The effect of age-related factors on behavior induced by cocaine

Age-related effects on cocaine-induced behavior (CIB) following acute and chronic administration of drug were evaluated in three groups of female rats representing increasing weights and ages. Three parameters of CIB, rated for 150 minutes during and following a 14-day treatment period, were measured: (1) latency of onset; (2) maximum level; and (3) duration of effect. Initially, the duration of CIB was significantly longer in the oldest, heaviest group. Decreases in latency of- and increases in maximum level of-CIB developed in all groups as a function of daily treatment with cocaine. These effects persisted throughout the 63-day post-treatment period. It was concluded that, in within-subject experimental designs, prolongation of CIB, which has been attributed to receptor supersensitivity, may reflect age-related factors, as heavier, older rats show prolonged CIB upon initial injection. In contrast, decreased latency of CIB, as well as increased maximum levels of CIB, were identified as indices of response augmentation which did not differ initially as a function of age-related factors, as they developed similarly in all groups with chronic treatment. Changes observed during and following chronic treatment are discussed in terms of possible changes in biotransformation and/or altered dopamine receptor function.     

Evidence of serotonin-dopamine involvement in the inhibition of d-amphetamine stereotypy and appearance of stereotyped movements found respectively after acute and long-term treatment with morphine and methadone in rats

P-chlorophenylalanine, an inhibitor of serotonin synthesis, was found to completely prevent the inhibitory effect of morphine and methadone on the stereotypy caused by d-amphetamine and methyl-phenidate in rats. d-Fenfluramine and m-chlorophenylpiperazine, two drugs supposed to increase serotonin transmission, and halo-peridol, an antagonist of dopamine at central receptors, blocked the stereotyped movements induced by repeated treatment with morphine and methadone. The results suggest that a) brain serotonin mediates the effect of morphine and methadone on amphetamine and methylphenidate stereotypy b) serotonin and dopamine are involved in the stereotyped movements caused by long-term treatment with these narcotics in the rat.     

Effect of acute or daily cocaine administration on cellular immune response and virus infection in mice

The effects of in vivo cocaine administrations on cellular cytotoxicity were studied. Cocaine induced a dose-related immunosuppression of natural killer cell activity, with maximal depression at 1-5 mg/kg. In addition, the degree of inhibition following a single intraperitoneal (i.p.) or intravenous cocaine dose (acute treatment, 1 mg/kg) was similar to that after repeated administration (subchronic treatment: 1 mg/kg/day i.p. for 7 consecutive days or subcutaneous administration by Alzet 2001 osmotic minipumps). T cells from cocaine-treated mice failed to generate cytotoxic T lymphocytes (CTL) in mixed lymphocyte cultures and acute or subchronic cocaine treatment also inhibited CTL generation in vivo. On the other hand, acute administration induced a very rapid (24-hour) inhibition of natural cytotoxicity, with a return to normal within 72 h after treatment. By contrast, repeated doses led to more protracted immunologic consequences and a delayed recovery (144 h). The effect of cocaine on susceptibility to influenza virus (PR8) infection was also investigated. Both acute and subchronic treatment significantly decreased resistance to PR8 infection. The results clearly indicate that cocaine has a potent suppressive effect on cellular immunity and that abuse can adversely affect the outcome of infectious diseases.     

Tolerance to d-amphetamine: behavioral specificity.

In a Y-maze exploratory task mice tend to enter that compartment which was least recently visited (spontaneous alternation). Low doses of d-amphetamine (1.0 mg/kg) reduce alternation to chance levels, while high doses (10.0 mg/kg) result in animals successively visiting only two compartments of the Y-maze (perseveration). Following daily d-amphetamine injection (1.0 or 10.0 mg/kg) over a 30 day period tolerance to the d-amphetamine induced perseveration was observed; however, chronic amphetamine treatment did not modify the locomotor stimulating effects of d-amphetamine or the reduction of alternation to chance levels produced by low doses of the drug. It was hypothesized that tolerance to d-amphetamine occurs exclusively to behaviors mediated by norepinephrine.     

Prior exposure to methylenedioxyamphetamine (MDA) induces serotonergic loss and changes in spontaneous exploratory and amphetamine-induced behaviors in rats

The substituted amphetamine 3,4 methylenedioxyamphetamine (MDA) is a popular recreational drug of abuse. Administration of MDA to experimental animals has been shown to induce damage to serotonergic axons and nerve terminals. However, there is a lack of information on whether these treatments can produce any long-term changes in behavioural performance particularly under stressful conditions. In the present study, MDA (7.5 mg/kg; i.p.) was administered twice daily to adult male Sprague Dawley rats for four days. Four weeks following the last dose, spontaneous behaviors of these animals were tracked and scored in a novel "open field" environment using an automated video registration and computer interpretation system. Changes in behavior were observed in MDA treated animals including reductions in exploratory oriented behaviors (locomotion and rearing) and increases in grooming behavior when compared to vehicle treated controls. MDA-treated animals also displayed an enhanced locomotor and stereotyped response to d-amphetamine (12 mg/kg; i.p.). Significant reductions in 5-HT concentrations (20-30%) were observed in the frontal cortex, amygdala, striatum, and hypothalamus as a result of MDA treatment. In addition, [3H] paroxetine binding was reduced by (40%) in the cortex of MDA treated rats indicating that the decrease in 5-HT concentrations were accompanied by a reduction in intact presynaptic 5-HT nerve terminals. Changes in behavioural performance in a novel "open field" environment and following d-amphetamine challenge might be considered as a behavioural model of serotonergic deficit induced by MDA. The findings of this study also suggest that MDA use may increase both the abuse potential, and the propensity to develop psychosis as a result of abusing other psychostimulants such as d-amphetamine.     

Extracellular Concentrations of Cocaine and Dopamine Are Enhanced During Chronic Cocaine Administration

Chronic cocaine administration produces significant increases in cocaine-induced locomotor activity and stereotypy. In vivo microdialysis procedures were used to monitor extracellular dopamine (DA) and cocaine concentrations in the nucleus accumbens (N ACC) and cocaine concentrations in plasma of animals that received chronic or acute cocaine treatments. Following a cocaine challenge injection, concentrations of both cocaine and DA increased to significantly higher levels over time in animals that had received daily cocaine injections for 10 or 30 days than in control animals that received daily injections of saline. Concentrations of cocaine and DA in the N ACC reached maximum levels in the first 30 min following a challenge injection of cocaine. The maximum cocaine concentrations of 10- and 30-day chronic animals were, respectively, 186% and 156%, whereas the maximum DA concentrations were 264% and 216% above the maximum values observed in acute control animals. The results indicate that reverse tolerance effects observed following chronic cocaine administration may in part be accounted for by increased cocaine concentrations. Furthermore, chronic cocaine administration (over a 10- or 30-day period) increased the concentration of cocaine detected in plasma above control levels following a challenge injection. The increase in brain concentrations of cocaine in chronic animals is apparently due to increased concentrations of cocaine in plasma. A physiological change occurs in the periphery as a result of chronic cocaine administration that increases cocaine concentrations in plasma, increases extracellular cocaine levels in the brain, and increases the extracellular concentration of DA in the N ACC.     

Repeated cocaine administration changes the function and subcellular distribution of adenosine A1 receptor in the rat nucleus accumbens

Adenosine A1 receptor (A1) protein and mRNA is increased in the nucleus accumbens following repeated cocaine treatment. In spite of this protein up-regulation, A1 agonist-stimulated [35S]GTPgammaS binding was attenuated in accumbens homogenates of rats withdrawn for 3 weeks from 1 week of daily cocaine injections. Cellular subfractionation revealed that the discrepancy between total A1 protein and G protein coupling resulted from a smaller proportion of receptors in the plasma membrane. The decrease in functional receptor in the plasma membrane was further indicated by diminished formation of heteromeric receptor complex consisting of A1 and dopamine D1A receptors. To explore the functional significance of the altered distribution of A1 receptors, at 3 weeks after discontinuing repeated cocaine or saline, animals were injected with cocaine and 45 min later the subcellular distribution of A1 receptors quantified. Whereas a cocaine challenge in repeated saline-treated animals induced a marked increase in membrane localization of the A1 receptor, the relative distribution of receptors in repeated cocaine rats was not affected by acute cocaine. These data suggest that the sorting and recycling of A1 receptors is dysregulated in the nucleus accumbens as the consequence of repeated cocaine administration.     

Rapid tolerance to ethanol and high voluntary alcohol consumption in mice selected for brain weight

Mice of two strains selected for small and large brain weight (SB and LB, respectively) had free access to 10% alcohol and water within three months. At the end of this period, they consumed alcohol in daily dose of 6.9 +/- 0.9 and 7.5 +/- 0.8 g/kg, respectively. After a period of imposed three-day abstinence, the alcohol consumption by the mice of these strains increased by 68.6 and 49.3%, respectively. Exploratory behavior of independent groups of mice from these strains was studied in the closed cross-maze. The animals were injected with ethanol (2.4 g/kg, i.p.) or vehicle twice with a weekly interval. In SB mice, the first ethanol administration increased the total time of maze exploration and the number of stereotyped visits. The second ethanol administration did not increase the time of exploration but increased the number of stereotyped visits even to the greater extent. The latter indicates the development of rapid tolerance and sensitization of these behaviors to the drug, respectively. The ethanol administration inhibited exploratory patrolling behavior and defecations. In LB mice, both the first and second ethanol administrations increased the number of stereotyped visits and decreased the exploration time and the number of defecations. The results do not support the psychomotor stimulant hypothesis of alcohol addiction. It is proposed that SB and LB mice may serve as models for Cloninger's types 1 and 2 alcoholics and may be useful for investigation of neuropharmacological mechanisms of stimulatory and inhibitory effects of ethanol.     

Neuroendocrine responses to cocaine do not exhibit sensitization following repeated cocaine exposure.

Cocaine-induced enhancement of motor activity and extracellular dopamine concentrations exhibits sensitization upon repeated exposure. In this study, the neuroendocrine responses to cocaine were examined following cocaine pretreatment regimens which have been shown to produce behavioral sensitization. Adult male rats were injected with cocaine (15 mg/kg, IP) once daily for 14 days, followed by a dose-response challenge with cocaine (1-15 mg/kg, IP) either 18 hours or 7 days after the final pretreatment injection. Blood was collected 15 minutes following injections for radioimmunoassay of ACTH, corticosterone, prolactin, and renin. Cocaine increased plasma ACTH and corticosterone, while it decreased prolactin and renin concentrations. Pretreatment with cocaine for 2 weeks did not alter any of these endocrine responses after either the 18 hour or 7 day interval between pretreatment and challenge injections. In contrast, sensitization to the locomotor stimulant effects of cocaine was observed on the final day of pretreatment injections, and 7 days later. These data suggest that these endocrine effects of cocaine do not exhibit sensitization following repeated cocaine exposure.     

Effects of cocaine on conflict behavior in the rat

The present studies examined the effects of acute cocaine administration, chronic cocaine administration and cocaine withdrawal on behavior in the Conditioned Suppression of Drinking (CSD) conflict paradigm, an animal model for the study of anxiety. In daily 10-minute sessions, water deprived rats were trained to drink from a tube that was occasionally electrified (0.25 mA), electrification being signalled by a tone. Within 3-4 weeks, control (i.e., non-drug) CSD behavior stabilized (30-50 shocks and 10-12 ml/session) and drug studies were initiated. Acute administration of cocaine (30-min pretreatment) produced a selective pro-conflict effect only at a dose of 10 mg/kg cocaine, with lower doses (2.5, 5 mg/kg) exerting no effect on CSD behavior and a higher dose (20 mg/kg) depressing both punished and unpunished responding. In a second experiment, cocaine (10 mg/kg, IP, 2/day) or saline was administered to separate groups of subjects for 7 weeks. In this chronic treatment study, CSD testing was conducted 12 hours after each evening cocaine administration. Although it had no effect on CSD behavior during the first week of treatment, this chronic cocaine administration produced a significant and selective pro-conflict effect which was stable during the period from Weeks 2-7. In a final experiment, a high dose of cocaine (20 mg/kg, 3/day) or saline was given to separate groups of subjects for 2 weeks and the behavioral effects of these treatments and their subsequent termination were examined. In this study, CSD testing was conducted 8 hours after each evening cocaine treatment. During the first week of high dose cocaine treatment, a decrease in punished responding was observed; this parameter returned to baseline levels by Week 2. Discontinuation of this high dose chronic cocaine treatment resulted in a selective decrease in punished responding. This pro-conflict effect was greatest at 3 days, and lasted for 6 days after the last cocaine dose. These data are consistent with clinical findings demonstrating the anxiogenic effects of both acute and chronic cocaine treatment as well as cocaine withdrawal and suggest that conflict paradigms such as the CSD may be useful for the study of cocaine-induced anxiety states.     

Subchronic steroid administration induces long lasting changes in neurochemical and behavioral response to cocaine in rats

The abuse of anabolic androgenic steroids (AASs), such as nandrolone, is not only a problem in the world of sports but is associated with the polydrug use of non-athletes. Among other adverse effects, AAS abuse has been associated with long term or even persistent psychiatric problems. We have previously found that nandrolone decanoate treatment could produce prolonged changes in rats’ brain reward circuits associated to drug dependence. The aim in this study was to evaluate whether AAS-induced neurochemical and behavioral changes are reversible.The increases in extracellular dopamine (DA) and serotonin (5-HT) concentration, as well as stereotyped behavior and locomotor activity (LMA) evoked by cocaine were attenuated by pretreatment with nandrolone. The recovery period, which was needed for the DA system to return back to the basic level, was fairly long compared to the dosing period of the steroid. In the 5-HT system, the time that system needed to return back to the basal level, was even longer than in the DA system. The attenuation was still seen though there were no detectable traces of nandrolone in the blood samples.Given that accumbal outflow of DA and 5-HT, as well as LMA and stereotyped behavior are all related to reward of stimulant drugs, this study suggests that nandrolone decanoate has significant, long-lasting but reversible effects on the rewarding properties of cocaine.     

Increased Acute Cocaine Sensitivity and Decreased Cocaine Sensitization in GABAA Receptor β3 Subunit knockout Mice

The role of the GABA(A) receptor beta3 subunit in determining acute cocaine sensitivity and behavioral sensitization to repeated cocaine was measured in mice missing both (-/-), one (+/-), or neither (+/+) allele of the beta3 gene. Locomotor stimulation induced by one cocaine injection (20 mg/kg, i.p.) was found to be greater in -/- mice compared with +/+ mice, whereas cocaine-induced behaviors were intermediate in +/- mice. Amphetamine did not cause greater locomotor responses in -/- mice, suggesting that the increased sensitivity of -/- mice to cocaine does not generalize to other psychomotor stimulants. GABA-stimulated chloride uptake was 51% lower in striatum of -/- mice compared with +/+ mice, but only 27% lower in cortex. After 14 daily cocaine injections, the behavioral response to cocaine was increased in +/+ and +/- mice, but was not increased further in -/- mice. Additionally, repeated cocaine exposure decreased striatal GABA(A) receptor function in +/+ and +/- mice. In -/- mice, GABA(A) receptor function was not decreased any further by repeated cocaine injections. Thus, alterations in the beta3 subunit may be responsible for determining the behavioral responses induced by acute and repeated cocaine treatment, as well as mediating the neurochemical adaptation that occurs during sensitization to repeated cocaine.     

Neuroadaptations in Ionotropic and Metabotropic Glutamate Receptor mRNA Produced by Cocaine Treatment

Abstract : The expression of glutamate receptor/subunit mRNAs was examined 3 weeks after discontinuing 1 week of daily injections of saline or cocaine. The level of mRNA for GluR1-4, NMDAR1, and mGluR5 receptors was measured with in situ hybridization and RT-PCR. In nucleus accumbens, acute cocaine treatment significantly reduced the mRNA level for GluR3, GluR4, and NMDAR1 subunits, whereas repeated cocaine reduced the level for GluR3 mRNA. Acute cocaine treatment also reduced the NMDAR1 mRNA level in dorsolateral striatum and ventral tegmental area. In prefrontal cortex, repeated cocaine treatment significantly increased the level of GluR2 mRNA. The GluR2 mRNA level was not changed by acute or repeated cocaine in any other brain regions examined. Repeated cocaine treatment also significantly increased mGluR5 mRNA levels in nucleus accumbens shell and dorsolateral striatum. Functional properties of the ionotropic glutamate receptors are determined by subunit composition. In addition, metabotropic glutamate receptors can modulate synaptic transmission and the response to stimulation of ionotropic receptors. Thus, the observed changes in levels of AMPA and NMDA receptor subunits and the mGluR5 metabotropic receptor may alter excitatory neurotransmission in the mesocorticolimbic dopamine system, which could play a significant role in the enduring biochemical and behavioral effects of cocaine.     

Study of pharmacological activation of the male sexual behavior

The model of sexual exhaustion of male rats was used in the study. The specific aim was to compare the effects of cocaine on the mount latency, number of mounts, intromissions and ejaculations during the entire copulatory cycle with the same indices during the first 30 min of observation (the latter is most frequently used in laboratory settings). Experiments consisted of four 3-day test periods. On days 1 and 2, male rats were allowed to interact with receptive females until the satiation criterion was reached (30 min without mounts). On day 3, male rats were injected with cocaine (5, 10, or 30 mg/kg, i.p.) or its vehicle 15 min prior to testing. Cocaine administration in a dose-dependent way increased the total number of mounts and ejaculations during the entire observation session but not during the initial 30-min period. The mount latency was unaffected by cocaine treatment. The results suggest that the expression of the stimulating effects of cocaine on sexual behavior depends on the duration of the observation period.     

Augmented behavioral response and enhanced synaptosomal calcium transport induced by repeated cocaine administration are decreased by calcium channel blockers

Recent studies suggest that calcium influx via L-type calcium channels is necessary for psychostimulant-induced behavioral sensitization. In addition, chronic amphetamine upregulates subtype Cav1.2-containing L-type calcium channels. In the present studies, we assessed the effect of calcium channel blockers (CCBs) on cocaine-induced behavioral sensitization and determined whether the functional activity of L-type calcium channels is altered after repeated cocaine administration. Rats were administered daily intraperitoneal injections of either flunarizine (40 mg/kg), diltiazem (40 mg/kg) or cocaine (20 mg/kg) and the combination of the CCBs and cocaine for 30 days. Motor activities were monitored on Day 1, and every 6th day during the 30-day treatment period. Daily cocaine administration produced increased locomotor activity. Maximal augmentation of behavioral response to repeated cocaine administration was observed on Day 18. Flunarizine pretreatment abolished the augmented behavioral response to repeated cocaine administration while diltiazem was less effective. Measurement of tissue monoamine levels on Day 18 revealed cocaine-induced increases in DA and 5-HT in the nucleus accumbens. By contrast to behavioral response, diltiazem was more effective in attenuating increases in monoamine levels than flunarizine. Cocaine administration for 18 days produced increases in calcium uptake in synaptosomes prepared from the nucleus accumbens and frontal cortex. Increases in calcium uptake were abolished by flunarizine and diltiazem pretreatment. Taken together, the augmented cocaine-induced behavioral response on Day 18 may be due to increased calcium uptake in the nucleus accumbens leading to increased dopamine (DA) and serotonin (5-HT) release. Flunarizine and diltiazem attenuated the behavioral response by decreasing calcium uptake and decreasing neurochemical release.     

Circadian discrimination of reward: evidence for simultaneous yet separable food- and drug-entrained rhythms in the rat

A unique extra-suprachiasmatic nucleus (SCN) oscillator, operating independently of the light-entrainable oscillator, has been hypothesized to generate feeding and drug-related rhythms. To test the validity of this hypothesis, sham-lesioned (Sham) and SCN-lesioned (SCNx) rats were housed in constant dim-red illumination (LL(red)) and received a daily cocaine injection every 24 h for 7 d (Experiment 1). In a second experiment, rats underwent 3-h daily restricted feeding (RF) followed 12 d later by the addition of daily cocaine injections given every 25 h in combination with RF until the two schedules were in antiphase. In both experiments, body temperature and total activity were monitored continuously. Results from Experiment 1 revealed that cocaine, but not saline, injections produced anticipatory increases in temperature and activity in SCNx and Sham rats. Following withdrawal from cocaine, free-running temperature rhythms persisted for 2-10 d in SCNx rats. In Experiment 2, robust anticipatory increases in temperature and activity were associated with RF and cocaine injections; however, the feeding periodicity (23.9 h) predominated over the cocaine periodicity. During drug withdrawal, the authors observed two free-running rhythms of temperature and activity that persisted for >14 d in both Sham and SCNx rats. The periods of the free-running rhythms were similar to the feeding entrainment (period = 23.7 and 24.0 h, respectively) and drug entrainment (period = 25.7 and 26.1 h, respectively). Also during withdrawal, the normally close correlation between activity and temperature was greatly disrupted in Sham and SCNx rats. Taken together, these results do not support the existence of a single oscillator mediating the rewarding properties of both food and cocaine. Rather, they suggest that these two highly rewarding behaviors can be temporally isolated, especially during drug withdrawal. Under stable dual-entrainment conditions, food reward appears to exhibit a slightly greater circadian influence than drug reward. The ability to generate free-running temperature rhythms of different frequencies following combined food and drug exposures could reflect a state of internal desynchrony that may contribute to the addiction process and drug relapse.     

To our readers

Mallard duckling distress calls consist of a series of stereotyped notes and are usually given in calling bouts. When two or more ducklings are separated from their brood and begin to distress call, they alternate their calls, with each bird inhibiting its own vocalizations during those of another bird. In two playback experiments we reduced the acoustic variability found in distress calls and examined the effect this had on the alternation response of ducklings. In Exp. 1, one treatment involved an unedited tape-recording of a natural bout of 8 distress calls. Three other treatments involved edited tapes in which (a) the original 8 calls were presented, but at a constant intercall period, or (b) a single call was repeated 8 times at the natural (variable) intercall periods, or (c) a single call was repeated 8 times at a constant intercall period. The two tapes on which the same call was repeated 8 times elicited significantly weaker alternation responses from ducklings than the two tapes on which the original 8 calls were presented; the manipulation of the intercall period had no significant effect on the alternation response. In Exp. 2, analogous manipulations were performed to remove the variability between the notes within a single distress call or between the internote periods within that call. Ducklings alternated significantly better with the unedited distress call than with the distress calls in which variability had been removed. These results suggest that the variability found within many “Fixed Action Patterns” may serve an important antihabituation function.     

Muscimol differentially facilitates stereotypy but antagonizes motility induced by dopaminergic drugs: a complex GABA-dopamine interaction

Muscimol is the most potent and specific GABA agonist presently available. The influence of muscimol on two behavioral parameters, dependent on dopamine was studied: locomotor activity and stereotyped gnawing induced by apomorphine, cocaine or methylphenidate. In mice pretreated with a non-sedative subcutaneous dose of muscimol, a sedative effect was seen a few minutes after the injection of a stimulant dose of the dopaminergic drugs; the combination muscimol - apomorphine being most sedative. Contrastingly, muscimol strongly facilitates the development of stereotyped gnawing induced by higher doses of cocaine, methylphenidate or apomorphine. Pretreatment with α-methyltyrosine, an inhibitor of the catecholamine synthesis given before muscimol, did not antagonize the stereotyped gnawing after cocaine or methylphenidate. This finding suggests that the muscimol effect primarily depends on a direct GABA-ergic mechanism facilitating stereotyped gnawing.     

Differential sensitivity to cocaine in spontaneously hypertensive and Wistar-Kyoto rats

Physiological, pharmacological and toxicological responses to two regimens of cocaine administration were compared between spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. An initial experiment examined renal excretory and hemodynamic function in response to an acute volume load in anesthetized SHR and WKY following subacute cocaine treatment (20 mg/kg, s.c., twice a day for 9 days). Anticipated renal responses to volume loading were obtained but the responses of cocaine-treated SHR and WKY did not differ from vehicle-treated rats. A second group of experiments compared responses to continuous i.v. infusions of cocaine (1.25 mg/kg.min). In freely moving animals, no differences were noted between SHR and WKY in the increases in mean blood pressure (MBP) and heart rate (HR) produced during cocaine infusion. The elapsed time-to-onset of convulsions (Tc) elicited by cocaine was similar in both strains. However, when rats were subjected to restraint during the infusion period, pressor and tachycardic responses were observed to be significantly less in WKY than in SHR or in freely moving rats of either strain. Restraint also differentially affected rectal temperature (RT) responses to cocaine. Hypothermic responses to cocaine were observed in all WKY. Both hypothermic and hyperthermic responses were observed in SHR. A significant correlation was demonstrated between the Tc and the maximal change in RT produced during cocaine infusion. Division of SHR into two arbitrary groups was made, based on the direction of cocaine-induced change in RT. A significant (p less than 0.01) shortening of the Tc was obvious in SHR (8 of 15) in whom cocaine produced a hyperthermia. These animals were designated SHRH. The mean value for Tc in those SHR which demonstrated a lowering in RT (SHRL; 7 of 15) in response to cocaine was similar to that for WKY. Moreover, the SHRH evidenced significantly greater increases in HR, but not MBP, to cocaine infusion than did SHRL. The results indicate that restraint stress causes expression of a significant heterogeneity in the RT response of SHR to cocaine. The magnitude and direction of the RT responses are negatively correlated with sensitivity to the convulsive effects of cocaine in SHR. Stress may modify toxic responses to cocaine by interactions with body temperature homeostasis.     

Virus-Mediated shRNA Knockdown of Prodynorphin in the Rat Nucleus Accumbens Attenuates Depression-Like Behavior and Cocaine Locomotor Sensitization

Dynorphins, endogenous opioid peptides that arise from the precursor protein prodynorphin (Pdyn), are hypothesized to be involved in the regulation of mood states and the neuroplasticity associated with addiction. The current study tested the hypothesis that dynorphin in the nucleus accumbens (NAcc) mediates such effects. More specifically, we examined whether knockdown of Pdyn within the NAcc in rats would alter the expression of depressive-like and anxiety-like behavior, as well as cocaine locomotor sensitization. Wistar rats were injected with adeno-associated viral (AAV) vectors encoding either a Pdyn-specific short hairpin RNA (AAV-shPdyn) or a scrambled shRNA (AAV-shScr) as control. Four weeks later, rats were tested for anxiety-like behavior in the elevated plus maze test and depressive-like behavior in the forced swim test (FST). Finally, rats received one daily injection of saline or cocaine (20 mg/kg, i.p.), followed by assessment of locomotion for 4 consecutive days. Following 3 days of abstinence, the rats completed 2 additional daily cocaine/saline locomotor trials. Pdyn knockdown in the NAcc led to a significant reduction in depressive-like behavior in the FST, but had no effect on anxiety-like behavior in the elevated plus maze. Pdyn knockdown did not alter baseline locomotor behavior, the locomotor response to acute cocaine, or the initial sensitization of the locomotor response to cocaine over the first 4 cocaine treatment days. However, following 3 days abstinence the locomotor response to the cocaine challenge returned to their original levels in the AAV-shPdyn rats while remaining heightened in the AAV-shScr rats. These results suggest that dynorphin in a very specific area of the nucleus accumbens contributes to depressive-like states and may be involved in neuroadaptations in the NAcc that contribute to the development of cocaine addiction as a persistent and lasting condition.