The enhancement of retention induced by vasopressin in mice may be mediated by an activation of central nicotinic cholinergic mechanisms.

Immediate post-training subcutaneous administration of lysine vasopressin (LVP, 0.003-1.00 microgram/kg) enhanced retention, whereas the vasopressin antagonist AAVP (0.01-0.30 microgram/kg) impaired it, in male Swiss mice tested 48 h after training in an inhibitory avoidance task. Both effects were dose-dependent. Neither LVP nor AAVP affected response latencies in mice not given the footshock on the training trial. The simultaneous administration of AAVP at a dose (0.01 microgram/kg) which had no effect on retention shifted the dose-response curve of LVP to the right. Nicotine (1.0-30.0 micrograms/kg, sc), a central nicotinic cholinergic agonist, also facilitated retention in a dose-related manner without affecting the retention performance of unshocked mice. The effect of nicotine was prevented by the central acting nicotinic cholinergic receptor antagonist mecamylamine (5 mg/kg, sc.). In contrast, neither hexamethonium (5 mg/kg, sc), a peripheral acting nicotinic receptor blocker, nor atropine (0.5 mg/kg, sc) or methylatropine (0.5 mg/kg, sc), two anticholinergic drugs which are known to act on muscarinic cholinergic receptors, prevented the effect of post-training nicotine. The effects of LVP and nicotine were time-dependent, suggesting that both treatments enhanced retention by influencing post-training processes involved in memory storage. Low doses of nicotine (1.50 microgram/kg, sc) or the central anticholinesterase physostigmine (35 micrograms/kg, sc) and LVP (0.003 microgram/kg, sc), which had no effect on retention when administered alone, produced a synergistic interaction when given together following training. The influence of LVP (0.03 microgram/kg, sc) on retention was prevented not only by AAVP (0.01 microgram/kg, sc) but also by mecamylamine (5 mg/kg, sc), whereas the effects of nicotine (10.0 micrograms/kg, sc) were prevented only by mecamylamine. These results suggest that the enhancement of retention induced by vasopressin is probably due to an activation of central nicotinic cholinergic mechanisms which are critical for memory formation.     

Functional interaction of mGlu5 and NMDA receptors in aversive learning in rats

Metabotropic glutamate receptor 5 (mGlu5) has been implicated in a variety of learning processes and is important for inhibitory avoidance and conditioned taste aversion learning. MGlu5 receptors are physically connected with NMDA receptors and they interact with, and modulate, the function of one another in several brain regions. The present studies used systemic co-administration of an mGlu5 receptor positive allosteric modulator, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and an NMDA receptor antagonist dizocilpine maleate (MK-801) to characterize the interactions of these receptors in two aversive learning tasks. Male Sprague-Dawley rats were trained in a single-trial step-down inhibitory avoidance or conditioned taste aversion task. CDPPB (3 or 10mg/kg, s.c.), delivered by itself prior to the conditioning trial, did not have any effect on performance in either task 48 h after training. However, CDPPB (at 3mg/kg) attenuated the MK-801 (0.2mg/kg, i.p.) induced learning deficit in both tasks. CDPPB also reduced MK-801-induced hyperactivity. These results underlie the importance of mGlu5 and NMDA receptor interactions in modulating memory processing, and are consistent with findings showing the efficacy of positive allosteric modulators of mGlu5 receptors in reversing the negative effects of NMDA receptor antagonists on other behaviors such as stereotypy, sensorimotor gating, or working, spatial and recognition memory.     

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.     

The Impairment of Retention Induced by Insulin in Mice May Be Mediated by a Reduction in Central Cholinergic Activity

Immediate posttraining intraperitoneal injection of nonconvulsive doses of insulin (2-20 IU/kg) significantly impaired retention of male Swiss mice tested 24 h after training in a one-trial step-through inhibitory avoidance task. The dose-response curve showed a U-shaped form. However, of the doses tested, only 8 IU/kg was effective. Insulin did not affect response latencies in mice not given the footshock on the training trial, indicating that the actions of insulin on retention performance were not due to nonspecific proactive effects on response latencies. The impairing effects of insulin (8 IU/kg) on retention were time-dependent, which suggests that insulin impaired memory storage. The simultaneous administration of glucose (10-1000 mg/kg) antagonized, in a dose-related manner, the actions of insulin (8 IU/kg) on retention, suggesting that the hormone may have produced a hypoglycemic response leading to a decrease in CNS glucose availability with a subsequent memory impairment. Low subeffective doses of atropine (0.5 mg/kg) or mecamylamine (5 mg/kg), but not methylatropine (0.5 mg/kg) or hexamethonium (5 mg/kg), given immediately after training but 10 min before an ineffective dose of insulin (4 IU/kg), interacted with and impaired retention. The central anticholinesterase physostigmine (35 or 70 μg/kg), but not its quaternary analog neostigmine (35 or 70 μg/kg), prevented the memory impairment induced by insulin (8 IU/kg). Considered together, these findings are consistent with the view that a decrease in the CNS glucose availability impairs the synthesis and/or release of acetylcholine in brain regions critically involved in memory storage.     

Modulatory influence of dopamine receptors on consolidation of object recognition memory

The role of dopamine receptors in regulating the formation of recognition memory remains poorly understood. Here we show the effects of systemic administration of dopamine receptor agonists and antagonists on the formation of memory for novel object recognition in rats. In Experiment I, rats received an intraperitoneal (i.p.) injection of vehicle, the selective D1 receptor agonist SKF38393 (1.0 and 5.0mg/kg), or the D2 receptor agonist quinpirole (1.0 and 5.0mg/kg) immediately after training. In Experiment II, rats received an injection of vehicle, the dopamine receptor antagonist SCH23390 (0.1 and 0.05 mg/kg), or the D2 receptor antagonist raclopride (0.5 and 0.1mg/kg) before training, followed by an injection of vehicle or the nonselective dopamine receptor agonist apomorphine (0.05 mg/kg) immediately after training. SKF38393 at 5mg/kg produced an enhancement of novel object recognition memory measured at both 24 and 72 h after training, whereas the dose of 10mg/kg impaired 24-h retention. Posttraining administration of quinpirole did not affect 24-h retention. Apomorphine enhanced memory in rats given pretraining raclopride, suggesting that the effect was mediated by selective activation of D1 receptors. The results indicate that activation of D1 receptors can enhance recognition memory consolidation. Importantly, pharmacological activation of D1 receptors enhanced novel object recognition memory even under conditions in which control rats showed significant retention.     

Opioid peptidergic systems modulate the activity of beta-adrenergic mechanisms during memory consolidation processes

Post-training administration of the opioid receptor antagonist naloxone (0.1 mg/kg) facilitated 48-hr retention, in mice, of a one-trial step-through inhibitory avoidance response. The naloxone-induced memory facilitation was blocked in animals given the selective brain-noradrenergic neurotoxin DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) (50.0 mg/kg, ip) 7 days before training. Pretreatment with the norepinephrine-uptake inhibitor desmethylimipramine (10.0 mg/kg, ip, 30 min), but not with the serotonin-uptake inhibitor fluoxetine (5.0 mg/kg, ip, 30 min), prevented this antagonism. The simultaneous administration of the central beta-adrenoceptor blocker l-propranolol (2.0 mg/kg, ip), also blocked the effects of naloxone on memory. The effects of naloxone were not blocked by d-propranolol (2.0 mg/kg, ip), the peripheral beta-adrenoceptor blocker sotalol (2.0 mg/kg, ip), the alpha-adrenoceptor blocker phenoxybenzamine (10.0 mg/kg, ip), or the predominantly peripheral alpha-adrenoceptor blocker phentolamine (10.0 mg/kg, ip). These findings suggest that central beta-adrenergic mechanisms are involved in the effects of naloxone on memory. Naloxone (0.1 mg/kg, ip) potentiated the effects of the central beta-adrenoceptor agonist clenbuterol (0.001-1.00 mg/kg, ip), which, when administered alone, facilitates or impairs retention as a function of the dose injected. The simultaneous administration of beta-endorphin (0.1 micrograms/kg, ip) exerted effects opposite to those elicited by naloxone, that is, shifted the dose-response curve of clenbuterol to the right. Considered together, these findings are consistent with the view that the facilitatory action of naloxone on memory results from the release of central beta-adrenergic mechanisms from an inhibition induced by opioid peptides released during or immediately after training.     

The behavioral effects of depletions of brain serotonin induced by 5,7-dihydroxytryptamine vary with time after administration

Ether-anesthetized Sprague-Dawley rats were depleted of brain serotonin (5HT) by intraventricular injections of 50 micrograms 5,7-dihydroxtryptamine (57DHT). Oral pretreatment with 25 mg/kg desmethylimipramine was used to protect brain noradrenergic neurons from 57DHT. Liquid chromatographic assays revealed that this treatment did not significantly alter catecholamine levels but depleted hippocampal 5HT by 92% and striatal 5HT by 45%. Three or eleven days after lesioning, locomotor and exploratory behavior was characterized in separate groups of animals with a behavioral pattern monitor (BPM). On Days 4 and 12, the animals were retested following saline or 1.0 mg/kg amphetamine. Three days after depletion, lesioned rats exhibited a decrease rate of habituation of locomotor activity relative to controls. When challenged with amphetamine (1.0 mg/kg), 5HT-depleted rats exhibited increased corner and decreased center activity, as well as stereotyped patterns of locomotion. Eleven days following lesion, 5HT-depleted rats exhibited habituation rates greater than controls; amphetamine challenge yielded patterns of activity similar to those of control animals. These results show that central serotonergic pathways play an important role in modulating both spontaneous and amphetamine-elicited activity in rats, and that compensatory mechanisms operate over time to alter the behavioral effects of 57DHT-induced depletions of brain 5HT.     

Rapid visual learning in the rat: Effects at the 5-HT 1a receptor subtype

The 5-hydroxytryptamine 1a (5-HT 1a ) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 0.15 mg/kg) impaired rats' rapid visual learning on a computerized maze. This treatment also increased decision time (DT) but the learning impairment was not necessarily a side-effect of slower responding because, in this task, responses made at long DT are more accurate than those at short DT. The selective 5-HT 1a receptor antagonist WAY-100635 (0.3 mg/kg) was itself without effect on accuracy, but was effective in reversing effects of 8-OH-DPAT (on both accuracy and DT). Within problems (i.e., over the 40-60 trials of a single discrimination), performance was reduced by treatment with 8-OH-DPAT at all stages of learning. We conclude that this effect is mediated through the 5-HT 1a receptor site (rather than through some other serotonergic receptor site or non-specific mechanism) as it was reversible by treatment with WAY-100635. Although it could still arise from behaviourally non-specific effects, the performance deficit finds its best account in terms of the psychological processes necessary to visual learning. Its reversal with WAY-100635 offers support to the hypothesis that 5-HT 1a receptor antagonists could improve cognitive function, under conditions of pre-existing impairment due to overactive serotonergic inhibition, as is thought to occur in Alzheimer's disease.     

N-Methyl-D-aspartate receptors in the ventral tegmental area are involved in retrieval of inhibitory avoidance memory by nicotine

The interaction of opiate, cholinergic, glutamatergic and (possibly) dopaminergic inputs in the ventral tegmental area (VTA) influencing a learned behavior is certainly a topic of great interest. In the present study, the effect of intra-VTA administration of N-methyl-d-aspartate (NMDA) receptor agents on nicotine's effect in morphine state-dependent learning was investigated. An inhibitory avoidance (IA) task was used for memory assessment in male Wistar rats. Subcutaneous (s.c.) administration of morphine (5 and 7.5mg/kg) immediately after training decreased IA response on the test day, which was reinstated by pre-test administration of the same doses of the opioid; this is known as state-dependency. Moreover, pre-test administration of nicotine (0.2, 0.4 and 0.6 mg/kg, s.c.) also reversed the decrease in IA response because of post-training morphine (5mg/kg). Here, we also show that when infused into the VTA before testing, NMDA (0.01 and 0.1 microg/rat) reverse the post-training morphine effect on memory. In addition, the sub-effective doses of NMDA (0.0001 and 0.001 microg/rat) in combination with a low dose of nicotine (0.1mg/kg) which had no effects by themselves, synergistically improved retrieval of IA memory on the test day. In contrast, pre-test administration of a competitive NMDA receptor antagonist D-AP5 (0.5, 1 and 2 microg/rat) which had no effect alone prevented the nicotine reversal of morphine effect on memory. Our data indicate that NMDA receptors in the VTA are involved in the reversing effect of nicotine on morphine induced state-dependency.     

Interaction of methadone, reinforcement history, and variable-interval performance.

In the present study, we examined how a reinforcement schedule history that generated high or low rates of responding influenced the effects of acute (Experiment 1) and chronic (Experiment 2) methadone administration. Initially, key-peck responses of pigeons were maintained under a variable-interval 90-s schedule of food presentation, and a methadone dose-response curve was determined with doses of 0.6, 1.2, and 2.4 mg/kg. The pigeons were then exposed, for at least 40 sessions, to either a fixed-ratio 50 schedule or a differential-reinforcement-of-low-rate 10-s schedule, or were given continued exposure to the variable-interval schedule. The methadone dose-response curve was redetermined after all pigeons again were responding under the variable-interval schedule. The effects of two different daily methadone doses (9.0 and 12.0 mg/kg/day) and withdrawal precipitated by naloxone also were assessed. Experience with a fixed-ratio or differential reinforcement of low rate schedule did not result in significantly different response rates under the variable-interval schedule and, in general, the acute effects of methadone did not have differential effects correlated with schedule history. However, for 2 of 4 subjects the rate-decreasing effects of methadone on rates of key pecking were greater following a history of low-rate responding, suggesting a possible interaction between schedule history and effects of methadone. Daily methadone administration under the variable-interval schedule revealed that pigeons with experience under the differential reinforcement of low rate schedule developed more rapid and complete tolerance to the rate-decreasing effects of methadone. Three of the 4 subjects in this group showed rate increases above drug-free baselines during chronic methadone dosing. Pigeons with a history of fixed-ratio responding also developed tolerance to the rate-decreasing effects of methadone but without the subsequent rate increases seen by subjects with low-rate histories. No subjects with variable-interval histories showed complete recovery of drug-free baselines, suggesting that interpolated training under other schedules may attenuate the rate-altering effects of chronically administered drugs. Naloxone (1.0 mg/kg), administered during the chronic methadone phase, resulted in greater disruption of responding by pigeons with a history of low-rate responding, as compared to subjects in the other two groups.(ABSTRACT TRUNCATED AT 400 WORDS)     

Beta1-adrenoceptor or alpha1-adrenoceptor activation initiates early odor preference learning in rat pups: support for the mitral cell/cAMP model of odor preference learning

We proposed that mitral cell beta1-adrenoceptor activation mediates rat pup odor preference learning. Here we evaluate beta1-, beta2-, alpha1-, and alpha2-adrenoceptor agonists in such learning. The beta1-adrenoceptor agonist, dobutamine, and the alpha1-adrenoceptor agonist, phenylephrine, induced learning, and both exhibited an inverted U-curve dose-response relationship to odor preference learning. Phenylephrine-induced learning occurred in the presence of propranolol to prevent indirect activation of beta-adrenoceptors. Alpha1-adrenoceptor mediation may represent a novel mechanism inducing learning or may increase cAMP in mitral cells via indirect activation of GABA(B) receptors. Neither the beta2-adrenoceptor agonist, salbutamol, nor the alpha2-adrenoceptor agonist, clonidine, induced learning.     

Characterization of the discriminative stimulus effects of lorcaserin in rats

Lorcaserin is approved by the Food and Drug Administration for treating obesity and is under consideration for treating substance use disorders; it has agonist properties at serotonin (5‐HT)_2C receptors and might also have agonist properties at other 5‐HT receptor subtypes. This study used drug discrimination to investigate the mechanism(s) of action of lorcaserin. Male Sprague–Dawley rats discriminated 0.56 mg/kg i.p. lorcaserin from saline while responding under a fixed‐ratio 5 schedule for food. Lorcaserin (0.178‐1.0 mg/kg) dose‐dependently increased lorcaserin‐lever responding. The 5‐HT_2C receptor agonist mCPP and the 5‐HT_2A receptor agonist DOM each occasioned greater than 90% lorcaserin‐lever responding in seven of eight rats. The 5‐HT_1A receptor agonist 8‐OH‐DPAT occasioned greater than 90% lorcaserin‐lever responding in four of seven rats. The 5‐HT_2C receptor selective antagonist SB 242084 attenuated lorcaserin‐lever responding in all eight rats and the 5‐HT_2A receptor selective antagonist MDL 100907 attenuated lorcaserin‐lever responding in six of seven rats. These results suggest that, in addition to agonist properties at 5‐HT_2C receptors, lorcaserin also has agonist properties at 5‐HT_2A and 5‐HT_1A receptors. Because some drugs with 5‐HT_2A receptor agonist properties are abused, it is important to fully characterize the behavioral effects of lorcaserin while considering its potential for treating substance use disorders.     

Evaluation of the interaction between D1 and D2 receptors in a drug discrimination paradigm

Recent research has suggested that there is a synergistic interaction between D1 and D2 dopamine (DA) receptors and that D1 stimulation by endogenous DA is necessary for the expression of some D2-mediated behavioral effects. The purpose of the present experiment was to examine further the interactions between D1 and D2 receptors using drug discrimination (DD), a behavioral paradigm that is sensitive and selective for D1 and D2 agonist and antagonist activity. Two groups of male Sprague-Dawley rats (N = 8/group) were trained to discriminate the D2 agonist quinpirole (QUIN; either 0.05 or 0.012 mg/kg, ip, 10 min pre-session) from saline (1.0 ml/kg, ip, 10 min pre-session) in a two-lever, food-reinforced DD paradigm. QUIN (0.0015-0.1 mg/kg) produced a dose-related increase in QUIN-appropriate responding in both groups of rats. The D1 agonist SKF 38393 (SKF; 6.4-12.8 mg/kg, ip) given alone did not substitute for QUIN in either of the two training dose groups. The administration of SKF 30 min before QUIN had no effect on the QUIN dose-response function in either group of rats. These results indicate that stimulation of D1 receptors failed to potentiate a behavioral effect mediated by D2 receptors. The D1 antagonist SCH 23390 (SCH; 0.0015-0.05 mg/kg, ip) partially substituted for QUIN in the group trained with the 0.05 dose of QUIN, and to a larger extent in the group trained with the 0.012 dose of QUIN. SCH did not alter the effect of the training dose of QUIN except at a dose high enough to virtually eliminate lever pressing in the group trained to discriminate the high dose of QUIN. The failure of SCH to block QUIN suggests that D1 receptor stimulation by endogenous DA is not necessary for this D2 effect to be expressed. These results may be accounted for by assuming a presynaptic site of action for QUIN in the QUIN discrimination. Further, they demonstrate that the interaction between D1 and D2 receptors cannot be simply characterized as synergistic.     

Induction of arginine vasopressin-enhanced green fluorescent protein expression in the locus coeruleus following kainic acid-induced seizures in rats

Seizure causes autonomic, neuroendocrine and stress responses. We examined the effects of kainic acid (KA)-induced seizures on the expression of the arginine vasopressin (AVP)-enhanced green fluorescent protein (eGFP) in the locus coeruleus (LC), an area known to contain noradrenergic cells, in AVP-eGFP transgenic male and female rats, with the rationale to identify stressors which induce AVP synthesis in the LC. Subcutaneous (s.c.) administration of KA caused a progressive development of seizure behavior within 24 h. AVP-eGFP fluorescence in the LC was detected 6, 24, and 48 h and 1 week after administration of KA (12 mg/kg). From a nearly undetectable level, it reached a maximum at 48 h after s.c. administration of KA and returned to the basal levels after 2 weeks. AVP-eGFP fluorescence in the LC after s.c. administration of KA was significantly reduced by the pretreatment with MK-801 (nonselective N-methyl-D-aspartate (NMDA) receptor antagonist). In the KA-administered rats, immunohistochemistry for tyrosine hydroxylase (TH) revealed that the eGFP fluorescence was co-localized with TH-immuno-reactivity in the LC. These results suggest that the synthesis of AVP-eGFP is potentially up-regulated in noradrenergic neurons in the LC after KA-induced seizures through the activation of NMDA receptors.     

Effects of MK-801 and ethanol combinations on memory consolidation in CD1 mice: involvement of GABAergic mechanisms

In the present research the effect of the noncompetitive N-methyl-d-aspartate receptor antagonist MK-801 and ethanol combinations on memory consolidation and the involvement of GABAergic mechanisms in this effect were investigated in CD1 mice injected intraperitoneally with the drugs immediately or 120 min after training in a one-trial inhibitory avoidance apparatus and tested for retention 24 h later. The results showed that (a) the retention performances of mice were impaired in a dose-dependent manner by immediate posttraining MK-801 (0.2 and 0.3, but not 0.1 mg/kg) and ethanol (1 and 2, but not 0.5 g/kg) administrations; (b) an otherwise ineffective dose of MK-801 (0.1 mg/kg) enhanced the deleterious effect exerted by ethanol (1 and 2 g/kg); (c) an otherwise ineffective dose of muscimol (0.5 mg/kg) enhanced, while otherwise ineffective doses of picrotoxin (0.25 mg/kg) or bicuculline (0.1 mg/kg) antagonized, this effect; and (d) no effect was observed when the treatments were carried out 120 min after training, suggesting that the effects observed following immediate posttraining administrations were due to the influence on the consolidation of memory. From these experiments it is evident that (a) MK-801 enhances ethanol's effects on memory consolidation and (b) GABAergic mechanisms are involved in this effect.     

Role of 5HT1A receptors in a variety of kinds of aggressive behavior in wild rats and counterparts selected for low defensiveness towards man

The 5HT_1A receptor agonist ipsapirone (10 mg/kg) suppressed shock-induced aggression in wild and domesticated rats but did not affect predatory aggression in either group of animals. Ipsapirone decreased neophobia and inhibited defensive reactions by wild rats towards man in the glove test. [³H]8-OH-DPAT binding, which labels 5HT_1A receptors, was significantly increased in the hypothalamus of domesticated rats in comparison with wild counterparts, while 5HT_1A density was unchanged in the frontal cortex in domesticated animals. In essence, the aggressive reactions contributing to the defensive behavior complex in wild rats appear to be regulated through 5HT_1A receptors. © 1992 Wiley-Liss, Inc.     

Effects of anandamide and morphine combinations on memory consolidation in cd1 mice: involvement of dopaminergic mechanisms

In the present research the interaction between the endogenous ligand for the cannabinoid CB1 receptor anandamide (arachidonylethanolamide) and morphine in memory consolidation was investigated. Four sets of experiments were carried out with CD1 mice tested in a one-trial inhibitory avoidance task. The drugs were administered intraperitoneally after training of the animals in the apparatus. In the first set of experiments morphine (0.3 or 0.5, but not 0.15mg/kg) or anandamide (3 or 6 but not 1.5mg/kg) dose-dependently impaired memory consolidation. In the second set of experiments the administration of an otherwise ineffective dose of anandamide (1.5mg/kg) enhanced the memory impairment exerted by morphine (0.3 and 0.5mg/kg) when the drugs were injected immediately after training. In the third set of experiments the combined treatments of anandamide (1.5mg/kg) and morphine (0.5mg/kg) 2h after training were ineffective showing that the effects observed on performance following immediate posttraining administration of anandamide and morphine combinations were reflecting direct influences on memory consolidation. In the fourth set of experiments otherwise ineffective doses of the D1 DA receptor agonist SKF 38393 or the D2 DA receptor agonist LY 171555 antagonized the memory impairment produced by anandamide and morphine in combination, suggesting a possible involvement of dopaminergic mechanisms.     

AF-DX 116, a Presynaptic Muscarinic Receptor Antagonist, Potentiates the Effects of Glucose and Reverses the Effects of Insulin on Memory

Male Swiss mice were tested 24 h after training in a one-trial step-through inhibitory avoidance task. Low subeffective doses of -(+)-glucose (10 mg/kg, ip), but not its stereoisomer -(−)-glucose (30 mg/kg, ip), administered immediately after training, and AF-DX 116 (0.3 mg/kg, ip), a presynaptic muscarinic receptor antagonist, given 10 min after training, interact to improve retention. Insulin (8 IU/kg, ip) impaired retention when injected immediately after training, and the effects were reversed, in a dose-related manner, by AF-DX 116 (0.3, 1.0, or 3.0 mg/kg, ip) administered 10 min following insulin. Since AF-DX 116 possibly blocks autoreceptors mediating the inhibition of acetylcholine release from cholinergic nerve terminals, the present data support the view that changes in the central nervous system glucose availability, subsequent to modification of circulating glucose levels, influence the activity of central cholinergic mechanisms involved in memory storage of an inhibitory avoidance response in mice.     

Selective blockade of 5-HT2A receptors attenuates the increased temperature response in brown adipose tissue to restraint stress in rats

Previous studies have demonstrated that 5-HT2A receptors may be involved in the central control of thermoregulation and of the cardiovascular system. Our aim was to test whether these receptors mediate thermogenic and tachycardiac responses induced by acute psychological stress. Three groups of adult male Hooded Wistar rats were instrumented with: (i) a thermistor in the interscapular area (for recording brown adipose tissue temperature) and an ultrasound Doppler probe (to record tail blood flow); (ii) temperature dataloggers to record core body temperature; (iii) ECG electrodes. On the day of the experiment, rats were subjected to a 30-min restraint stress preceded by s.c. injection of either vehicle or SR-46349B (a serotonin 2A receptor antagonist) at doses of 0.01, 0.1 and 1.0 mg/kg. The restraint stress caused a rise in brown adipose tissue temperature (from, mean +/- s.e.m., 36.6 +/- 0.2 to 38.0 +/- 0.2 degrees C), transient cutaneous vasoconstriction (tail blood flow decreased from 12 +/- 2 to 5 +/- 1 cm/s), increase in heart rate (from 303 +/- 15 to 453 +/- 15 bpm at the peak, then reduced to 393 +/- 12 bpm at the steady state), and defaecation (6 +/- 1 pellets per restraint session). The core body temperature was not affected by the restraint. Blockade of 5-HT2A receptors attenuated the increase in brown adipose tissue temperature and transient cutaneous vasoconstriction, but not tachycardia and defaecation elicited by restraint stress. These results indicate that psychological stress causes activation of 5-HT2A receptors in neural pathways that control thermogenesis in the brown adipose tissue and facilitate cutaneous vasoconstriction.     

NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse

Previous research from our laboratory has implicated the basolateral amygdala (BLA) complex in the acquisition and consolidation of cue-cocaine associations, as well as extinction learning, which may regulate the long-lasting control of conditioned stimuli (CS) over drug-seeking behavior. Given the well established role of NMDA glutamate receptor activation in other forms of amygdalar-based learning, we predicted that BLA-mediated drug-cue associative learning would be NMDA receptor dependent. To test this hypothesis, male Sprague-Dawley rats self-administered i.v. cocaine (0.6 mg/kg/infusion) in the absence of explicit CS pairings (2-h sessions, 5 days), followed by a single 1-h classical conditioning (CC) session, during which they received passive infusions of cocaine discretely paired with a light+tone stimulus complex. Following additional cocaine self-administration sessions in the absence of the CS (2-h sessions, 5 days) and extinction training sessions (no cocaine or CS presentation, 2-h sessions, 7 days), the ability of the CS to reinstate cocaine-seeking on three test days was assessed. Rats received bilateral intra-BLA infusions (0.5 microl/hemisphere) of vehicle or the selective NMDA receptor antagonist, 2-amino-5-phosphonovalerate (AP-5), immediately prior to the CC session (acquisition), immediately following the CC session (consolidation), or immediately following reinstatement testing (consolidation of conditioned-cued extinction learning). AP-5 administered before or after CC attenuated subsequent CS-induced reinstatement, whereas AP-5 administered immediately following the first two reinstatement tests impaired the extinction of cocaine-seeking behavior. These results suggest that NMDA receptor-mediated mechanisms within the BLA play a crucial role in the consolidation of drug-CS associations into long-term memories that, in turn, drive cocaine-seeking during relapse.