Glucocorticoid enhancement of dorsolateral striatum-dependent habit memory requires concurrent noradrenergic activity.

Previous findings indicate that post-training administration of glucocorticoid stress hormones can interact with the noradrenergic system to enhance consolidation of hippocampus- or amygdala-dependent cognitive/emotional memory. The present experiments were designed to extend these findings by examining the potential interaction of glucocorticoid and noradrenergic mechanisms in enhancement of dorsolateral striatum (DLS)-dependent habit memory. In experiment 1, different groups of adult male Long-Evans rats received training in two DLS-dependent memory tasks. In a cued water maze task, rats were released from various start points and were reinforced to approach a visibly cued escape platform. In a response-learning version of the water plus-maze task, animals were released from opposite starting positions and were reinforced to make a consistent egocentric body-turn to reach a hidden escape platform. Immediately post-training, rats received peripheral injections of the glucocorticoid corticosterone (1 or 3 mg/kg) or vehicle solution. In both tasks, corticosterone (3 mg/kg) enhanced DLS-dependent habit memory. In experiment 2, a separate group of animals received training in the response learning version of the water plus-maze task and were given peripheral post-training injections of corticosterone (3 mg/kg), the ß-adrenoreceptor antagonist propranolol (3 mg/kg), corticosterone and propranolol concurrently, or control vehicle solution. Corticosterone injections again enhanced DLS-dependent memory, and this effect was blocked by concurrent administration of propranolol. Propranolol administration by itself (3 mg/kg) did not influence DLS-dependent memory. Taken together, the findings indicate an interaction between glucocorticoid and noradrenergic mechanisms in DLS-dependent habit memory. Propranolol administration may be useful in treating stress-related human psychopathologies associated with a dysfunctional DLS-dependent habit memory system.

Peripheral and intra-dorsolateral striatum injections of the cannabinoid receptor agonist WIN 55,212-2 impair consolidation of stimulus-response memory.

The endocannabinoid system plays a major role in modulating memory. In the present study, we examined whether cannabinoid agonists influence the consolidation of stimulus-response/habit memory, a form of memory dependent upon the dorsolateral striatum (DLS). In Experiment 1, rats were trained in a cued platform water maze task in which animals were released from different start points and in order to escape had to find a cued platform which was moved to various spatial locations across trials. Immediately following training, rats received an i.p. injection of the cannabinoid receptor agonist WIN 55,212-2 (1 or 3mg/kg) or a vehicle solution. In Experiment 2, rats were trained in a forced-response version of the water plus-maze task in which a consistent body-turn response was reinforced across trials. Immediately following training, rats received an i.p. injection of WIN 55,212-2 (3 mg/kg) or vehicle. In Experiment 3, rats were trained in the cued platform task and after training received bilateral intra-DLS WIN 55,212-2 (100 ng/.5 µL or 200 ng/.5 µL) or vehicle. In Experiments 1-3, the higher doses of WIN 55,212-2 were associated with significant memory impairments, relative to vehicle-treated controls. The results indicate that peripheral or intra-DLS administration of a cannabinoid receptor agonist impairs consolidation of DLS-dependent memory. The findings are discussed within the context of previous research encompassing cannabinoids and DLS-dependent learning and memory processes, and the possibility that cannabinoids may be used to treat some habit-like human psychopathologies (e.g. posttraumatic stress disorder) is considered.

Peripheral anxiogenic drug injections differentially affect cognitive and habit memory: role of basolateral amygdala.

Findings from single-solution plus-maze tasks that require the use of either place or response learning indicate that post-training intra-basolateral amygdala (BLA) administration of the anxiogenic alpha-2 adrenoreceptor antagonist RS 79948 can both enhance dorsal striatal-dependent response learning and impair hippocampus-dependent place learning. Whether post-training peripheral administration of RS 79948 can also enhance and impair response and place learning respectively, is not known. If peripheral drug administration can also produce this "dual" effect on cognitive and habit memory, it would be of interest to know whether the functional integrity of the BLA is critical. In order to examine these questions, the present experiments combined peripheral administration of RS 79948 with concurrent neural inactivation of the BLA. Adult male Long-Evans rats were trained in place or response learning tasks in a water plus-maze. On days 1-3 of training, rats received post-training peripheral injections of saline or RS 79948 (0.1 mg/kg) combined with intra-BLA injections of saline or the sodium channel blocker bupivacaine (1.0% solution, 0.5 microl). Post-training peripheral injections of RS 79948 enhanced acquisition of response learning, and impaired acquisition of place learning. Bupivacaine infusions into the BLA had no effect on acquisition of either task. However, intra-BLA infusions of bupivacaine blocked both the enhancement of response learning and the impairment of place learning produced by RS 79948. Taken together, the findings indicate that although the functional integrity of BLA is not necessary for acquisition of place and response learning, BLA activity is critical in order for peripheral injections of an anxiogenic drug to differentially modulate hippocampus-dependent and dorsal striatal-dependent memory.

Affective modulation of multiple memory systems.

The hippocampus and caudate nucleus are anatomical components of relatively independent memory systems and recent research has focused on the nature of the interaction between these two systems. The amygdala exerts a general modulatory influence on memory storage processes related, in part, to an organism's level of affective or emotional arousal. Moreover, affective state can influence the use of different memory systems, and the amygdala may mediate this effect of emotion on memory. Recent evidence indicates that the amygdala modulates the separate types of memory mediated by the hippocampus and caudate nucleus. Recent human brain imaging studies also point to both sex- and hemisphere-related asymmetries in amygdala participation in emotionally influenced memory.

Amygdala is critical for stress-induced modulation of hippocampal long-term potentiation and learning.

Stress is a biologically significant factor shown to influence synaptic plasticity and memory functioning in the hippocampus. This study examined the role of the amygdala, a brain structure implicated in coordinating stress behaviors and modulating memory consolidation, in mediating stress effects on hippocampal long-term potentiation (LTP) and memory in rats. Electrolytic lesions of the amygdala effectively blocked the adverse physiological and behavioral effects of restraint and tailshock stress, without impeding the increase in corticosterone secretion to stress. Physiologically, hippocampal slices from stressed animals exhibited impaired LTP relative to slices from unstressed control animals, whereas hippocampal slices from stressed animals with amygdalar lesions exhibited normal LTP. Behaviorally, stressed animals were impaired in retention of a hippocampal-dependent hidden platform version of the Morris water maze task, and this impairment was blocked by amygdalar lesions. In a fixed location-visible platform water maze task that can be acquired by independent hippocampal and nonhippocampal memory systems, stress enhanced the use of nonhippocampal-based memory to acquire the task. These results indicate that an intact amygdala is necessary for the expression of the modulatory effects of stress on hippocampal LTP and memory.

Differential interaction of platelet-activating factor and NMDA receptor function in hippocampal and dorsal striatal memory processes.

The interaction between platelet activating factor (PAF) and NMDA receptor function in hippocampal and dorsal striatal memory processes was examined. In both a hidden and a visible platform water maze task, peripheral post-training injection of MK-801 (0.05 mg/kg) impaired memory. Post-training intrahippocampal infusions of PAF (1.0 microg/0.5 microl) enhanced memory in the hidden platform task, while intradorsal striatal infusion of PAF (1.0 microg/0.5 microl) enhanced memory in the visible platform task. The memory impairing effects of post-training injection of MK-801 was blocked by concurrent intrahippocampal infusion of PAF. In contrast, post-training injection of MK-801 blocked the memory enhancing effects of concurrent intradorsal striatal infusion of PAF. The results suggest that (1) the memory enhancing effects of intracerebral PAF infusion involve an interaction with NMDA receptor function, and (2) the nature of this interaction may represent a differential mechanism mediating the distinct roles of the hippocampus and dorsal striatum in cognitive memory and stimulus-response habit formation, respectively.

Task-dependent role for dorsal striatum metabotropic glutamate receptors in memory.

The effect of post-training intradorsal striatal infusion of metabotropic glutamate receptor (mGluR) drugs on memory consolidation processes in an inhibitory avoidance (IA) task and visible/hidden platform water maze tasks was examined. In the IA task, adult male Long-Evans rats received post-training intracaudate infusions of the broad spectrum mGluR antagonist alpha-methyl-4-carboxyphenylglycine (MCPG; 1.0, 2.0 mM/0.5 microL), the group I/II mGluR agonist 1-aminocyclopentane-1,3-carboxylic acid (ACPD; 0.5 or 1.0 microM/0.5 microL), or saline immediately following footshock training, and retention was tested 24 h later. In the visible- and hidden-platform water maze tasks, rats received post-training intracaudate infusions of ACPD (1.0 microM), MCPG (2.0 mM), or saline immediately following an eight-trial training session, followed by a retention test 24 h later. In the IA task, post-training infusion of ACPD (0.5 and 1.0 microM) or MCPG (1.0 and 2.0 mM) impaired retention. In the IA and visible-platform water maze tasks, post-training infusion of ACPD (1.0 microM), or MCPG (2.0 mM) impaired retention. In contrast, neither drug affected retention when administered post-training in the hidden-platform task, consistent with the hypothesized role of the dorsal striatum in stimulus-response habit formation. When intradorsal striatal injections were delayed 2 h post-training in the visible-platform water maze task, neither drug affected retention, indicating a time-dependent effect of the immediate post-training injections on memory consolidation. It is hypothesized that MCPG impaired memory via a blockade of postsynaptic dorsal striatal mGluR's, while the impairing effect of ACPD may have been caused by an influence of this agonist on presynaptic "autoreceptor" striatal mGluR populations.

Role of dopamine receptor subtypes in the acquisition of a testosterone conditioned place preference in rats.

The present experiments investigated the neurochemical bases of the rewarding properties of testosterone, focusing on the role of dopaminergic function in the acquisition of a testosterone conditioned place preference (CPP). In two experiments for 8 alternating days adult male Long-Evans rats received peripheral injections of testosterone in a water-soluble hydroxypropyl-beta-cyclodextrin inclusion complex (0.8 mg/kg) or saline immediately prior to being confined for 30 min to one of two compartments of a place preference apparatus. On day 10 the rats were given a 20-min test session and allowed access to all compartments of the apparatus. No hormone was injected prior to the test, and the amount of time spent in each compartment of the apparatus was recorded. In each experiment administration of testosterone was found to induce a CPP. Injections of the mixed D1/D2 receptor antagonist alpha-flupenthixol (0.3 mg/kg), the selective D1 antagonist SCH 23390 (0.1 mg/kg), or the selective D2 antagonist sulpiride (20 mg/kg), each blocked acquisition of the testosterone CPP. The findings suggest a role for both dopamine D1 and D2 receptor subtypes in the acquisition of testosterone CPP.

Glutamate infused posttraining into the hippocampus or caudate-putamen differentially strengthens place and response learning.

A cross-maze task that can be acquired through either place or response learning was used to examine the hypothesis that posttraining neurochemical manipulation of the hippocampus or caudate-putamen can bias an animal toward the use of a specific memory system. Male Long-Evans rats received four trials per day for 7 days, a probe trial on day 8, further training on days 9-15, and an additional probe trial on day 16. Training occurred in a cross-maze task in which rats started from a consistent start-box (south), and obtained food from a consistent goal-arm (west). On days 4-6 of training, rats received posttraining intrahippocampal (1 microgram/0.5 microliter) or intracaudate (2 microgram/0.5 microliter) injections of either glutamate or saline (0.5 microliter). On days 8 and 16, a probe trial was given in which rats were placed in a novel start-box (north). Rats selecting the west goal-arm were designated "place" learners, and those selecting the east goal-arm were designated "response" learners. Saline-treated rats predominantly displayed place learning on day 8 and response learning on day 16, indicating a shift in control of learned behavior with extended training. Rats receiving intrahippocampal injections of glutamate predominantly displayed place learning on days 8 and 16, indicating that manipulation of the hippocampus produced a blockade of the shift to response learning. Rats receiving intracaudate injections of glutamate displayed response learning on days 8 and 16, indicating an accelerated shift to response learning. The findings suggest that posttraining intracerebral glutamate infusions can (i) modulate the distinct memory processes mediated by the hippocampus and caudate-putamen and (ii) bias the brain toward the use of a specific memory system to control learned behavior and thereby influence the timing of the switch from the use of cognitive memory to habit learning to guide behavior.

Affective properties of intra-medial preoptic area injections of testosterone in male rats.

On alternating days, adult male Long-Evans rats implanted with unilateral cannulae in the medial preoptic area (MPOA) received intracerebral injections of testosterone (0.05, 0.1 or 0.2 microg/0.5 microl), or saline immediately prior to confinement for 30 min to one of two compartments of a place preference apparatus. All rats received 8 days of pairings (4 hormone and 4 saline). On day 9, the rats were given a hormone-free 20-min test session during which they had access to all compartments of the apparatus. Intra-MPOA injections of testosterone (0.1 microg) produced a conditioned place preference, while injections of a higher dose (0.2 microg) produced a conditioned place aversion. The rewarding effects of intra-MPOA testosterone may in part mediate the facilatory effects of testosterone on motivational aspects of sexual behavior.

Posttraining estrogen and memory modulation.

The present paper provides a review of recent research carried out in this laboratory investigating the effects of posttraining peripheral and intrahippocampal injection of estradiol on memory in rats, and estradiol-acetylcholine interactions in memory modulation. Ovariectomized rats received an eight-trial training session in a hippocampal-dependent hidden platform water maze task. Immediately following training, rats received a posttraining peripheral or intrahippocampal injection of estradiol-cyclodextrin complex or vehicle. Twenty-four hours later rats were returned to the maze for a retention test session, and latency to escape was used as a measure of memory for the previous day's training. Peripheral posttraining injection of estradiol enhances memory relative to vehicle-treated rats. Injections of estradiol given 2 h posttraining has no effect on retention, indicating a time-dependent effect of estradiol on memory storage processes. A time-dependent memory enhancing effect of posttraining intrahippocampal injections of estradiol has also been observed in both male and ovariectomized female rats. The memory enhancing effect of peripheral posttraining injection of estradiol in ovariectomized rats is blocked by a subeffective dose of the acetylcholine muscarinic receptor antagonist scopolamine, suggesting that estradiol interacts with cholinergic systems in memory modulation. Concurrent peripheral posttraining injection of a subeffective dose of estradiol and a subeffective dose of the cholinergic agonist oxotremorine produces a synergistic memory enhancing effect. The findings suggest that: (1) estradiol selectively influences memory storage independent of an effect on nonmnemonic processes, (2) the hippocampus is a potential neuroanatomical site of action mediating estrogenic effects on memory, and (3) estradiol interacts with cholinergic systems in memory modulation.

Effects of posttraining intrahippocampal injections of platelet-activating factor and PAF antagonists on memory.

The present experiments examined the effects of posttraining intrahippocampal injections of the degradative enzyme-resistant methylcarbamyl analog of the bioactive phospholipid platelet-activating factor (mc-PAF) and the platelet-activating factor (PAF) receptor antagonists BN52021 and BN 50730 on memory in male Long-Evans rats trained in a hidden platform version of the Morris water maze. Following an eight-trial training session, rats received a unilateral intrahippocampal injection of mc-PAF (0.5, 1.0, or 2.0 microgram/0.5 microliter), lyso-PAF (1.0 microgram/0.5 microliter), the cell surface PAF receptor antagonist BN 52021 (0.25, 0.5, or 1.0 micrigram/0.5 microliter/, the intracellular PAF receptor antagonist BN 50730 (2.0, 5.0, or 10.0 microgram/0.5 microliter), or vehicle (50% DMSO in 0.9% saline; 0.5 microliter). On a retention test conducted 24 h after training, the escape latencies of rats administered mc-PAF (1.0 or 2.0 microgram) were significantly lower than those of the vehicle-injected controls, demonstrating a memory-enhancing effect of mc-PAF. Injections of lyso-PAF, a structurally similar metabolite of PAF, had no influence on memory, indicating that the memory-enhancing effect of mc-PAF is not caused by membrane perturbation by the phospholipid. The retention test escape latencies of rats administered BN 52021 (0.5 microgram) and BN 50730 (5.0 or 10 microgram) were significantly higher than those of the controls, indicating a memory impairing effect of both PAF antagonists. When mc-PAF, BN 52021, or BN 50730 was administered 2 h posttraining, no effect on retention was observed, indicating a time-dependent effect of the neuroactive substances on memory storage. The findings suggest a role for endogenous PAF in hippocampal-dependent memory processes.

Expression of testosterone conditioned place preference is blocked by peripheral or intra-accumbens injection of alpha-flupenthixol.

Previous evidence indicates that peripheral and intranucleus accumbens injections of testosterone have rewarding effects in male rats as measured in a conditioned place preference (CPP) paradigm. The present study investigated the neurochemical bases of the rewarding properties of testosterone by examining the effect of peripheral and intranucleus accumbens injection of the dopamine receptor antagonist alpha-flupenthixol on expression of testosterone-induced CPP. On alternating days, adult male Long-Evans rats received peripheral injections of testosterone in a water-soluble hydroxypropyl-beta-cyclodextrin (HBC) inclusion complex (0.8 mg/kg) or saline-HBC immediately prior to being confined for 30 min to one of two compartments of a place preference apparatus. All rats received 8 days of pairings (four hormone pairings, four saline pairings). On day 9 the rats were given a 20-min test session during which they had access to all compartments of the apparatus. No hormone was injected prior to the test session; however, rats received a peripheral (20 min prior; 0.2, 0.3 mg/kg) or intra-accumbens (2 min prior, 5.0 micrograms) injection of alpha-flupenthixol or saline. On the test day, rats receiving saline injections spent significantly more time in the compartment previously paired with injections of testosterone than in the compartment previously paired with vehicle injections. In contrast, rats receiving peripheral or intra-accumbens alpha-flupenthixol injections did not spend significantly more time in the compartment previously paired with testosterone. The blockade of testosterone CPP was not due to an effect of alpha-flupenthixol on motor behavior. The findings provide further evidence of the rewarding affective properties of testosterone and indicate that peripheral administration and intra-accumbens administration of alpha-flupenthixol block expression of testosterone CPP. The rewarding affective properties of testosterone are mediated, at least in part, via an interaction with the mesolimbic dopamine system.

Amygdala modulation of multiple memory systems: hippocampus and caudate-putamen.

A series of five experiments examined the differential mnemonic roles of the hippocampus and caudate-putamen and the modulatory influence of the amygdala on hippocampal and caudate-putamen memory processes. Findings indicate that (a) posttraining intrahippocampal injections of amphetamine selectively enhance memory in a hidden platform water maze task, (b) posttraining intracaudate injections of amphetamine selectively enhance memory in a visible platform water maze task, (c) posttraining intra-amygdala injections of amphetamine enhance memory in both water maze tasks, (d) preretention intrahippocampal lidocaine injections block expression of the memory enhancing effects of posttraining intrahippocampal amphetamine injections in the hidden platform task, (e) preretention intracaudate lidocaine injections block expression of the memory enhancing effects of posttraining intracaudate amphetamine injections in the visible platform task, (f) preretention intra-amygdala lidocaine injections do not block the memory enhancing effect of posttraining intra-amygdala amphetamine injections on either task, (g) in the hidden platform task, posttraining intrahippocampal, but not intracaudate, lidocaine injections block the memory enhancing effects of posttraining intra-amygdala amphetamine, (h) in the visible platform task, posttraining intracaudate, but not intrahippocampal, lidocaine injections block the memory enhancing effects of posttraining intra-amygdala amphetamine. The findings indicate a double dissociation between the roles of the hippocampus and caudate-putamen in memory and suggest that the amygdala exerts a modulatory influence on both the hippocampal and caudate-putamen memory systems.

Posttraining estradiol injections enhance memory in ovariectomized rats: cholinergic blockade and synergism.

The present experiments examined acute posttraining estrogenic influences on memory in ovariectomized rats. In experiment 1 rats received a single 8-trial (30-s ITI) training session with a submerged escape platform located in the same quadrant of a circular water maze on all trials. Following trial 8, rats received a posttraining intraperitoneal injection of either an estradiol-cyclodextrin inclusion complex (0.1, 0.2, or 0.4 mg/kg) or saline. On a retention test session 24 h later, the escape latencies of rats given injections of estradiol (0.2 mg/kg) were significantly lower than those of saline-treated rats, indicating an enhancement of memory. Injections of estradiol delayed 2 h posttraining did not affect retention, demonstrating a time-dependent effect of estradiol on memory storage processes. In experiment 2a, posttraining injections of the cholinergic muscarinic receptor antagonist scopolamine (0.4 mg/kg) impaired memory in ovariectomized rats. In experiment 2b, the memory-enhancing effect of estradiol (0.2 mg/kg) was blocked by concurrent posttraining administration of a subeffective dose (0.1 mg/kg) of scopolamine, suggesting an interaction between estradiol and muscarinic cholinergic systems in memory modulation. In experiment 3a, posttraining injections of the cholinergic muscarinic receptor agonist oxotremorine (0.2 mg/kg) enhanced memory in ovariectomized rats. In experiment 3b, concurrent posttraining injection a subeffective dose of estradiol (0.1 mg/kg) and a subeffective dose of oxotremorine (0.1 mg/kg) enhanced memory, indicating a synergistic effect of estradiol and muscarinic receptor activation on memory.

Intra-hippocampal estradiol infusion enhances memory in ovariectomized rats.

Ovariectomized adult Long-Evans rats received an eight-trial training session in a hippocampal-dependent hidden platform water maze task. Following trial 8, rats received an intra-hippocampal injection of estradiol in a water soluble cyclodextrin inclusion complex (1.0, 2.0 or 5.0 micrograms/0.5 microliter), or saline. Twenty-four hours later, the retention test escape latencies of rats administered post-training intra-hippocampal injections of estradiol (5.0 micrograms) were significantly lower than those of saline treated rats, indicating a memory-enhancing effect of estradiol. Injections of estradiol (5.0 micrograms) given 2 h post-training had no effect on retention, indicating a time-dependent effect of estradiol on memory storage processes.

Posttraining injections of MK-801 produce a time-dependent impairment of memory in two water maze tasks.

The role of glutamatergic N-methyl-D-aspartate (NMDA) receptors in memory storage processes was examined using systemic posttraining injections of MK-801. Male Long-Evans rats received an eight-trial (30-s ITI) training session on a spatial or cued water maze task. In the spatial task, a submerged escape platform was located in the same quadrant of the maze on all trials. In the cued task, a visible escape platform was located in a different quadrant of the maze on each trial. Following Trial 8 in both tasks, the rats received a posttraining intraperitoneal injection of the NMDA receptor antagonist MK-801 (0.025, 0.05, 0.1, or 0.2 mg/kg) or saline. On a retention test session 24 h later, latency to mount the escape platform was used as a measure of memory. In both tasks, the retention test escape latencies of animals given MK-801 (0.05 and 0.1 mg/kg) were significantly higher than those of saline-injected controls, indicating a drug-induced impairment of memory. Injections of MK-801 (0.05 mg/kg) did not affect retention when administered 2 h posttraining in either task, indicating that the effects of MK-801 on retention are not due to an influence on non-mnemonic factors. Control experiments indicated that the memory impairing effects of MK-801 were due to an influence on memory for the type of discrimination training given (i.e., spatial or cued) and not due to an influence on a mnemonic strategy common to both tasks. The findings indicate a time-dependent role for NMDA receptor function in memory storage processes.

Double dissociation of hippocampal and dorsal-striatal memory systems by posttraining intracerebral injections of 2-amino-5-phosphonopentanoic acid.

Rats received an 8-trial training session on a spatial or cued task in a water maze, followed by a posttraining intracerebral injection of AP5 or saline. On a retention test 24 hr later, latency to mount the escape platform was used as a measure of memory. Intrahippocampal (10 micrograms), but not intra-dorsal striatal (2, 5, or 10 micrograms), injection of AP5 impaired memory in the spatial task. In contrast, intra-dorsal striatal (2 micrograms), but not intrahippocampal (2, 5, or 10 micrograms) injection of AP5 impaired memory in the cued task. Intracerebral injections of AP5 delayed 2 hr posttraining were ineffective. The findings indicate a double dissociation of the roles of the hippocampus and dorsal striatum in memory, a role for N-methyl-D-aspartate receptor function in posttraining memory processes, and a glutamatergic modulation of both hippocampal and dorsal striatal memory processes, suggesting that different forms of memory may share a similar neurochemical basis.

Rewarding affective properties of intra-nucleus accumbens injections of testosterone.

On alternating days, adult male Long-Evans rats implanted with bilateral cannulas in the nucleus accumbens received intracerebral injections of testosterone in a water-soluble cyclodextrin inclusion complex (0.125, 0.25, or 0.5 microg/0.5 microl saline) or saline immediately prior to being confined for 30 min to 1 of 2 compartments of a place-preference apparatus. All rats received 8 days of pairings (4 hormone and 4 saline). On Day 9 the rats were given a 20-min test session during which they had access to all compartments of the apparatus. No hormone was injected prior to the test session. On the test day, rats spent significantly more time in the compartment previously paired with bilateral intra-accumbens injections of testosterone (0.25 and 0.5 microg/0.5 microl saline) than in the compartment previously paired with saline injections. The findings indicate that intra-accumbens injections of testosterone are sufficient to produce reward.

Bioactive lipids in excitatory neurotransmission and neuronal plasticity.

Long-term potentiation (LTP), a model of activity-dependent synaptic plasticity and of certain forms of memory, comprises the persistent enhancement of excitatory neurotransmission that results from high-frequency activation. A presynaptic component of LTP is thought to be modulated by a retrograde messenger generated by the postsynaptic neuron. Arachidonic acid, nitric oxide, carbon monoxide and PAF have each been proposed as retrograde messengers in LTP, but arachidonic acid, unlike PAF, requires NMDA receptor activation. A PAF antagonist (BN 52021) that provides neuroprotection in ischemia-reperfusion displaces [3H] PAF bound to presynaptic membranes, blocks PAF-induced glutamate exocytosis and inhibits LTP. An antagonist selective for the intracellular PAF binding site (BN 50730) did not affect LTP, nor did BN 52021 modify NMDA currents. LTP was induced with weak synaptic stimulation coupled with postsynaptically administered enzyme resistant mcPAF. Theta-burst stimulation (10 min) after bath applications of mcPAF (1 microM) induced APV-independent LTP that was blocked by 5 microM BN 52021. When this antagonist was infused into the hippocampus before or immediately after training, it impaired memory of inhibitory avoidance training in the rat. Memory was not altered if the antagonist is infused 30 or 60 min after training. Moreover, mcPAF enhances memory on retention test performance of step-down inhibitory avoidance habituation and learning in rats. Also, memory was studied using a caudate nucleus-dependent cued water maze task. Rats received an 8 trial (30 s intertrial interval) training session in which a visible cued escape platform was located in a different quadrant of the maze of each trial. Following trial 8, the rats received a unilateral post-training intra-caudate injection of mcPAF (1 microgram/0.5 microliter), BN 52021 (0.5 microgram/0.5 microliter) or vehicle. On a retention test session 24 h later, latency to mount the escape platform was used as a measure of memory. The retention test escape latencies of rats given mcPAF were significantly lower than those of the vehicle-injected controls, indicating a memory enhancing effect of mcPAF. Injection of mcPAF did not affect retention when administered 2 h post-training, indicating a time-dependent effect of mcPAF on memory. The latencies for animals injected with BN 52021 were significantly higher than those of the controls, indicating that antagonism of endogenous PAF impairs memory. The findings show that PAF plays a role in memory formation in a caudate-mediated cued discrimination task. Administration of BN 52021 2 h post-training had no affect on retention, indicating a time-dependent effect of endogenous PAF on memory formation. PAF, the most potent bioactive lipid known, modulates excitatory synaptic transmission, neuronal plasticity and memory. When PAF production is overstimulated as in seizures or ischemia, it becomes neurotoxic.