituation at the highest dose, but not at the two lower doses. When injected 5 h after the learning trial, nicotine (40 microg) and mecamylamine (10 microg) impaired habituation on the subsequent day. A control experiment did not provide evidence for possible proactive effects of mecamylamine. These findings are discussed with respect to the possible behavioral functions of cholinergic, and especially nicotinic, mechanisms in the nucleus accumbens. They may also be relevant for understanding cholinergic-linked psychopathologies such as Alzheimer's disease, since the nucleus accumbens is one of the sites where cholinergic neurons are lost in this neurodegenerative disease.     

Histamine reverses a memory deficit induced in rats by early postnatal maternal deprivation

Early partial maternal deprivation causes long-lasting neurochemical, behavioral and brain structural effects. In rats, it causes a deficit in memory consolidation visible in adult life. Some of these deficits can be reversed by donepezil and galantamine, which suggests that they may result from an impairment of brain cholinergic transmission. One such deficit, representative of all others, is an impairment of memory consolidation, clearly observable in a one-trial inhibitory avoidance task. Recent data suggest a role of brain histaminergic systems in the regulation of behavior, particularly inhibitory avoidance learning. Here we investigate whether histamine itself, its analog SKF-91844, or various receptor-selective histamine agonists and antagonists given into the CA1 region of the hippocampus immediately post-training can affect retention of one-trial inhibitory avoidance in rats submitted to early postnatal maternal deprivation. We found that histamine, SKF-91844 and the H2 receptor agonist, dimaprit enhance consolidation on their own and reverse the consolidation deficit induced by maternal deprivation. The enhancing effect of histamine was blocked by the H2 receptor antagonist, ranitidine, but not by the H1 receptor antagonist pyrilamine or by the H3 antagonist thioperamide given into CA1 at doses known to have other behavioral actions, without altering locomotor and exploratory activity or the anxiety state of the animals. The present results suggest that the memory deficit induced by early postnatal maternal deprivation in rats may in part be due to an impairment of histamine mediated mechanisms in the CA1 region of the rat hippocampus.     

Differential dependence of Pavlovian incentive motivation and instrumental incentive learning processes on dopamine signaling

Here we attempted to clarify the role of dopamine signaling in reward seeking. In Experiment 1, we assessed the effects of the dopamine D(1)/D(2) receptor antagonist flupenthixol (0.5 mg/kg i.p.) on Pavlovian incentive motivation and found that flupenthixol blocked the ability of a conditioned stimulus to enhance both goal approach and instrumental performance (Pavlovian-to-instrumental transfer). In Experiment 2 we assessed the effects of flupenthixol on reward palatability during post-training noncontingent re-exposure to the sucrose reward in either a control 3-h or novel 23-h food-deprived state. Flupenthixol, although effective in blocking the Pavlovian goal approach, was without effect on palatability or the increase in reward palatability induced by the upshift in motivational state. This noncontingent re-exposure provided an opportunity for instrumental incentive learning, the process by which rats encode the value of a reward for use in updating reward-seeking actions. Flupenthixol administered prior to the instrumental incentive learning opportunity did not affect the increase in subsequent off-drug reward-seeking actions induced by that experience. These data suggest that although dopamine signaling is necessary for Pavlovian incentive motivation, it is not necessary for changes in reward experience, or for the instrumental incentive learning process that translates this experience into the incentive value used to drive reward-seeking actions, and provide further evidence that Pavlovian and instrumental incentive learning processes are dissociable.