Use of virtual meeting and survey technology to assess Covid-19-related mental well-being of healthcare workers.

Background and aims: Healthcare workers (HCWs) throughout the world have been exposed to economic and existential stress during the Covid-19 pandemic. The American Medical Association (AMA) has documented that increased healthcare burden correlates with increased stress, burnout, and psychological burden in HCWs. However, limits on personnel, time, and in person interactions make it challenging to assess mental health outcomes during a pandemic. This pilot study used virtual technology to efficiently assess these outcomes. Setting: Data were collected based on voluntary participation in the Coping with Covid-19 for Caregivers Survey created by AMA. The survey was sent out to approximately 300 participants who included local physicians, medical residents, medical students, and allied health professionals and students who attended a virtual Mental Health Summit. Methods: The AMA developed survey included questions about demographics, overall stress, fear of infection and transmission of the virus, perceived anxiety or depression due to Covid-19, work overload, childcare issues, and sense of meaning and purpose. The AMA allows for up to five additional questions to be added to their survey, therefore five questions regarding support service utilization, perseverance, and resilience during the Covid-19 pandemic, and two items to further understand students' areas of medical interest. The survey was administered using an online platform through the AMA. The data were analyzed using descriptive statistics. Results: There were 81 survey respondents. Based on the results of the survey, "high stress" was found in 52 (64%) participants. 66 (81%) were afraid (moderately or to a great extent) of exposure or transmission, 61 (75%) described high levels of anxiety or depression, and 67 (84%) noted work overload. Despite this increase in stress, most respondents (77%) said they were not likely to reduce their devoted hours to clinical care or research in the next 12 months, and 81% answered that they would not leave their practice or research within two years. Conclusion: Covid-19 has negatively affected the well-being of HCWs. This is a similar trend seen during other times of healthcare strain. Mental health support, work modulation, and various provisions should be explored as means to reduce Covid-19-related negative impacts. The use of an online summit and online data collection methods were appropriate for collecting data on the impact of the Covid-19 pandemic on mental health. This pilot study supports the larger scale implementation of this technology for health informatics research.

Differential modulation of the discriminative stimulus effects of methamphetamine and cocaine by alprazolam and oxazepam in male and female rats.

Drug users often combine benzodiazepines with psychostimulants, such as methamphetamine. However, very little research has been conducted on this type of polydrug use, particularly in female subjects. The present study was therefore designed to examine the effects of two benzodiazepines, alprazolam and oxazepam, on the discriminative stimulus effects of methamphetamine and cocaine in both male and female rats. Rats were trained to discriminate methamphetamine (1.0 mg/kg, ip) or cocaine (10 mg/kg, ip) from saline using a two-lever operant, food-reinforced, drug discrimination design. Pretreatment with oxazepam (5, 10 and 20 mg/kg, ip) significantly attenuated methamphetamine discrimination in both male and female rats. In contrast, however, the high dose of alprazolam (4 mg/kg, ip) actually augmented the subjective effects of lower doses of methamphetamine (0.125 and 0.25 mg/kg, ip). Oxazepam produced similar effects on the subjective effects of cocaine as with methamphetamine, significantly reducing cocaine discrimination in both male and female rats. However, neither the high nor low dose of alprazolam (2 and 4 mg/kg, ip) produced any apparent effect on cocaine discrimination. Finally, while similar results were observed in both male and female rats across these experiments, methamphetamine and cocaine discrimination were more sensitive to oxazepam in female subjects. The results of these experiments suggest that alprazolam and oxazepam can differentially affect the subjective effects of methamphetamine and cocaine. These results also demonstrate that alprazolam can differentially affect the discriminative stimulus effects of methamphetamine and cocaine.

CP-154,526, a CRF type-1 receptor antagonist, attenuates the cue-and methamphetamine-induced reinstatement of extinguished methamphetamine-seeking behavior in rats.

RATIONALE: Previous studies from our laboratory and others have indicated a role for the hypothalamo-pituitary-adrenal (HPA) axis in the extinction/reinstatement animal model of cocaine relapse OBJECTIVE: This present study was designed to investigate the potential role for the HPA axis in the cue- and methamphetamine-induced reinstatement of extinguished methamphetamine-seeking behavior by determining the effects of ketoconazole and the corticotropin-releasing hormone (CRF) type 1 receptor antagonist, CP-154,526, on these behaviors. MATERIALS AND METHODS: Male Wistar rats were trained to self-administer methamphetamine (0.03 mg/kg/infusion). The delivery of methamphetamine was paired with the presentation of a tone and the illumination of a house light. Once stable responding was reached, the rats were placed into extinction. The effects of pretreatment with ketoconazole (25, 50, or 100 mg/kg, i.p.) or CP-154,526 (20 or 40 mg/kg, i.p.; 3 micro g, i.c.v) on cue-induced reinstatement were then evaluated. RESULTS: Cue-induced reinstatement was not significantly attenuated by pretreatment with peripherally administered CP-154,526 or by pretreatment with ketoconazole. However, centrally administered CP-154,526 (3 micro g, i.c.v.) significantly attenuated cue-induced reinstatement. In a separate group of rats, CP-154,526 (20 mg/kg, i.p.) attenuated methamphetamine-induced reinstatement (0.12 mg/kg priming infusion); whereas a higher dose (40 mg/kg) was necessary to attenuate reinstatement induced by a priming infusion of 0.24 mg/kg/infusion. Ketoconazole (50 mg/kg) did not affect reinstatement induced by a 0.12 mg/kg priming infusion and, therefore, was not tested at the higher methamphetamine priming dose. CONCLUSIONS: These data suggest an important role for CRF in the cue- and methamphetamine-induced reinstatement of extinguished methamphetamine-seeking behavior.

Neither non-contingent electric footshock nor administered corticosterone facilitate the acquisition of methamphetamine self-administration.

Previous research has indicated a role for the hypothalamo-pituitary-adrenal (HPA) axis in the acquisition of intravenous cocaine self-administration since both exposure to stressors and exogenous injections of corticosterone facilitate this behavior. The present experiment was designed to determine whether electric footshock or pretreatment with corticosterone would produce similar effects on the acquisition of methamphetamine self-administration in male Wistar rats. Following initial food training, the rats were allowed to self-administer methamphetamine in ascending doses (0.0075-0.12 mg/kg/infusion) that were doubled weekly. Neither non-contingent electric footshock nor treatment with corticosterone (2.0 mg/kg, i.p.) affected the lowest dose at which the rats first acquired methamphetamine self-administration (0.015 mg/kg/infusion). The treatment groups all had similar inverted "U"-shaped acquisition curves typical of psychostimulants. Although these experiments do not indicate a major role for the HPA axis in the acquisition of methamphetamine self-administration, more studies need to be conducted to further evaluate the effects of the HPA axis on the acquisition of methamphetamine self-administration before a potential role can be ruled out.

Pretreatment with corticosterone attenuates the nucleus accumbens dopamine response but not the stimulant response to cocaine in rats.

It has been suggested that stress, via corticosterone secretion, can modulate some of the behavioural responses to cocaine. In particular, we have demonstrated that daily exposure to electric footshock stress or daily pretreatment with corticosterone shifts the ascending limb of the dose-response curve for the acquisition of cocaine self-administration upwards and to the left. It has been suggested that this corticosterone-induced increase in sensitivity to low doses of cocaine is associated with an enhancement of dopaminergic neurotransmission. The present study was designed to test this hypothesis. Adult male rats were pretreated with corticosterone (2.0 mg/kg intraperitoneally) 15 min prior to an injection of cocaine (5.0, 10.0 or 20.0 mg/kg intraperitoneally), and motor activity and extracellular dopamine concentrations in the nucleus accumbens were monitored. Cocaine administration resulted in dose-related increases in motor activity that were unaffected by pretreatment with corticosterone. However, rather than augmenting cocaine-induced increases in dopamine in the nucleus accumbens, corticosterone pretreatment actually caused attenuation at the two highest doses of cocaine tested. These data suggest dissociation between locomotor activation and nucleus accumbens dopamine responses to cocaine, and indicate that other brain regions and/or mechanisms may be involved in the changes in sensitivity to cocaine induced by corticosterone.

Effects of CP-154,526 on responding during extinction from cocaine self-administration in rats.

Conditioned cues associated with cocaine induce craving and relapse. Although the role of corticotropin releasing hormone (CRH) in stress- and cocaine-induced relapse has been reported, its involvement in cue-induced behavior has not been established. Using responding during extinction as a model of cue-induced craving, we tested the effects of a selective CRH1 receptor antagonist, CP-154,526 (butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine). Rats were trained to respond on a multiple schedule of cocaine self-administration and food reinforcement. On extinction test days, saline was substituted for cocaine. Pretreatment with CP-154,526 (20 mg/kg, i.p.) decreased responding on the cocaine-associated lever during extinction, suggesting an involvement of CRH1 receptors in cue-induced craving.

Effects of saline substitution on responding and plasma corticosterone in rats trained to self-administer different doses of cocaine.

Research from our laboratory has explored the role of the hypothalamo-pituitary-adrenal (HPA) axis in cocaine reinforcement. These experiments were designed to determine the involvement of the HPA axis in extinction. Male Wistar rats were trained to self-administer cocaine [0.125, 0.25, or 0.5 mg/kg/infusion (inf)] and food pellets (45 mg) under a multiple, alternating schedule of reinforcement. When self-administration was stable, saline was substituted for cocaine. Blood samples were taken at the end of the sessions following cocaine self-administration, the first exposure to saline substitution (first); and once the criteria for extinction were met (final). Plasma corticosterone was measured using radioimmunoassays. Although there was a significant increase in the number of infusions obtained during the first saline substitution test by rats trained with 0.5 mg/kg/inf of cocaine, there was a decrease in infusions received when 0.125 mg/kg/inf of cocaine was tested. Following repeated exposure to the extinction conditions, responding by rats trained to self-administer all three doses of cocaine was decreased to similar levels. In addition, there were significant differences in plasma corticosterone in rats trained with different doses of cocaine. Lever-pressing behavior and plasma corticosterone varied during extinction in relation to the training dose of cocaine and according to whether the rats had been exposed to single or repeated extinction testing. These data are discussed in terms of the potential difficulties involved in interpreting the effects of compounds intended to reduce drug reinforcement.

Effects of the CRH receptor antagonist CP-154,526 on intravenous cocaine self-administration in rats.

The role for corticotropin-releasing hormone (CRH) receptors in the maintenance of intravenous cocaine self-administration in rats was investigated using the centrally active, small molecule CRH1 receptor antagonist CP-154,526. In these experiments, adult male Wistar rats were allowed alternating 15-min periods of access to food reinforcement and cocaine self-administration (0.125, 0.25 or 0. 5 mg/kg/infusion) during daily 2-h sessions. A 1-min timeout separated access to the two reinforcers. Pretreatment with CP-154, 526 produced dose-related decreases in cocaine self-administration without affecting food-reinforced responding, suggesting a specific effect of the antagonist on cocaine-maintained behavior. Drug intake was decreased across several doses of cocaine, with the dose-response curve for cocaine self-administration shifted downward and flattened, suggesting that CP-154,526 decreased cocaine reinforcement. Furthermore, responding on the cocaine lever following CP-154,526 pretreatment was significantly suppressed, even during the first 15 min of the session, a time when rats typically sample the cocaine lever during extinction, suggesting that CRH receptors may also be involved in some of the conditioned effects of cocaine as well. These data are discussed in terms of the role for CRH in the neurobehavioral effects of cocaine.

Effects of cocaine self-administration on plasma corticosterone in rats: relationship to hippocampal type II glucocorticoid receptors.

1. The effects of chronic (i.e., 30-day), high-dose (i.e., 1.0 mg/kg/infusion) intravenous cocaine self-administration and non-contingent infusions of cocaine and saline on plasma corticosterone and hippocampal Type II glucocorticoid receptors (GR) were investigated in adult male Wistar rats implanted with indwelling jugular catheters using a self-administration/yoked infusion triad design. 2. In self-administering rats and rats receiving yoked infusions of cocaine, basal corticosterone measured 24 hours after the experimental sessions was reduced relative to yoked-saline controls and to pre-acquisition values. 3. In contrast, corticosterone measured immediately following the self-administration sessions remained unaltered throughout the course of the experiment. 4. In cocaine self-administering rats, the effects on basal corticosterone were observed earlier than they were in rats receiving yoked infusions of cocaine. 5. The effects of self-administered and yoked cocaine were associated with statistically non-significant increases in hippocampal GR density relative to yoked-saline controls as measured by Western blot analysis using the anti-GR monoclonal antibody BuGR2.

Intra-medial prefrontal cortex injections of scopolamine increase instrumental responses for cocaine: an intravenous self-administration study in rats.

The present experiments examined the effects of muscarinic cholinergic receptor blockade in the nucleus accumbens (NAC) and medial prefrontal cortex (MPC) on intravenous cocaine self-administration. Adult male Sprague-Dawley rats were implanted with chronic indwelling jugular catheters and guide cannulae stereotaxically aimed at the NAC or MPC. The rats were then given the opportunity to intravenously self-administer cocaine (0.8 mg/kg/infusion) during daily 2-h sessions. Intra-NAC microinjections of methyl-scopolamine (2, 4, 8, 16, and 32 microg/side) or vehicle did not affect either the number of lever presses made or infusions delivered. On the other hand, intra-MPC injections of scopolamine significantly increased responding, although there was only a trend for an increase in the number of cocaine infusions. The effects of intra-MPC injections of scopolamine (8 and 16 microg/side) on locomotor activity were also evaluated. Intra-MPC injections of scopolamine (16 microg/side) produced significant increases in locomotor activity. However, these same microinjections decreased locomotor activity when the animals also received cocaine (15 mg/kg, i.p.). These results suggest that cholinergic neurotransmission at muscarinic receptors in the MPC is involved in regulating cocaine-maintained responding.

Ketoconazole does not block cocaine discrimination or the cocaine-induced reinstatement of cocaine-seeking behavior.

Ketoconazole is an FDA-approved antifungal agent that also blocks the synthesis of adrenocorticosteroids and functions as a glucocorticoid receptor antagonist. It has been previously demonstrated that this drug blocks the stress-induced reinstatement of cocaine-seeking behavior and reduces low-dose cocaine self-administration in rats. In the present experiments, the effects of ketoconazole on the cocaine-induced reinstatement of extinguished cocaine-seeking behavior and on cocaine discrimination were investigated in male Wistar rats. In rats trained to self-administer cocaine (0.5 mg/kg/infusion) by pressing a lever under a fixed-ratio 4 schedule of reinforcement, cocaine (5-20 mg/kg, IP) dose dependently reinstated cocaine-seeking behavior following at least 10 days of extinction, during which responding on the cocaine lever resulted in no programmed consequences. Ketoconazole (50 mg/kg, IP) failed to block cocaine-induced reinstatement despite blocking cocaine-induced increases in plasma corticosterone. Ketoconazole (25 or 50 mg/kg) also failed to block cocaine discrimination in rats trained to discriminate 10 mg/kg cocaine from saline. In these rats, generalization to the training dose of cocaine was observed in the absence of increases in plasma corticosterone. The results of these experiments indicate that corticosterone may mediate the effects of stressors on cocaine-seeking behavior but not the direct effects of cocaine itself.

Ketoconazole blocks the stress-induced reinstatement of cocaine-seeking behavior in rats: relationship to the discriminative stimulus effects of cocaine.

RATIONALE: Ketoconazole (Keto) is an antifungal agent that also inhibits the synthesis of adrenocorticosteroids and has been reported to act as a glucocorticoid receptor antagonist. OBJECTIVE: The present experiments investigated the effects of Keto on the stressor-induced reinstatement of extinguished cocaine-seeking behavior and on the generalization of a stressor-induced discriminative stimulus to cocaine in rats. METHODS: In the first experiment, male Wistar rats were trained to self-administer cocaine (0.5 mg/kg per infusion, IV) under a fixed-ratio 4 schedule of reinforcement with a 90-s limited hold. Following ten consecutive extinction sessions, the effects of Keto (25 or 50 mg/kg, IP) or vehicle on the ability of EFS (electric footshock; 15 min) to reinstate extinguished cocaine-lever responding were investigated. In the second experiment, rats were trained to discriminate cocaine (10 mg/kg, IP) from saline using a two-lever, food-reinforced drug discrimination design. The effects of Keto (50 mg/kg, IP) or vehicle on the EFS-induced generalization to cocaine were determined. RESULTS: EFS reinstated extinguished cocaine- but not food-reinforced responding. Keto (25 and 50 mg/kg, IP) blocked the EFS-induced reinstatement of cocaine-seeking behavior and significantly attenuated the plasma corticosterone response to EFS. These same doses of Keto failed to affect responding in rats trained to self-administer food pellets under an FR4 schedule of reinforcement. EFS also produced significant cocaine-appropriate responding in rats trained to discriminate the drug from saline. However, Keto (50 mg/kg) failed to block the EFS-induced generalization to cocaine. CONCLUSIONS: Overall, these data suggest that corticosterone contributes to the stressor-induced reinstatement of extinguished cocaine-seeking behavior.

Microinjections of dopamine agonists and cocaine elevate plasma corticosterone: dissociation effects among the ventral and dorsal striatum and medial prefrontal cortex.

There is evidence suggesting the involvement of central dopamine (DA) systems in the regulation of plasma corticosterone (CORT). We examined whether or not microinjections of DA agonists and cocaine into three DA-rich terminal regions, the medial prefrontal cortex (MPC), ventral striatum (VStr) and dorsal striatum (DStr), would increase plasma CORT in Sprague-Dawley rats. The highest dose tested (18 nmol) of a mixture of the dopamine D1 receptor agonist SKF 38393 and the D2 agonist quinpirole (SKF/Quin) increased plasma CORT when injected into each of the three brain regions. Microinjections of the medium dose (i.e., 3 nmol) of SKF/Quin into the VStr also increased plasma CORT, while the injections into the MPC and DStr did not. Systemic pretreatment with haloperidol attenuated the elevated CORT induced by intra-VStr injections of SKF/Quin. Cocaine (25, 50, and 100 microg) also increased CORT when injected into the VStr, but not into the MPC or DStr. Microinjections of local anesthetics, lidocaine (100 microg) and procaine (100 microg), which have similar chemical structures to cocaine, into the VStr did not increase CORT. These results suggest that the VStr plays an important role in mediating the elevated plasma CORT induced by DA agonists and cocaine administration.

Corticosterone facilitates the acquisition of cocaine self-administration in rats: opposite effects of the type II glucocorticoid receptor agonist dexamethasone.

The effect of corticosterone on the acquisition of cocaine-seeking behavior was investigated in rats using ascending dose-response curves for intravenous cocaine self-administration. Rats pretreated daily with corticosterone (2.0 mg/kg i.p.) acquired cocaine self-administration at a lower dose compared with vehicle-treated controls. In contrast, daily corticosterone pretreatment did not alter food-maintained responding. Cocaine self-administration was not affected by the type I (mineralocorticoid) receptor agonist, aldosterone (100 microgram/kg). However, rats treated with the type II (glucocorticoid) receptor agonist, dexamethasone (10 or 100 microgram/kg) did not acquire self-administration at any dose tested. The 100 microgram/kg dose of dexamethasone attenuated food-reinforced behavior and decreased body weight, but these effects were not observed with the 10 microgram/kg dose. Dexamethasone dose-dependently attenuated the plasma corticosterone response to self-administered infusions or intraperitoneal injections of cocaine, indicating that the ability of dexamethasone to block cocaine-induced corticosterone secretion may have contributed to its effects on self-administration. Administration of aldosterone (100 microgram/kg) together with 10 microgram/kg dexamethasone restored self-administration to the level of vehicle-treated rats, suggesting that type I receptor occupation by corticosterone may be required for the acquisition of this behavior. These results indicate that stress-induced corticosterone secretion may provide a substrate through which stressors interact with cocaine reinforcement. Additionally, the finding that dexamethasone blocks the acquisition of cocaine self-administration may be relevant to the development of novel approaches to the treatment of cocaine addiction.

Generalization of a restraint-induced discriminative stimulus to cocaine in rats.

The ability of the interoceptive cues produced following exposure to restraint stress to generalize to the discriminative stimulus effects of cocaine was investigated. Rats were trained to discriminate cocaine (10 mg/kg, IP, n=10; or 20 mg/kg, IP, n=6) from saline using a two-choice, food-reinforced, drug discrimination design. Substitution for the 10 mg/kg training dose of cocaine was observed subsequent to exposure to 15 min of restraint when administered immediately following an injection of saline. Restraint-induced generalization in the 20 mg/kg training group was substantial, but not statistically significant. These data suggest that a component of the subjective effects of cocaine may be associated with "anxiety".

Ketoconazole reduces low dose cocaine self-administration in rats.

Ketoconazole is an oral antimycotic agent approved by the FDA for the treatment of fungal disease which also blocks the synthesis of adrenocorticosteroids and functions as a glucocorticoid receptor antagonist. In these experiments, adult male Wistar rats were allowed alternating 15-min periods of access to food reinforcement and cocaine self-administration (0.125, 0.25 or 0.5 mg/kg per infusion) during daily 2-h sessions. A 1-min timeout separated access to the two reinforcers. Pretreatment with ketoconazole (25 mg/kg, i.p.) significantly decreased plasma corticosterone and reduced low dose (i.e. 0.125-0.25 mg/kg per infusion) cocaine self-administration without affecting food-reinforced responding. In fact, pretreatment with ketoconazole resulted in rates and patterns of self-administration at these doses that were indistinguishable from those observed during cocaine extinction. However, cocaine self-administration at the highest dose tested in these experiments (i.e. 0.5 mg/kg per infusion) was not significantly affected by ketoconazole. These data suggest the potential utility of ketoconazole or related drugs as adjuncts in the treatment of cocaine abuse and further underscore the role for corticosterone in cocaine reinforcement.

Tolerance and sensitization to the behavioral effects of cocaine in rats: relationship to benzodiazepine receptors.

Tolerance and sensitization to the behavioral effects of cocaine were investigated in rats responding under a fixed-consecutive-number eight schedule of food reinforcement. The development of tolerance or sensitization was induced by delivering the drug either immediately before or after each behavioral session during chronic administration. Chronic cocaine administered before each session resulted in tolerance, as indicated by the shift to the right in the cocaine dose response curve. This tolerance was more likely to develop in the presence of an external discriminative stimulus. On the other hand, when cocaine was delivered after each session, the injections did not disrupt responding and sensitization or increased sensitivity rather than tolerance developed. This sensitization was more likely to occur when the external discriminative stimulus was not present. These data suggest that either tolerance or sensitization to the behavioral effects of cocaine can occur following the same number of chronic injections, with the effect dependent on the context under which the drug is delivered. Significant differences in benzodiazepine receptor binding measured autoradiographically using [3H]flumazenil were observed between rats that received cocaine before or after each session, suggesting that the development of tolerance and sensitization may be mediated through changes in benzodiazepine receptors in discrete brain regions.

A neuroendocrine role in cocaine reinforcement.

Cocaine stimulates the secretion of corticosterone and ACTH, probably through a CRF-related mechanism, indicating that the drug activates the HPA axis. Indeed, cocaine has been reported to produce anxiety and to precipitate episodes of panic attack during chronic use and withdrawal in humans and to induce anxiogenic behavior in animals. Cocaine also alters benzodiazepine receptor binding in discrete regions of the rat brain. Some of these changes in binding are obviously related to the convulsions and seizures which are often observed in an acute cocaine overdose. However, data from behavioral studies have suggested that some of these effects may be related directly to cocaine reinforcement since receptor changes also were observed when binding in the brains of rats that self-administered cocaine was compared with that from animals that had received identical yoked, but non-contingent infusions of the drug. In this regard, pretreatment with the benzodiazepine receptor agonists chlordiazepoxide and alprazolam decreased cocaine self-administration without decreasing food-reinforced responding, suggesting that these effects were specific for cocaine. Since this attenuation of self-administration was reversed by increasing the unit dose of cocaine, it is likely that these drugs were decreasing cocaine reinforcement. In contrast, exposure to stress increases vulnerability to self-administer psychostimulants. In these experiments, low-dose cocaine self-administration was related directly to stress-induced increases in plasma corticosterone, such that plasma corticosterone was always greater than 150 ng/ml for rats which subsequently self-administered cocaine at doses of 0.125 mg/kg/infusion or lower, suggesting a threshold for the hormone in cocaine reinforcement. In other experiments, bilateral adrenalectomy completely abolished the acquisition of intravenous cocaine self-administration in naive rats, while metyrapone decreased ongoing self-administration. In addition, ketoconazole pretreatment resulted in patterns of self-administration that were virtually indistinguishable from that observed during saline extinction, suggesting that plasma corticosterone is not only important, but may even be necessary for cocaine reinforcement. The mechanisms through which adrenocorticosteroids alter cocaine reinforcement remain to be determined, but there is increasing evidence that the mesocorticolimbic dopaminergic system is involved. In particular, the medial prefrontal cortex appears to be at least one brain region where dopamine and adrenocorticosteroids may interact to affect cocaine reinforcement.

Dexamethasone suppression of the effects of cocaine on adrenocortical secretion in Lewis and Fischer rats.

There is evidence to suggest that cocaine acts centrally to enhance adrenocortical secretory activity and this effect may be associated with the reinforcing properties of this drug. Lewis (LEW) and Fischer (F344) rats are inbred strains which differ in their responses to the reinforcing effects of cocaine. Previous findings from this laboratory have demonstrated differences in the hypothalamic-pituitary-adrenocortical (HPA) responses to cocaine between these strains. To determine whether strain differences in glucocorticoid responsiveness play a role in the differential effects of cocaine on plasma corticosterone (CS) secretion in these strains, experiments were designed to suppress the HPA response to cocaine in these two rat strains. HPA activity was attenuated by central administration of the glucocorticoid agonist dexamethasone (DEX) using osmotic minipumps. A constant infusion of artificial cerebrospinal fluid or DEX (50, 100 or 500 ng/h) was delivered into the lateral ventricle of LEW and F344 rats. Four days later, the rats were challenged with cocaine HCl (0, 20 and 40 mg/kg, i.p.), and the plasma CS response 15 min later was quantified. Cocaine-induced alterations in circulating plasma CS were reduced in a dose-related manner by centrally administered DEX in both strains. Significant strain differences in the effects of DEX on the plasma CS response to cocaine were observed, suggesting that LEW rats were more sensitive to DEX suppression of HPA activity than F344 rats. DEX also produced dose-related effects on body weight in both strains and decreased adrenal weight at the highest dose in F344 rats. Blood collected on the final day of the experiment demonstrated that central infusions of DEX decreased plasma ACTH concentrations in both strains compared to control rats. These studies indicate that central administration of DEX produces a feedback inhibition of cocaine-induced glucocorticoid release and that LEW rats are more sensitive to DEX suppression than F344 rats.