Ines B. Introini-Collison

Memory-enhancing effects of posttraining naloxone: involvement of ß-noradrenergic influences in the amygdaloid complex

Rats (220-250 g) were bilaterally implanted with cannulae in the amygdala, trained on an inhibitory avoidance response and two weeks later, on a Y-maze discrimination response. Immediately following the training on each task, they were injected intraperitoneally (i.p.) or intra-amygdally. Retention was tested one week after training for each task. Retention of the Y-maze task was assessed by discrimination reversal training. Naloxone administered i.p. (3.0 mg/kg) significantly facilitated retention of both tasks in unoperated control rats as well as in rats implanted bilaterally with amygdala cannulae. The memory-enhancing effect of naloxone i.p. was blocked by propranolol (0.3 or 1.0 microgram) injected in the amygdala, but not when this beta-noradrenergic antagonist was injected (0.3 micrograms) into either the caudate or the cortex dorsal to the amygdala. Further, intra-amygdala injections of the beta 1-adrenoceptor blocker atenolol (0.3 or 1.0 microgram) and the beta 2-adrenoceptor blocker zinterol (0.3 or 1.0 microgram), in doses which were ineffective when administered alone, blocked naloxone-induced (3.0 mg/kg, i.p.) memory facilitation. In contrast, posttraining intra-amygdala administration (1.0 micrograms) of the alpha-antagonists prazosin (alpha 1) or yohimbine (alpha 2) did not attenuate the memory-enhancing effects of systemically administered naloxone. These findings support the view that naloxone-induced enhancement of memory is mediated by the activation of beta- but not alpha-noradrenergic receptors located within the amygdaloid complex.

Neuromodulatory systems and memory storage: Role of the amygdala

This article reviews findings of research examining the interaction of peripheral adrenergic systems with cholinergic, opioid peptidergic and GABAergic systems in modulating memory storage. It is well established that retention is enhanced by posttraining systemic or intra-amygdala injections of adrenergic agonists, opiate antagonists and GABAergic antagonists. These influences appear to be mediated by activation of NE receptors within the amygdala, as intra-amygdala injections of beta-adrenergic antagonists block the memory-modulating effects of hormones and drugs affecting these systems. Furthermore, these influences also appear to involve, at a subsequent step, activation of a cholinergic system: atropine blocks the memory-enhancing effects of adrenergic agonists and opiate and GABAergic antagonists and oxotremorine attenuate the memory-impairing effects of opiate agonists and GABAergic agonists. These findings suggest that the amygdala integrates the memory-modulating effects of neuromodulatory systems activated by learning experiences.

Involvement of the amygdaloid complex in neuromodulatory influences on memory storage

Neuromodulatory systems activated by training experiences appear to play a role in influencing memory storage processes. The research summarized in this paper examined the effects, on memory, of posttraining administration of treatments affecting adrenergic, opioid peptidergic and GABAergic systems. When administered after training, drugs affecting these systems all produce dose- and time-dependent effects on memory storage. The drug effects on memory are blocked by lesions of the amygdaloid complex as well as lesions of the stria terminalis, a major amygdala pathway. The effects of drugs affecting these neuromodulatory systems are also blocked by injections of beta-adrenergic antagonists administered to the amygdaloid complex. Thus, the findings suggest that the neuromodulatory systems affect memory storage through influences involving the activation of beta-adrenergic receptors within the amygdala. These findings are consistent with the view that the amygdala is involved in regulating the storage of memory in other brain regions.

Memory enhancement with intra-amygdala post-training naloxone is blocked by concurrent administration of propranolol

Sprague-Dawley rats were first trained on an inhibitory avoidance task (IA) and then, two weeks later, on a Y-maze discrimination task (YMD). Bilateral intra-amygdala injections were given through implanted cannulae immediately post-training. Retention was evaluated one week following training on each task. Naloxone (0.1, 0.3 or 1.0 microgram) facilitated retention performance in both tasks. The most effective doses were 0.1 microgram for the IA task and 0.3 microgram for the YMD task. Since naloxone (0.1 microgram) did not affect retention when administered via cannulae implanted in either the caudate-putamen or cortex dorsal to the amygdala, the effects of intra-amygdala naloxone is not due to diffusion of the drug to these brain regions. Intra-amygdala injections of the beta 1,2-adrenoceptor blocker propranolol (0.3 microgram) blocked the memory enhancing effects of intra-amygdala naloxone (IA: 0.1 microgram; YMD: 0.3 microgram) administered concurrently immediately post-training. We interpret these findings as indicating that the enhancing effects of intra-amygdala naloxone are mediated by the activation of beta-noradrenergic receptors within the amygdala. Such effects are presumably due to blocking of inhibitory effects of opioid peptides on the release of norepinephrine.

Amygdala β-Noradrenergic Influences on Memory Storage Involve Cholinergic Activation

These experiments examined the involvement of the amygdaloid complex as a site of interaction of adrenergic and muscarinic cholinergic influences on memory storage. Male Sprague-Dawley rats (60 days old; 250-300 g) were given a single training trial in an inhibitory avoidance task and a retention test trial 48 h later. Immediately after training buffer control or drug solutions (0.5 microliter) were infused into the amygdala and, in the first experiment only, other drugs were administered intraperitoneally (ip). The first experiment examined the effects of post-training systemic injections of the muscarinic agonist oxotremorine (100.0 micrograms/kg) administered alone or together with intraamygdala injections of either the muscarinic antagonist atropine (1.0 microgram) or the beta-noradrenergic antagonist propranolol (0.3 microgram). Oxotremorine enhanced retention and atropine, but not propranolol, attenuated the effects of oxotremorine. In the second experiment intraamygdala infusions of the beta-noradrenergic agonist clenbuterol (10.0 ng) were administered either alone or together with atropine (1.0 microgram). Clenbuterol enhanced retention and atropine blocked the effects of clenbuterol. In the third experiment intraamygdala infusions of oxotremorine (3, 10, 30, or 100 ng) were administered either alone or together with propranolol (0.3 microgram). Oxotremorine (3.0 and 10.0 ng) enhanced retention and propranolol did not block the effects of oxotremorine. These findings are consistent with the view that memory storage is regulated by an interaction of beta-noradrenergic and cholinergic influences and suggest that the noradrenergic influences are mediated by the release of acetylcholine and activation of muscarinic cholinergic receptors within the amygdala.

Memory-enhancing effects of post-training dipivefrin and epinephrine : involvement of peripheral and central adrenergic receptors

These experiments examined the effects, in mice, of post-training i.p. injections of dipivefrin (DPE), a lipophilic prodrug of epinephrine, and epinephrine (EPI) on 48-h retention assessed in inhibitory avoidance and Y-maze discrimination tasks. DPE, in doses of 0.3-10 micrograms/kg significantly facilitated retention: the effects were approximately 10-fold more potent than those of EPI obtained with similar experimental conditions. The alpha-adrenergic antagonists prazosin (alpha 1; 3.0 mg/kg; i.p.), yohimbine (alpha 2; 3.0 mg/kg; i.p.) and phentolamine (alpha 1 and alpha 2; 3.0 mg/kg; i.p.) did not block the enhancement of retention induced by either DPE (10.0 micrograms/kg; i.p.) or EPI (0.1 mg/kg; i.p.). However, the beta-adrenergic antagonist propranolol (2.0 mg/kg; i.p.) attenuated the effects of both DPE and EPI. Sotalol (2.0 mg/kg; i.p.), a peripherally-acting beta-adrenergic antagonist, attenuated the effects of EPI but not those of DPE. These findings suggest the DPE-induced enhancement of memory involves central beta- but not alpha-adrenergic mechanisms while EPIs effects are initiated by activation of peripheral beta-adrenergic systems.

Involvement of the amygdala in the memory-enhancing effects of clenbuterol

Male Sprague Dawley rats with stria terminalis (ST) or sham lesions were trained in an inhibitory avoidance task, injected immediately post-training with clenbuterol hydrochloride (0.03 mg/kg; IP), and tested for retention 48 h later. Clenbuterol enhanced retention of the sham-lesioned animals but did not affect retention of the ST-lesioned animals. Clenbuterol injected intra-amygdally immediately after training also enhanced retention of the inhibitory avoidance task. These results agree with other evidence suggesting the participation ofβ-noradrenergic mechanisms in the amygdala in the modulation of memory storage.

Epinephrine modulates long-term retention of an aversively motivated discrimination

These experiments examined the effects of post-training epinephrine (Epi) on retention of an aversively motivated discrimination task. Male CFW mice were trained to escape from footshock by entering one of two alleys of a Y-maze. On a 24-h retention test (six trials) the correct alley was reversed. The findings of Experiment 1 indicate that errors on the discrimination reversal varied directly with number of trials (criterion of 0, 3, or 6 successive correct choices) on the original training. These findings indicate that errors on discrimination reversal training provide a sensitive index of retention of the original training. In Experiment 2, mice were trained to a criterion of three successive correct choices and were given post-training injections of saline or Epi (0.1, 0.3, or 1.0 mg/kg ip). On a 24-h discrimination reversal test mice given the low doses of Epi made more errors than did saline controls while mice given the high dose made fewer errors. In Experiment 3, mice trained as in Exp 2 received post-training saline or Epi (0.3 or 1.0 mg/kg) and were tested for retention either 1 week or 1 month later. At each retention interval, performance was comparable to that found with a 24-h retention interval. The findings provide additional evidence that post-training Epi produces long-lasting dose-dependent modulating effects on memory storage.

Noradrenergic and cholinergic interactions in the amygdala and the modulation of memory storage

Numerous studies have reported that, in rats, memory can be affected by manipulations of the amygdala noradrenergic system. Typically, low doses of norepinephrine facilitate while higher doses impair memory storage. Muscarinic cholinergic agonists facilitate, while antagonists impair memory storage. Recent evidence from studies using systemic injection of drugs, indicates that these two systems interact in modulating memory storage. The experiments reported here examined interactions between the amygdala noradrenergic and muscarinic cholinergic systems. The results indicate that activation of muscarinic cholinergic mechanisms in the amygdala enhances retention, and that such activation mediates the facilitatory effects of systemically administered oxotremorine. beta-Noradrenergic agonists appear to exert their effects in the amygdala by activating the release of acetylcholine.

Interaction of GABAergic and β-noradrenergic drugs in the regulation of memory storage

These experiments examined the interaction of drugs affecting noradrenergic and GABAergic systems, administered post-training, in influencing retention of an inhibitory avoidance response. Male CD1 mice (23-28 g) were trained in an inhibitory avoidance task, given immediate post-training ip injections of saline or GABAergic and adrenergic drugs administered either alone or concurrently. Retention was tested 48 h later. In agreement with extensive previous evidence, the GABAergic antagonist bicuculline (0.3, 1.0, or 3.0 mg/kg) produced dose-dependent (inverted-U) enhancement of retention and the GABAergic agonist muscimol (1.0 mg/kg) impaired retention. The retention-enhancing effects of bicuculline were blocked by concurrent administration of the beta-nor-adrenoceptor antagonist propranolol (2.0 mg/kg). Also in agreement with previous evidence, the beta-adrenoceptor agonist clenbuterol (0.030, 0.100, or 0.300 mg/kg, ip) produced dose-dependent (inverted-U) enhancement of retention. Clenbuterol also blocked the retention-impairing effects of muscimol (1.0 mg/kg). In addition, propranolol (2.0 mg/kg) potentiated the retention impairing effects of muscimol (1.0 or 3.0 mg/kg, ip). These findings support the view that GABAergic systems modulate memory through an interaction with beta-noradrenergic mechanisms.