Disruptive Effects Of Cocaine Research Articles

Cocaine diminishes consolidation of cued fear memory in female rats through interactions with ventral hippocampal D2 receptors

In addition to cocaine's addictive properties, cocaine use may lead to heightened risk-taking behavior. The disruptive effects of cocaine on aversive memory formation may underlie this behavior. The present study investigated the effects of cocaine on fear memory using a cued fear conditioning paradigm in female Sprague Dawley rats, and further determined the role of D2 receptors in modulating the effect of cocaine on cued fear expression. Animals received six evenly spaced shocks preceded by a tone. The following day, rats were returned to the fear chamber where tones, but no shocks, were delivered. In Experiment 1, separate or concurrent administrations of cocaine (15 mg/kg; i.p.) and the D2 receptor antagonist eticlopride (0.1 mg/kg; i.p.) were given immediately after conditioning trials. It was determined that cocaine administration during the consolidation period diminished the expression of cued fear during the subsequent test day. Concurrent eticlopride administration attenuated this effect, indicating the involvement of D2 receptors in the deleterious effects of cocaine on fear memory consolidation. In Experiment 2, eticlopride (0.05 μg) was infused directly into the ventral hippocampus (VH) after fear conditioning and before cocaine administration. Cocaine continued to disrupt consolidation of cued and contextual fear memory, and concurrent intra-VH eticlopride blocked this effect, thereby demonstrating that VH D2 receptors mediate cocaine-induced impairment of fear memory consolidation. Overall, the present study provides evidence that acute cocaine administration impairs aversive memory formation and establishes a potential circuit through which cocaine induces its detrimental effects on fear memory consolidation.

Effects of chronic cocaine self-administration and N-acetylcysteine on learning, cognitive flexibility, and reinstatement in nonhuman primates

Cocaine use disorder (CUD) is associated with cognitive deficits that have been linked to poor treatment outcomes. An improved understanding of cocaine's deleterious effects on cognition may help optimize pharmacotherapies. Emerging evidence implicates abnormalities in glutamate neurotransmission in CUD and drugs that normalize glutamatergic homeostasis (e.g., N-acetylcysteine [NAC]) may attenuate CUD-related relapse behavior. The present studies examined the impact of chronic cocaine exposure on touchscreen-based models of learning (repeated acquisition) and cognitive flexibility (discrimination reversal) and, also, the ability of NAC to modulate cocaine self-administration and its capacity to reinstate drug-seeking behavior. First, stable repeated acquisition and discrimination reversal performance was established. Next, high levels of cocaine-taking behavior (2.13-3.03mg/kg/session) were maintained for 150 sessions during which repeated acquisition and discrimination reversal performance was probed periodically. Finally, the effects of NAC treatment were examined on cocaine self-administration and, subsequently, extinction and reinstatement. Cocaine self-administration significantly impaired performance under both cognitive tasks; however, discrimination reversal was disrupted considerably more than acquisition. Performance eventually approximated baseline levels during chronic exposure. NAC treatment did not perturb ongoing self-administration behavior but was associated with significantly quicker extinction of drug-lever responding. Cocaine-primed reinstatement did not significantly differ between groups. The disruptive effects of cocaine on learning and cognitive flexibility are profound but performance recovered during chronic exposure. Although the effects of NAC on models of drug-taking and drug-seeking behavior in monkeys are less robust than reported in rodents, they nevertheless suggest a role for glutamatergic modulators in CUD treatment programs.

Chronic cocaine causes long-term alterations in circadian period and photic entrainment in the mouse

The disruptive effects of cocaine on physiological, behavioral and genetic processes are well established. However, few studies have focused on the actions of cocaine on the adult circadian timekeeping system, and none have explored the circadian implications of long-term (weeks to months) cocaine exposure. The present study was undertaken to explore the actions of such long-term cocaine administration on core circadian parameters in mice, including rhythm period, length of the nocturnal activity period and photic entrainment. For cocaine dosing over extended periods, cocaine was provided in drinking water using continuous and scheduled regimens. The impact of chronic cocaine on circadian regulation was evidenced by disruptions of the period of circadian entrainment and intrinsic free-running circadian period. Specifically, mice under a skeleton photoperiod (1-min pulse of dim light delivered daily) receiving continuous ad libitum cocaine entrained rapidly to the light pulse at activity onset. Conversely, water controls entrained more slowly at activity offset through a process of phase-delays, which resulted in their activity rhythms being entrained 147° out of phase with the cocaine group. This pattern persisted after cocaine withdrawal. Next, mice exposed to scheduled daily cocaine presentations exhibited free-running periods under constant darkness that were significantly longer than water controls and which also persisted after cocaine withdrawal. These cocaine-induced perturbations of clock timing could produce chronic psychological and physiological stress, contributing to increased cocaine use and dependence.

Cocaine withdrawal influences paternal behavior and associated central expression of vasopressin, oxytocin and tyrosine hydroxylase in mandarin voles

Although the disruptive effects of cocaine on the maternal care are well known, little is known about paternal care in the context of cocaine abuse. Vasopressin (AVP), oxytocin (OT) and dopamine (DA) have been found to regulate paternal behavior and are also involved in cocaine abuse. Mandarin voles (Microtus mandarinus) are socially monogamous and display high levels of paternal care. Here, we investigated whether paternal behavior and associated central levels of AVP, OT and DA were altered following 24h of withdrawal from 4day administration of 20mg/kg/day cocaine. Our data shows that vole fathers did not experience altered levels of locomotion during an open field test. However, compared to controls, cocaine attenuated licking/grooming and contact behavior and shortened the latency to crouching, contact and pup retrieval. Last, fewer AVP and OT immunoreactive neurons in the paraventricular nucleus and more tyrosine hydroxylase immunoreactive neurons in the ventral tegmental area were observed in cocaine-treated fathers. These results indicate that cocaine withdrawal disturbs the expression of partial paternal behavior by altering central levels of AVP, OT and DA.

Tolerance to cocaine's effects following chronic administration of a dose without detected effects on response rate or pause.

To observe tolerance to drug effects on operant behavior, the dose that researchers have often selected for chronic administration is one that disrupts, but does not abolish, responding. Some evidence suggests that tolerance may develop after chronic administration of relatively smaller doses. The purpose of the present experiment was to assess systematically effects of chronic administration of a dose without detected effect on responding. Specifically, response rates and post-reinforcement pauses of five pigeons key pecking under a three-component multiple fixed-ratio schedule of food reinforcement were observed under chronic cocaine administration. We evaluated the effects of a range of doses (1.0 mg/kg to 17.0 mg/kg) during acute administration. The largest dose that failed to alter responding acutely then was administered chronically (1.0 mg/kg for 1 pigeon, 3.0 mg/kg for 3 pigeons, and 5.6 mg/kg for 1 pigeon). After 30 consecutive sessions of chronic administration, smaller and larger doses occasionally were substituted for the chronic dose. Pigeons then received pre-session saline administration for 30 consecutive sessions, and the post-chronic effects of the series of doses on responding were determined. All subjects developed tolerance to doses of cocaine that initially had caused large decreases in rate, with the magnitude of the effects varying across components of the multiple schedule and subjects. Specifically, tolerance generally was greatest in the components with smaller ratios. Following post-chronic saline administration, tolerance was usually diminished. Overall, the results demonstrate that under these conditions, repeated experience with disruptive effects of cocaine on food-maintained responding is not a necessary factor in the development of tolerance.

Interaction of cocaine with positive GABAA modulators on the repeated acquisition and performance of response sequences in rats

Although positive GABA(A) modulators can attenuate several cocaine-induced behavioral effects, there is a paucity of data on their interaction with cocaine on transition behavior or learning. The current study examined the effects of cocaine (3.2-32 mg/kg), pregnanolone (3.2-24 mg/kg), and lorazepam (0.1-10 mg/kg) alone and in combination in rats responding under a multiple schedule of repeated acquisition and performance. In the acquisition component, subjects acquired a different three-response sequence each session, whereas in the performance component, they responded on the same three-response sequence each session. All three drugs produced dose-dependent rate-decreasing and error-increasing effects. Cocaine was the least effective in decreasing rates and the most effective in increasing the percentage of errors. In combination with pregnanolone (3.2 or 10 mg/kg), the rate-decreasing effects of cocaine were relatively unchanged in both components, but 3.2 mg/kg of pregnanolone enhanced its error-increasing effects and the 10-mg/kg dose produced a significant dose-dependent interaction on errors. The combination of cocaine with lorazepam (0.32 mg/kg, 70-min pretreatment) produced significantly greater rate-decreasing and error-increasing effects than cocaine alone. A 15-min pretreatment with the same dose of lorazepam enhanced the error-increasing effects of small doses and attenuated the effects of larger doses of cocaine. Combinations of pregnanolone and lorazepam produced greater rate-decreasing and error-increasing effects in both components than either drug alone. The present data show that cocaine is more disruptive to learning in rats than pregnanolone or lorazepam, and that the disruptive effects of cocaine can be enhanced by CNS depressants.