Psychostimulants and cognition: a continuum of behavioral and cognitive activation.

Psychostimulants such as cocaine have been used as performance enhancers throughout recorded history. Although psychostimulants are commonly prescribed to improve attention and cognition, a great deal of literature has described their ability to induce cognitive deficits, as well as addiction. How can a single drug class be known to produce both cognitive enhancement and impairment? Properties of the particular stimulant drug itself and individual differences between users have both been suggested to dictate the outcome of stimulant use. A more parsimonious alternative, which we endorse, is that dose is the critical determining factor in cognitive effects of stimulant drugs. Herein, we review several popular stimulants (cocaine, amphetamine, methylphenidate, modafinil, and caffeine), outlining their history of use, mechanism of action, and use and abuse today. One common graphic depiction of the cognitive effects of psychostimulants is an inverted U-shaped dose-effect curve. Moderate arousal is beneficial to cognition, whereas too much activation leads to cognitive impairment. In parallel to this schematic, we propose a continuum of psychostimulant activation that covers the transition from one drug effect to another as stimulant intake is increased. Low doses of stimulants effect increased arousal, attention, and cognitive enhancement; moderate doses can lead to feelings of euphoria and power, as well as addiction and cognitive impairment; and very high doses lead to psychosis and circulatory collapse. This continuum helps account for the seemingly disparate effects of stimulant drugs, with the same drug being associated with cognitive enhancement and impairment.

MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression.

Memory impairment is a common feature of conditions that involve changes in inflammatory signaling in the brain, including traumatic brain injury, infection, neurodegenerative disorders, and normal aging. However, the causal importance of inflammatory mediators in cognitive impairments in these conditions remains unclear. Here we show that specific immune proteins, members of the major histocompatibility complex class I (MHC class I), are essential for normal hippocampus-dependent memory, and are specifically required for NMDAR-dependent forms of long-term depression (LTD) in the healthy adult hippocampus. In ß2m(-/-)TAP(-/-)mice, which lack stable cell-surface expression of most MHC class I proteins, NMDAR-dependent LTD in area CA1 of adult hippocampus is abolished, while NMDAR-independent forms of potentiation, facilitation, and depression are unaffected. Altered NMDAR-dependent synaptic plasticity in the hippocampus of ß2m(-/-)TAP(-/-)mice is accompanied by pervasive deficits in hippocampus-dependent memory, including contextual fear memory, object recognition memory, and social recognition memory. Thus normal MHC class I expression is essential for NMDAR-dependent hippocampal synaptic depression and hippocampus-dependent memory. These results suggest that changes in MHC class I expression could be an unexpected cause of disrupted synaptic plasticity and cognitive deficits in the aging, damaged, and diseased brain.

The competitive NMDA receptor antagonist CPP disrupts cocaine-induced conditioned place preference, but spares behavioral sensitization.

Recently, the notion that memory and addiction share similar neural substrates has become widely accepted. N-methyl-d-aspartate receptors (NMDAR) are the cornerstones of synaptic models of memory. The present study examined the effect of the competitive NMDAR antagonist CPP on the induction of behavioral sensitization and conditioned place preference to cocaine. Conditioned place preference is an associative memory model of drug seeking, while sensitization is a non-associative model of the transition from casual to compulsive use. There were three principal findings: (1) co-administration of CPP and cocaine altered the acute response to cocaine, suggesting a direct interaction between the two drugs; (2) NMDAR antagonism had no effect on behavioral sensitization; and (3) NMDAR antagonism abolished conditioned place preference. A review of prior evidence supporting a role for NMDARs in sensitization suggests that NMDAR antagonists directly interfere with cocaine's psychostimulant effects, and this interaction could be misinterpreted as a disruption of sensitization. Finally, we suggest that addiction recruits multiple kinds of plasticity, with sensitization recruiting NMDAR-independent mechanisms.

Interactions between modafinil and cocaine during the induction of conditioned place preference and locomotor sensitization in mice: implications for addiction.

Modafinil is a wake-promoting drug effective at enhancing alertness and attention with a variety of approved and off-label applications. The mechanism of modafinil is not well understood but initial studies indicated a limited abuse potential. A number of recent publications, however, have shown that modafinil can be rewarding under certain conditions. The present study assessed the reinforcing properties of modafinil using conditioned place preference and locomotor sensitization in mice. Experiment 1 examined a high dose of modafinil (75 mg/kg) as well as its interactions with cocaine (15 mg/kg). Cocaine alone and modafinil co-administered with cocaine induced sensitization of locomotor activity; modafinil alone showed little or no locomotor sensitization. Animals given modafinil alone, cocaine alone, and modafinil plus cocaine exhibited a strong and roughly equivalent place preference. When tested for sensitization using a low challenge dose of modafinil, cross-sensitization was observed in all cocaine-pretreated mice. Experiment 2 examined a low dose of modafinil that is similar to the dose administered to humans and has been shown to produce cognitive enhancements in mice. Low dose modafinil (0.75 mg/kg) did not produce conditioned place preference or locomotor sensitization. Together, these results suggest that modafinil has the potential to produce reward, particularly in cocaine addicts, and should be used with caution. However, the typical low dose administered likely moderates these effects and may account for lack of addiction seen in humans.

Automated assessment of pavlovian conditioned freezing and shock reactivity in mice using the video freeze system.

The Pavlovian conditioned freezing paradigm has become a prominent mouse and rat model of learning and memory, as well as of pathological fear. Due to its efficiency, reproducibility and well-defined neurobiology, the paradigm has become widely adopted in large-scale genetic and pharmacological screens. However, one major shortcoming of the use of freezing behavior has been that it has required the use of tedious hand scoring, or a variety of proprietary automated methods that are often poorly validated or difficult to obtain and implement. Here we report an extensive validation of the Video Freeze system in mice, a "turn-key" all-inclusive system for fear conditioning in small animals. Using digital video and near-infrared lighting, the system achieved outstanding performance in scoring both freezing and movement. Given the large-scale adoption of the conditioned freezing paradigm, we encourage similar validation of other automated systems for scoring freezing, or other behaviors.

Sleep deprivation and Pavlovian fear conditioning.

Sleep has been suggested to play a role in memory consolidation. Prior rodent studies have used sleep deprivation to examine this relationship. First, we reexamined the effects of sleep deprivation on Pavlovian fear conditioning. We found that the deprivation method itself (i.e., gentle handling) induced deficits independent of sleep. Second, we examined an alternative method of sleep deprivation using amphetamine and found that this method failed to induce amnesia. These data indicate that sleep deprivation is a problematic way to examine the role of sleep in memory consolidation, and an alternative paradigm is proposed.

Sleep selectively enhances hippocampus-dependent memory in mice.

Sleep has been implicated as playing a critical role in memory consolidation. Emerging evidence suggests that reactivation of memories during sleep may facilitate the transfer of declarative memories from the hippocampus to the neocortex. Previous rodent studies have utilized sleep-deprivation to examine the role of sleep in memory consolidation. The present study uses a novel, naturalistic paradigm to study the effect of a sleep phase on rodent Pavlovian fear conditioning, a task with both hippocampus-dependent and -independent components (contextual vs. cued memories). Mice were trained 1 hour before their sleep/rest phase or awake/active phase and then tested for contextual and cued fear 12 or 24 hr later. The authors found that hippocampus-dependent contextual memory was enhanced if tested after a sleep phase within 24 hr of training. This enhancement was specific to context, not cued, memory. These findings provide direct evidence of a role for sleep in enhancing hippocampus-dependent memory consolidation in rodents and detail a novel paradigm for examining sleep-induced memory effects.

Cocaine and Pavlovian fear conditioning: dose-effect analysis.

Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1-15mg/kg of cocaine on Pavlovian contextual and cued fear conditioning in mice. As expected, pre-training cocaine dose-dependently produced hyperactivity and disrupted freezing. Surprisingly, when the mice were tested off-drug later, the group pre-treated with a moderate dose of cocaine (15mg/kg) displayed significantly less contextual and cued memory, compared to saline control animals. Conversely, mice pre-treated with a very low dose of cocaine (0.1mg/kg) showed significantly enhanced fear memory for both context and tone, compared to controls. These results were not due to cocaine's anesthetic effects, as shock reactivity was unaffected by cocaine. The data suggest that despite cocaine's reputation as a performance-enhancing and anxiogenic drug, this effect is seen only at very low doses, whereas a moderate dose disrupts hippocampus and amygdala-dependent fear conditioning.

Context fear learning in the absence of the hippocampus.

Lesions of the rodent hippocampus invariably abolish context fear memories formed in the recent past but do not always prevent new learning. To better understand this discrepancy, we thoroughly examined the acquisition of context fear in rats with pretraining excitotoxic lesions of the dorsal hippocampus. In the first experiment, animals received a shock immediately after placement in the context or after variable delays. Immediate shock produced no context fear learning in lesioned rats or controls. In contrast, delayed shock produced robust context fear learning in both groups. The absence of fear with immediate shock occurs because animals need time to form a representation of the context before shock is presented. The fact that it occurs in both sham and lesioned rats suggests that they learn about the context in a similar manner. However, despite learning about the context in the delay condition, lesioned rats did not acquire as much fear as controls. The second experiment showed that this lesion-induced deficit could be overcome by increasing the number of conditioning trials. Lesioned animals learned normally after multiple shocks, regardless of freezing level or trial spacing. The last experiment showed that animals with complete hippocampus lesions could also learn about the context, although the same lesions produced devastating retrograde amnesia. These results demonstrate that alternative systems can acquire context fear but do so less efficiently than the hippocampus.

Role of the basolateral amygdala in the storage of fear memories across the adult lifetime of rats.

The basolateral amygdala (BLA) is intimately involved in the development of conditional fear. Converging lines of evidence support a role for this region in the storage of fear memory but do not rule out a time-limited role in the memory consolidation. To examine this issue, we assessed the stability of BLA contribution to fear memories acquired across the adult lifetime of rats. Fear conditioning consisted of 10 tone-shock pairings in one context (remote memory), followed 16 months later by 10 additional tone-shock pairings with a novel tone in a novel context (recent memory). Twenty-four hours after recent training, rats were given NMDA or sham lesions of the BLA. Contextual and tone freezing were independently assessed in individual test sessions. Sham-lesioned rats showed high and comparable levels of freezing across all context and tone tests. In contrast, BLA-lesioned rats displayed robust freezing deficits across both recent and remote tests. Subsequent open-field testing revealed no effects of BLA lesions on activity patterns in a dark open field or during bright light exposure. Lesioned rats were able to reacquire normal levels of context-specific freezing after an overtraining procedure (76 unsignaled shocks). Together, these findings indicate that BLA lesions do not disrupt freezing behavior by producing hyperactivity, an inability to suppress behavior, or an inability to freeze. Rather, the consistent pattern of freezing deficits at both training-to-lesion intervals supports a role for the BLA in the permanent storage of fear memory.

Analysis of probabilistic classification learning in patients with Parkinson's disease before and after pallidotomy surgery.

This study examined the characteristics of probabilistic classification learning, a form of implicit learning previously shown to be impaired in patients with basal ganglia dysfunction (e.g., Parkinson's disease). In this task, subjects learn to predict the weather using associations that are formed gradually across many trials, because of the probabilistic nature of the cue-outcome relationships. Patients with Parkinson's disease, both before and after pallidotomy, and age-matched control subjects, exhibited evidence of probabilistic classification learning across 100 training trials. However, pallidotomy appears to hinder the learning of associations most implicit in nature (i.e., weakly associated cues). Although subjects were most sensitive to single-cue associations when learning the task, there is evidence that cue combinations contribute significantly to probability learning. The utility of multiple dependent measures is discussed.