Suzanne Erb

Neurocognitive deficits in cocaine users: a quantitative review of the evidence.

Studies on the neurocognitive effects of cocaine abuse are equivocal with respect to the specific types of deficits observed, although the vast majority of studies indicate that at least some deficits in certain broad functions such as attention, learning and memory, executive functions, and response speed exist. All of these studies based their results on null hypothesis statistical significance testing (NHSST). It is argued that effect size analysis, which provides information about the magnitude of difference, offers a more valid index of cognitive impairments in a population when compared to NHSST. Accordingly, the objective of the current study was to conduct an effect size analysis (or a meta-analysis in cases where the same test measure was utilized in more than one study) to determine the type and the magnitude of the specific cognitive deficits found as a result of cocaine use. Effect sizes were calculated for each test variable across 15 empirical studies that met inclusion criteria. The results from 481 cocaine users and 586 healthy normal controls revealed that cocaine use had the largest effect on several measures of attention (0.40 0.50) were also obtained on tests of visual memory and working memory. Minimal effect sizes (d<0.30) were obtained on tests of verbal fluency and other language functions and sensory-perceptual functions. Tests of executive functioning produced mixed findings and were interpreted in terms of degree rather than nature of impairment. The results are consistent with findings from neuroimaging and neurochemical studies that have found cocaine use to be associated with dysfunctions in the anterior cingulate gyrus and orbitofrontal cortex; these regions are highly implicated in the mediation of attentional and executive functions, respectively. Methodological limitations of the empirical studies included in the analysis are discussed.

Evaluation of the relationship between anxiety during withdrawal and stress-induced reinstatement of cocaine seeking

The initial termination of cocaine consumption in human addicts is associated with heightened anxiety states and low levels of craving. Craving, however, tends to increase progressively over time, remains high for extended periods of time, and can be exacerbated by stressors, leading to relapse. Laboratory rats, likewise, exhibit heightened states of anxiety after withdrawal from drug, and follow a time course of cocaine seeking that parallels the time course of craving reported in humans. In addition, laboratory rats show heightened susceptibility to relapse when exposed to stressors after extended periods of withdrawal, and exhibit persistent and heightened expressions of stress-induced anxiety. The general objective of this paper is to consider the relationship between anxiety states after withdrawal from cocaine and stress-induced reinstatement of cocaine seeking in laboratory rats, and to identify the neural substrates involved. The focus of the review is on studies addressing the roles of corticotropin-releasing factor (CRF) and noradrenaline pathways of the extended amygdala circuitry, and their direct or indirect interactions with the mesocorticolimbic dopamine system, in anxiety after withdrawal from cocaine and stress-induced reinstatement of cocaine seeking. Furthermore, the effects of time after withdrawal from cocaine and amount of cocaine exposure during self-administration on the activity of CRF, noradrenaline, and dopamine pathways of the extended amygdala and mesocorticolimbic systems will be considered. The review will highlight how changing levels of activity within these systems may serve to alter the nature of the relationship between anxiety and stress-induced reinstatement of cocaine seeking at different times after withdrawal from cocaine.

Stress-induced Relapse to Drug Seeking in the Rat; Role of the Bed Nucleus of the Stria Terminalis and Amygdala

There is growing interest in the role that the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA), components of the extended amygdala, play in drug addiction. Within the BNST and CeA, there is an extensive system of intrinsic, primarily GABAergic, interconnections known to synthesize a variety of neuropeptides, including corticotrophin-releasing factor (CRF). The actions of CRF at extrahypothalamic sites, including the BNST and CeA, have been implicated in stress responses and in the aversive effects of withdrawal from drugs of abuse. Most recently, we have shown a critical role for extrahypothalamic CRF in stress-induced reinstatement of drug seeking in rats. In attempting to determine which brain circuitry mediates the effect of stress on relapse and, more specifically, where in the brain CRF acts to initiate the behaviours involved in relapse, we focused on the BNST and CeA. In the present paper, we summarize studies we have conducted that explore the role of these brain sites in stress-induced relapse to heroin and cocaine seeking, and then consider how our findings can be understood within the more general context of what is known about the role of the BNST and CeA in stress-related and general approach behaviours, such as drug seeking.

Effects of repeated yohimbine on the extinction and reinstatement of cocaine seeking.

Acute exposure to the pharmacological stressor yohimbine (YOH) reinstates drug seeking in rats. The present experiments investigated whether repeated exposure to YOH during extinction training affects the time-course of extinction and the magnitude of subsequent YOH- or footshock-induced reinstatement of cocaine seeking. Rats trained to self-administer cocaine were given five days of extinction training, during which they were injected with YOH (1.25 mg/kg, i.p.) either before or after daily extinction sessions. Following additional extinction training in the absence of YOH, animals were tested for reinstatement to a YOH (1.25 mg/kg, i.p.) or footshock (20 min, intermittent, 0.9 mA per 0.5 s shock) challenge. Animals injected with YOH before daily extinction sessions showed an attenuated rate of extinction, relative to control animals. Following additional extinction training in the absence of YOH treatment, these same animals showed a marked attenuation of YOH-induced reinstatement of cocaine seeking. YOH treatment during extinction did not, however, affect the magnitude of reinstatement induced by footshock. These findings demonstrate that repeated exposure to a stressor during extinction training can modulate the processes governing extinction learning and the subsequent reinstatement of drug seeking induced by that stressor.

Antagonism of cannabinoid 1 receptors reverses the anxiety-like behavior induced by central injections of corticotropin-releasing factor and cocaine withdrawal

The endocannabinoid (eCB) system is an important regulator of the stress response and mediates several stress-related behaviors, including anxiety. Despite anatomical evidence that eCBs interact with the principle stress peptide, corticotropin-releasing factor (CRF), few data exist that address functional interactions between these systems. Accordingly, we examined the effects of the CB1 receptor antagonist, AM251, on behavioral anxiety induced by (1) exogenous CRF, and (2) withdrawal from chronic cocaine exposure (mediated by CRF). After behavioral testing, we collected blood and assessed plasma corticosterone levels. In Experiment 1, male Long-Evans rats were pretreated with AM251 (0, 10, 100, or 200 μg, i.c.v.), followed by CRF (0 or 0.5 μg, i.c.v.), before testing for anxiety-like behavior in the elevated plus maze (EPM). In Experiment 2, rats were exposed to cocaine (20 mg/kg, i.p.) or saline for 14 consecutive days. Forty-eight hours following cocaine exposure, rats were pretreated with AM251 (0, 10, or 100 μg, i.c.v.) and tested in the EPM. AM251 produced an anxiogenic response at the highest dose, but reversed the behavioral anxiety induced by CRF and withdrawal from chronic cocaine in a dose-dependent manner. AM251 also increased plasma corticosterone levels, but did so irrespective of CRF treatment or cocaine preexposure. Our findings suggest that the anxiogenic effects of CRF and cocaine withdrawal are mediated, at least in part, by CB1 receptor transmission, and provide evidence in support of eCB-CRF interactions that are independent of the hypothalamic-pituitary-adrenal axis.

Cocaine pre-exposure enhances CRF-induced expression of c-fos mRNA in the central nucleus of the amygdala: An effect that parallels the effects of cocaine pre-exposure on CRF-induced locomotor activity

There is evidence that cocaine pre-exposure produces changes in the responsivity of central corticotropin-releasing factor (CRF) systems and that these systems mediate some of the drug-related behavioural effects of acute stressors. The present experiment was conducted to assess the effects of repeated cocaine exposure on CRF-induced neuronal activation within two regions of the extended amygdala, the central nucleus of the amygdala (CeA) and lateral bed nucleus of the stria terminalis (BNST). In addition, CRF-induced neuronal activation was compared with CRF-induced locomotor activity. Rats were injected for 7 days with cocaine (days 1 and 7 in test chambers; days 2-6 in homecages) or saline. After 10 drug-free days, locomotor responsiveness to intracerebroventricular (i.c.v.) injections of CRF and Vehicle was assessed over 2-h test periods. Twenty-four to 48 h following testing for locomotor activity, animals were injected with either CRF or Vehicle, 30 min before being sacrificed. Subsequently, the brains were processed by in situ hybridization for c-fos mRNA, a widely used marker of neuronal activation, in the CeA and BNST. In CeA, i.c.v. CRF enhanced the expression of c-fos mRNA in cocaine, but not saline, pre-exposed animals; in the same animals, i.c.v. CRF resulted in enhanced locomotor activity in cocaine, but not saline, pre-exposed animals. The results demonstrate that repeated exposure to cocaine changes the neuronal response to CRF in the CeA; furthermore, they suggest that these changes in the CeA could potentially be of functional significance in the effects of repeated cocaine exposure on CRF-induced locomotor activity.

Central injections of noradrenaline induce reinstatement of cocaine seeking and increase c-fos mRNA expression in the extended amygdala.

We recently reported that central injections of noradrenaline (NA) induce reinstatement of cocaine seeking in rats. Here, we replicate and extend our finding to an additional dose of NA and show that it is associated with the induction of c-fos mRNA expression (a marker of neuronal activation) in functionally relevant brain regions, including the bed nucleus of the stria terminalis and central nucleus of the amygdala.

Activation of central neurokinin-1 receptors induces reinstatement of cocaine-seeking behavior

A number of neurochemical systems have been implicated in mediating relapse to drug-seeking behavior. Substance P (SP) is a neuropeptide that interacts with some of these systems, suggesting a possible role for SP and its preferred receptor, the neurokinin-1 (NK-1) receptor, in the mediation of relapse. In this study, we examined whether selective activation of NK-1 receptors induces reinstatement of cocaine-seeking behavior, and whether endogenous activity at these receptors is involved in mediating cocaine-induced reinstatement. For each experiment, rats were trained to self-administer cocaine for 8--10 days, and following a period of extinction, tests for reinstatement were given. To examine the effects of NK-1 receptor activation on reinstatement of cocaine-seeking behavior, animals received an intracerebroventricular (ICV) infusion of the selective NK-1 receptor agonist, [Sar(9)Met(O(2))(11)]-SP (0, 1, 3 microg), immediately prior to the test session. To examine the role of endogenous NK-1 receptor activity on cocaine-induced reinstatement, rats were pretreated with ICV infusions of the selective NK-1 receptor antagonists, RP 67580 (0, 0.1, 0.5, 2.5 nmol) or GR 82334 (0, 2, 10, 50 pmol), prior to systemic priming injections of cocaine (10mg/kg or 20mg/kg; i.p.). The results showed that [Sar(9)Met(O(2))(11)]-SP induced reinstatement of cocaine-seeking behavior, but that RP 67580 and GR 82334 had no effect on cocaine-induced reinstatement. These findings suggest that while activation of NK-1 receptors is capable of inducing reinstatement of cocaine-seeking behavior, endogenous activity at these receptors is not involved in mediating the priming effects of cocaine on reinstatement of drug-seeking behavior.

Effects of central neurokinin-1 receptor antagonism on cocaine- and opiate-induced locomotor activity and self-administration behaviour in rats

The neuropeptide substance P (SP) and its preferred receptor, the neurokinin-1 (NK-1) receptor, have been implicated in some of the reward-related behavioural effects of abused drugs, including psychostimulants and opiates. The first objective of the present series of experiments was to assess the role of the NK-1 receptor in two reward-related behavioural effects of cocaine: locomotor activity and self-administration. In tests for locomotor activity, rats were given intracerebroventricular (ICV) infusions of the selective NK-1 receptor antagonist, GR82334 (0, 10, 50 pmol), prior to systemic injections of cocaine. In self-administration experiments, rats were trained to self-administer cocaine on a fixed-ratio 5 (FR5) schedule of reinforcement. Following acquisition of stable responding, animals were pretreated with GR82334 (0, 2, 10, 50 pmol; ICV) prior to subsequent self-administration sessions. Based on evidence suggesting a potentially selective role for NK-1 receptors in opiate reward, we also examined the effects of GR82334 on morphine-induced locomotor activity and heroin self-administration. Results showed that GR82334 had no effect on cocaine-induced locomotor activity or cocaine self-administration, but attenuated morphine-induced locomotor activity and increased heroin self-administration. These findings suggest that endogenous activity at NK-1 receptors may play a specific role in opiate-induced, but not cocaine-induced, locomotor activation and reinforcement.

A role for corticotropin-releasing factor in the long-term expression of behavioral sensitization to cocaine.

Corticotropin-releasing factor (CRF) has been implicated in a number of the behavioral and biochemical effects of cocaine. We recently reported that central injections of CRF produce a potentiated locomotor response in animals that had been given repeated injections of cocaine up to 4 weeks earlier. We now report that with as few as 1 or 3 exposures to cocaine (total of 45 mg/kg, i.p., per day), and a drug-free period of 28 days, i.c.v. injections of CRF (0.5 microg) produce augmented locomotor responses, similar to those induced by cocaine (10 mg/kg, i.p.) itself. In addition, in animals pre-exposed to cocaine for 3 days, pre-treatment with the CRF receptor antagonist, D-Phe CRF(12-41) (1 microg, i.c.v.), blocks the expression of behavioral sensitization to a cocaine challenge after a 28-day drug-free period. These results demonstrate that short-term exposure to cocaine produces a form of long-term sensitization within systems upon which CRF acts and that activation of CRF receptors is importantly involved in the expression of behavioral sensitization to cocaine.