Ability Of Cocaine Research Articles

Estrous cycle‐dependent alterations in cocaine affinity at the dopamine transporter underlie enhanced cocaine reward in females

While both males and females become addicted to cocaine, females transition to dependence faster, take more cocaine, experience more adverse consequences and have more difficulty remaining abstinent in both humans and animal models. The underlying neural mechanisms controlling these sexual‐dimorphisms in motivated behaviors and how they mediate the increased abuse liability of cocaine in females remain unclear. Here, we define a sex‐specific neural mechanism contributing to this enhanced cocaine reward in females. Using a combination of in vivo electrophysiology of ventral tegmental area (VTA) dopamine neurons and fast scan cyclic voltammetry in the nucleus accumbens (NAc), in vivo calcium imaging and conditioned place preference, we were able to record pathway specific VTA and NAc responses to contextual cues that were previously paired with cocaine in male mice and in intact females over different stages of the estrous cycle. Using ELISA we measured circulating levels of ovarian hormones and determined their relationship to estrous cycle dependent fluctuations in reward processing. Finally using designer receptors exclusively activated by designer drugs (DREADDs) we manipulated mesolimbic dopamine system activity to directly link downstream alterations in dopamine transporter function to activity dependent changes at the level of the VTA. We identified an estrous‐cycle dependent enhancement of dopaminergic function in both the VTA and NAc, which acts to increase dopaminergic responses to salient stimuli. This enhancement is converged with an increased ability of cocaine to augment synaptic dopamine levels due to a robust increase in cocaine's ability to bind directly to the dopamine transporter and inhibit its uptake function selectively during estrus. These changes were linked to alterations in circulating estradiol levels, which predicted changes in both VTA firing rate as well as cocaine effects at the dopamine transporter. Using DREADD‐induced activation of VTA dopamine neurons to enhance firing we were able to mimic the effects of estrous cycle on the dopamine system and subsequent reward processing in both diestrus females and males. Importantly, these changes lead to not only enhanced reward processing during estrus, but potent and long‐lasting associations between the rewarding effects of cocaine and associated environmental cues that extend to other stages of the estrous cycle. Together we define a basic mechanism by which estrous cycle dependent changes in the dopamine transporter underlies susceptibility to cocaine addiction by promoting persistent cue‐reward associations that can precipitate relapse. Since enhanced drug seeking is characteristic of individuals who transition to addiction, our findings which reveal novel sex‐specific factors controlling drug seeking are critical to guiding evidence‐based therapeutic interventions for female addicts.Support or Funding InformationThis work was supported by grants from the National Institute on Drug Abuse (E.J.N., R01 DA14133), (E.S.C. K99 DA042111); The Brain and Behavior Research Foundation (NARSAD, E.S.C.); National Institute of Mental Health (E.J.N., R01 MH51399, P50 MH096890) and National Institute of Alcoholism and Alcohol Abuse (M.H.H.R01 AA022445; B.J. F31 AA022862).

Dopamine Regulation of Lateral Inhibition between Striatal Neurons Gates the Stimulant Actions of Cocaine

Striatal medium spiny neurons (MSNs) form inhibitory synapses on neighboring striatal neurons through axon collaterals. The functional relevance of this lateral inhibition and its regulation by dopamine remains elusive. We show that synchronized stimulation of collateral transmission from multiple indirect-pathway MSNs (iMSNs) potently inhibits action potentials in direct-pathway MSNs (dMSNs) in the nucleus accumbens. Dopamine D2 receptors (D2Rs) suppress lateral inhibition from iMSNs to disinhibit dMSNs, which are known to facilitate locomotion. Surprisingly, D2R inhibition of synaptic transmission was larger at axon collaterals from iMSNs than their projections to the ventral pallidum. Targeted deletion of D2Rs from iMSNs impaired cocaine's ability to suppress lateral inhibition and increase locomotion. These impairments were rescued by chemogenetic activation of Gi-signaling in iMSNs. These findings shed light on the functional significance of lateral inhibition between MSNs and offer a novel synaptic mechanism by which dopamine gates locomotion and cocaine exerts its canonical stimulant response. VIDEO ABSTRACT.

DAT isn't all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling.

The initial reinforcing properties of drugs of abuse, such as cocaine, are largely attributed to their ability to activate the mesolimbic dopamine system. Resulting increases in extracellular dopamine in the nucleus accumbens (NAc) are traditionally thought to result from cocaine’s ability to block dopamine transporters (DATs). Here we demonstrate that cocaine also interacts with the immunosurveillance receptor complex, Toll-Like Receptor 4 (TLR4), on microglial cells to initiate central innate immune signaling. Disruption of cocaine signaling at TLR4 suppresses cocaine-induced extracellular dopamine in the NAc, as well as cocaine conditioned place preference and cocaine self-administration. These results provide a novel understanding of the neurobiological mechanisms underlying cocaine reward/reinforcement that includes a critical role for central immune signaling, and offer a new target for medication development for cocaine abuse treatment.

Brief intermittent cocaine self-administration and abstinence sensitizes cocaine effects on the dopamine transporter and increases drug seeking.

Although traditional sensitization paradigms, which result in an augmentation of cocaine-induced locomotor behavior and dopamine (DA) overflow following repeated experimenter-delivered cocaine injections, are often used as a model to study drug addiction, similar effects have been difficult to demonstrate following cocaine self-administration. We have recently shown that intermittent access (IntA) to cocaine can result in increased cocaine potency at the DA transporter (DAT); however, traditional sensitization paradigms often show enhanced effects following withdrawal/abstinence periods. Therefore, we determined a time course of IntA-induced sensitization by examining the effects of 1 or 3 days of IntA, as well as a 7-day abstinence period on DA function, cocaine potency, and reinforcement. Here we show that cocaine potency is increased following as little as 3 days of IntA and further augmented following an abstinence period. In addition, IntA plus abstinence produced greater evoked DA release in the presence of cocaine as compared with all other groups, demonstrating that following abstinence, both cocaine's ability to increase DA release and inhibit uptake at the DAT, two separate mechanisms for increasing DA levels, are enhanced. Finally, we found that IntA-induced sensitization of the DA system resulted in an increased reinforcing efficacy of cocaine, an effect that was augmented after the 7-day abstinence period. These results suggest that sensitization of the DA system may have an important role in the early stages of drug abuse and may drive the increased drug seeking and taking that characterize the transition to uncontrolled drug use. Human data suggest that intermittency, sensitization, and periods of abstinence have an integral role in the process of addiction, highlighting the importance of utilizing pre-clinical models that integrate these phenomena, and suggesting that IntA paradigms may serve as novel models of human addiction.

Assessment of the impact of pattern of cocaine dosing schedule during conditioning and reconditioning on magnitude of cocaine CPP, extinction, and reinstatement

We sought to examine the impact of differing cocaine administration schedules and dosing on the magnitude of cocaine conditioned place preference (CPP), extinction, and stress- and cocaine-induced reinstatement of CPP. First, in C57Bl/6J mice, we investigated whether total cocaine administration or pattern of drug exposure could influence the magnitude of cocaine CPP by conditioning mice with a fixed-low dose (FL; 7.5mg/kg; total of 30mg/kg), a fixed-high dose (FH; 16mg/kg; total of 64mg/kg), or an ascending dosing schedule (Asc; 2, 4, 8, and 16mg/kg; total of 30mg/kg). Next, we investigated if cocaine or saline is more effective at extinguishing preference by reconditioning mice with either a descending dosing schedule (Desc; 8, 4, 2, and 1mg/kg) or saline. Finally, we examined if prior conditioning and reconditioning history alters stress (~2-3-min forced swim test) or cocaine-induced (3.5mg/kg) reinstatement. We replicated and extended findings by Itzhak and Anderson (Addict. Biol. 17(4): 706-16, 2011) demonstrating that Asc conditioning produces a greater CPP than either the FL or FH conditioning schedules. The magnitude of extinction expressed was similar in the Desc reconditioned and saline groups. Moreover, only the saline, and not the Desc reconditioned mice, showed stress and cocaine-induced reinstatement of CPP. Our results suggest that the schedule of cocaine administration during conditioning and reconditioning can have a significant influence on the magnitude of CPP and extinction of preference and the ability of cocaine or a stressor to reinstate CPP.

One-trial behavioral sensitization in preweanling rats: differential effects of cocaine, methamphetamine, methylphenidate, and d-amphetamine

Preweanling rats exhibit robust one-trial cocaine-induced behavioral sensitization; however, it is uncertain whether other psychostimulants can also induce sensitization in young rats using the one-trial procedure. The purpose of this study was to determine whether methamphetamine, methylphenidate, and D: -amphetamine are capable of inducing one-trial locomotor sensitization in preweanling rats. In a series of four experiments, rats were pretreated with cocaine (30 mg/kg), methamphetamine (2-12 mg/kg), methylphenidate (5-20 mg/kg), or amphetamine (5 mg/kg) before being placed in a novel activity chamber or the home cage on PD 19. Rats were then challenged with the same psychostimulant (20 mg/kg cocaine, 1-8 mg/kg methamphetamine, 2.5-7.5 mg/kg methylphenidate, or 1-2 mg/kg amphetamine) on PD 21, with distance traveled being measured for 180 min. In a separate experiment, rats were pretreated with methamphetamine on PD 16-19 and challenged with methamphetamine on PD 21. Only cocaine, but not various dose combinations of other psychostimulants, was able to produce one-trial behavioral sensitization in preweanling rats. Context-dependent locomotor sensitization was also evident if rats were pretreated with methamphetamine on PD 16-19 and tested on PD 21. It is uncertain why only cocaine was able to induce one-trial locomotor sensitization in preweanling rats, but it is possible that: (a) the neural circuitry mediating sensitization differs according to psychostimulant, (b) cocaine is more readily associated with environmental contexts than other psychostimulants, or (c) affinity and pharmacokinetic factors may underlie cocaine's ability to induce one-trial behavioral sensitization in preweanling rats.

Cocaine potentiates the responses to methacholine and noradrenaline in the rat vas deferens.

The ability of cocaine (10 microM) to potentiate the contractile responses of the epididymal half of the rat vas deferens to methacholine was reversed by prazosin. Prazosin also partially reversed the ability of cocaine to increase the spontaneous overflow of 3H following loading of the tissue with [3H]noradrenaline. We suggest that cocaine potentiated the responses to methacholine by stimulating, directly or indirectly, alpha 1-adrenoceptors.

Muscarinic receptor blockade in the ventral tegmental area attenuates cocaine enhancement of laterodorsal tegmentum stimulation‐evoked accumbens dopamine efflux in the mouse

The reinforcing properties of cocaine have been related to increased extracellular concentrations of dopamine in the nucleus accumbens (NAc). M5 muscarinic acetylcholine receptors (mAChRs) on dopamine cells in the ventral tegmental area (VTA) facilitate mesoaccumbens dopamine transmission and are critically involved in mediating natural and drug reinforcement. We investigated the effects of pharmacological blockade of mAChRs in the VTA on cocaine's ability to enhance electrically evoked NAc dopamine efflux. Using fixed potential amperometry together with carbon fiber recording microelectrodes positioned in the NAc core, we quantified dopamine oxidation currents (dopamine efflux) evoked by brief stimulation (15 monophasic pulses at 50 Hz every 30 s) of the laterodorsal tegmentum (LDT) in urethane (1.5 g/kg, i.p.) anesthetized mice. Compared to predrug baseline responses, cocaine (5 or 10 mg/kg, i.p.) dose-dependently enhanced LDT stimulation-evoked NAc dopamine efflux, whereas the nonsubtype selective mAChR antagonist scopolamine (10 microg/0.5 microl) microinfused into the VTA diminished LDT-evoked NAc dopamine efflux. Preinfusion of scopolamine into the VTA diminished the facilitatory actions of cocaine on LDT stimulation-evoked NAc dopamine efflux, and when infused at the peak effect of cocaine attenuated LDT-evoked dopamine efflux to below predrug baseline levels. These findings suggest that LDT cholinergic inputs to dopamine neurons in the VTA, via activation of mAChRs (probably of the M5 subtype), are involved in modulating the facilitatory effects of cocaine on NAc dopamine neurotransmission. They also suggest that the development of antagonists aimed at selectively disrupting M5 receptor function may be valuable in reducing abuse liability of psychostimulants.

The Dopamine Uptake Inhibitor 3α-[bis(4′-fluorophenyl)metoxy]-tropane Reduces Cocaine-Induced Early-Gene Expression, Locomotor Activity, and Conditioned Reward

Benztropine (BZT) analogs, a family of high-affinity dopamine transporter ligands, are molecules that exhibit pharmacological and behavioral characteristics predictive of significant therapeutic potential in cocaine addiction. Here, we examined in mice the effects of 3 alpha-[bis(4'-fluorophenyl)metoxy]-tropane (AHN-1055) on motor activity, conditioned place preference (CPP) and c-Fos expression in the striatum. AHN-1055 produced mild attenuation of spontaneous locomotor activity at a low dose (1 mg/kg) and weak stimulation at a higher dose (10 mg/kg). In parallel, the BZT analog significantly increased c-Fos expression in the dorsolateral caudoputamen at the high dose, whereas producing marginal decreases at low and moderate doses (1, 3 mg/kg) in both dorsal and ventral striatum. Interaction assays showed that cocaine's ability to stimulate locomotor activity was decreased by AHN-1055 treatment, but not by treatment with D-amphetamine. Such reduced ability did not result from an increase in stereotyped behavior. Another dopamine uptake inhibitor, nomifensine, decreased cocaine-induced locomotor activity but evoked by itself intense motor stereotypies. Remarkably, the BZT analog dose-dependently blocked cocaine-induced CPP without producing CPP when given alone, and blocked in conditioned mice cocaine-stimulated early-gene activation in the nucleus accumbens and dorsomedial striatum. These observations provide evidence that AHN-1055 does not behave as a classical psychomotor stimulant and that some of its properties, including attenuation of cocaine-induced striatal c-Fos expression, locomotor stimulation, and CPP, support its candidacy, and that of structurally related molecules, as possible pharmacotherapies in cocaine addiction.

The rate of intravenous cocaine or amphetamine delivery does not influence drug-taking and drug-seeking behavior in rats

We studied the influence of rate of intravenous infusion of cocaine or amphetamine on drug-taking and seeking behavior. First, drug-naive rats were tested for acquisition of self-administration of increasing doses of amphetamine or cocaine infused over 5 or 100 s. Second, self-administration of cocaine or amphetamine infused over 5–100 s was assessed on fixed or progressive-ratio (PR) reinforcement schedules. Finally, the ability of a single 5 or 100 s amphetamine or cocaine infusion to reinstate extinguished drug seeking was assessed. Although slower infusion rates produced a small effect on drug taking under continuous-reinforcement conditions, infusion rate did not alter drug taking on intermittent or PR reinforcement schedules, or the ability of cocaine or amphetamine to reinstate drug seeking. Taken together, our results suggest that variation in drug delivery rate over a range that we previously found alters the induction of behavioral sensitization, gene-expression and striatal dopamine activity, does not markedly alter drug-taking or seeking behavior.

The effects of cocaine on regional brain glucose metabolism is attenuated in dopamine transporter knockout mice

Cocaine's ability to block the dopamine transporter (DAT) is crucial for its reinforcing effects. However the brain functional consequences of DAT blockade by cocaine are less clear since they are confounded by its concomitant blockade of norepinephrineand serotonin transporters. To separate the dopaminergic from the non-dopaminergic effects of cocaine on brain function we compared the regional brain metabolic responses to cocaine between dopamine transporter deficient (DAT(-/-)) mice with that of their DAT(+/+) littermates. We measured regional brain metabolism (marker of brain function) with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) and microPET (muPET) before and after acute cocaine administration (i.p. 10 mg/kg). Scans were conducted 2 weeks apart. At baseline DAT(-/-) mice had significantly greater metabolism in thalamus and cerebellum than DAT(+/+). Acute cocaine decreased whole brain metabolismand this effect was greater in DAT(+/+) (15%) than in DAT(-/-) mice (5%). DAT(+/+) mice showed regional decreases in the olfactory bulb, motor cortex, striatum, hippocampus, thalamus and cerebellum whereas DAT(-/-) mice showed decreases only in thalamus. The differential pattern of regional responses to cocaine in DAT(-/-) and DAT(+/+) suggests that most of the brain metabolic changes from acute cocaine are due to DAT blockade. Cocaine-induced decreases in metabolism in thalamus (region with dense noradrenergic innervation) in DAT(-/-) suggest that these were mediated by cocaine's blockade of norepinephrine transporters. The greater baseline metabolism in DAT(-/-) than DAT(+/+) mice in cerebellum (brain region mostly devoid of DAT) suggests that dopamine indirectly regulates activity of these brain regions.

Low and high locomotor responsiveness to cocaine predicts intravenous cocaine conditioned place preference in male Sprague–Dawley rats

Outbred, male Sprague–Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on cocaine-induced locomotor activity in an open-field arena. This difference reflects cocaine's ability to inhibit the striatal dopamine transporter and predicts development of sensitization. To investigate the relationship between initial cocaine locomotor responsiveness and cocaine reward, here we first classified rats as either LCRs or HCRs in a conditioned place preference (CPP) apparatus. Subsequently, we conducted cocaine conditioning trials, twice-daily over 4 days with vehicle and cocaine (10 mg/kg, i.p. or 1 mg/kg, i.v.). When cocaine was administered by the i.p. route, similar to previous findings in the open-field, LCRs and HCRs were readily classified and locomotor sensitization developed in LCRs, but not HCRs. However, cocaine CPP was not observed. In contrast, when cocaine was administered by the i.v. route, the LCR/HCR classification not only predicted sensitization, but also CPP, with only LCR rats exhibiting sensitization and cocaine conditioning. Our findings show that the initial locomotor response to cocaine can predict CPP in male Sprague–Dawley rats under conditions when place conditioning develops, and that LCRs may be more prone to develop conditioning in the context of cocaine reward.

Cocaine-induced conditioned taste avoidance over extended conditioned stimulus–unconditioned stimulus intervals

Although long-delay learning has been demonstrated numerous times in the conditioned taste avoidance procedure, the empirical evidence showing this is almost exclusively limited to studies using emetics. Given that compounds outside the emetic class (e.g. drugs of abuse) are also effective in inducing conditioned taste avoidances, the present study assessed the ability of cocaine, a non-emetic psychoactive compound, to support long-delay conditioning as the unconditioned stimulus in conditioned taste avoidance preparation. Using saccharin as the conditioned stimulus, two taste-drug pairings were followed by six extinction trials during which saccharin was presented without subsequent injections of cocaine. During the two conditioning trials, animals were injected subcutaneously with cocaine (32 mg/kg) at different conditioned stimulus-unconditioned stimulus intervals, that is, 10, 60, 120, 180, 240, 300, 420 and 540 min. A control group of animals was given an equi-volume injection of the drug vehicle at the 10-min conditioned stimulus-unconditioned stimulus interval. After two conditioning trials, all treatment groups consumed significantly less saccharin than controls, with the magnitude of the effect decreasing as the conditioned stimulus-unconditioned stimulus interval increased. After six extinction trials, animals injected with cocaine at 10, 60 and 120 min conditioned stimulus-unconditioned stimulus intervals still consumed significantly less than controls. These results with cocaine suggest that taste avoidance learning over long delays is not limited to classical emetic compounds and may, in fact, be characteristic of taste avoidance learning in general.

Chromatin Remodeling Is a Key Mechanism Underlying Cocaine-Induced Plasticity in Striatum

Given that cocaine induces neuroadaptations through regulation of gene expression, we investigated whether chromatin remodeling at specific gene promoters may be a key mechanism. We show that cocaine induces specific histone modifications at different gene promoters in striatum, a major neural substrate for cocaine's behavioral effects. At the cFos promoter, H4 hyperacetylation is seen within 30 min of a single cocaine injection, whereas no histone modifications were seen with chronic cocaine, consistent with cocaine's ability to induce cFos acutely, but not chronically. In contrast, at the BDNF and Cdk5 promoters, genes that are induced by chronic, but not acute, cocaine, H3 hyperacetylation was observed with chronic cocaine only. DeltaFosB, a cocaine-induced transcription factor, appears to mediate this regulation of the Cdk5 gene. Furthermore, modulating histone deacetylase activity alters locomotor and rewarding responses to cocaine. Thus, chromatin remodeling is an important regulatory mechanism underlying cocaine-induced neural and behavioral plasticity.

Neonatal isolation alters the estrous cycle interactions on the acute behavioral effects of cocaine

We demonstrated that neonatal isolation (ISO) increases acquisition of cocaine self-administration and alters psychostimulant-induced ventral striatal dopamine and serotonin levels in female rats. Both dopamine and serotonin modulate the behavioral effects of cocaine and these effects can vary across estrous stages. We now test whether ISO modifies the manner in which estrous stage affects the acute behavioral responses to cocaine. Litters were assigned to ISO (1 h/day isolation; post-natal days 2-9) or non-handled (NH) conditions. In Experiment 1, the ability of cocaine (0.3-30 mg/kg; IP) to disrupt schedule-controlled responding for food was assessed in proestrus, estrus, and diestrus stages. Diestrus and proestrus NH females showed increased response rates at low cocaine doses and decreased rates at higher doses relative to baseline. In contrast, estrus NH females showed decreased responding across all doses. ISO eliminated this estrous stage distinction; only decreased responding to high cocaine doses were seen. Yet, estrous cyclicity during food restriction (Experiment 2) did not differ by group. To confirm this ISO effect, proestrus or estrus rats were administered cocaine (0, 5, 10 mg/kg; IP) and activity monitored in Experiment 3. Locomotor activity differed by estrous stage in NH but not ISO rats. Cocaine plasma levels (Experiment 4) at the time of peak behavioral activity did not differ by group or estrous stage. Results extend prior studies to show estrous stage alters the behavioral effects of cocaine. Neonatal isolation eliminates these effects perhaps reflecting alterations in accumbens monoamine levels or the effects of estrogen on this system.

Prazosin, an α-1 Adrenergic Antagonist, Reduces Cocaine-Induced Reinstatement of Drug-Seeking

Norepinephrine is implicated in cocaine's behavioral effects. In this study, we tested the effect of prazosin, an alpha1-adrenergic receptor antagonist, on cocaine-induced reinstatement of drug-seeking behavior. Rats were trained to self-administer cocaine intravenously under a fixed-ratio 3 schedule of reinforcement. After behavior was established, cocaine was replaced with saline and behavior extinguished. The ability of cocaine (0, 5-20 mg/kg) alone or combined with prazosin (.3 mg/kg) to reinstate lever press responding was tested. The effects of prazosin on lever press responding for food was examined in another set of rats. Cocaine induced a dose-dependent reinstatement of drug-seeking behavior that was significantly attenuated by prazosin. This dose of prazosin did not alter lever press response rates for food. The attenuation in drug-induced reinstatement is likely not due to prazosin-induced suppression of activity. These results suggest alpha1-adrenergic mechanisms contribute to reinstatement in rats and perhaps, to relapse in addicts.

Electrophysiologic and hemodynamic effects of sodium bicarbonate in a canine model of severe cocaine intoxication.

Cocaine toxicity causes myocardial depression, malignant dysrhythmias, and sudden death, partially due to cocaine-related myocardial sodium channel blockade. Because of cocaine's ability to block cardiac sodium channels, sodium bicarbonate (NaHCO3) has been proposed as an antidote. The hypothesis of this study was that NaHCO3 would correct cocaine-induced conduction abnormalities and resultant hemodynamic compromise in an animal model simulating severe cocaine intoxication. Prospective, controlled, experimental study in which 15 anesthetized dogs were given three successive boluses of cocaine (7 mg/kg) and then randomized to receive NaHCO3, 2 mEq/kg (n = 8) or placebo (n =7). Arterial, left ventricular, and pulmonary artery pressures; cardiac output (CO); electrocardiogram (ECG); blood gases; and serum concentrations of cocaine were measured at baseline, at fixed time intervals after each bolus of cocaine, and then after administration of NaHCO3 or placebo. Statistical significance was determined by analysis of variance (ANOVA) for repeated measures. Seven dogs experienced significant arrhythmias, including VT, pulseless electrical activity, and third-degree atrioventricular block; 2 of these dogs expired prior to receiving NaHCO3 and were excluded. Immediately after administering NaHCO3, QRS duration decreased by 30% (p < 0.001), returning to baseline more quickly than in the control group. This effect was associated with a brief 30% decrease in MAP (p = NS). After NaHCO3, CO increased 78% and remained increased for 5 min (p < 0.007). One dog converted from complete heart block to sinus rhythm shortly after NaHCO3 administration. NaHCO3 improved ECG changes secondary to cocaine toxicity and improved myocardial function.

Conformationally restricted analogs of BD1008 and an antisense oligodeoxynucleotide targeting σ 1 receptors produce anti-cocaine effects in mice

Cocaine's ability to interact with σ receptors suggests that these proteins mediate some of its behavioral effects. Therefore, three novel σ receptor ligands with antagonist activity were evaluated in Swiss Webster mice: BD1018 (3 S-1-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[4.3.0]nonane), BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine), and LR132 (1 R,2 S-(+)- cis- N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)cyclohexylamine). Competition binding assays demonstrated that all three compounds have high affinities for σ 1 receptors. The three compounds vary in their affinities for σ 2 receptors and exhibit negligible affinities for dopamine, opioid, GABA A and NMDA receptors. In behavioral studies, pre-treatment of mice with BD1018, BD1063, or LR132 significantly attenuated cocaine-induced convulsions and lethality. Moreover, post-treatment with LR132 prevented cocaine-induced lethality in a significant proportion of animals. In contrast to the protection provided by the putative antagonists, the well-characterized σ receptor agonist di- o-tolylguanidine (DTG) and the novel σ receptor agonist BD1031 (3 R-1-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[4.3.0]nonane) each worsened the behavioral toxicity of cocaine. At doses where alone, they produced no significant effects on locomotion, BD1018, BD1063 and LR132 significantly attenuated the locomotor stimulatory effects of cocaine. To further validate the hypothesis that the anti-cocaine effects of the novel ligands involved antagonism of σ receptors, an antisense oligodeoxynucleotide against σ 1 receptors was also shown to significantly attenuate the convulsive and locomotor stimulatory effects of cocaine. Together, the data suggests that functional antagonism of σ receptors is capable of attenuating a number of cocaine-induced behaviors.

Effect of the kappa-opioid receptor agonist, U69593, on reinstatement of extinguished amphetamine self-administration behavior

Previous research has indicated that pretreatment with the kappa-opioid receptor agonist, U69593, decreased the ability of experimenter-administered cocaine to reinstate extinguished cocaine self-administration behavior. This effect was specific to cocaine-produced drug seeking since U69593 failed to attenuate the ability of experimenter-administered amphetamine to reinstate extinguished cocaine self-administration behavior. One possibility is that U69593 selectively attenuates the behavioral effects of the drug that was originally self-administered. In order to test this hypothesis, the present study examined the effect of U69593 (0.0 or 0.32 mg/kg) on the reinstatement of extinguished amphetamine self-administration behavior produced by experimenter-administered injections of cocaine and amphetamine. Following extinction of amphetamine self-administration (0.04 mg/kg/infusion) the ability of cocaine (0.0, 5.0, 10.0 or 20.0 mg/kg) or amphetamine (0.0, 0.3, 1.0 or 3.0 mg/kg) to reinstate extinguished self-administration behavior was measured. Both drugs reinstated extinguished responding and the reinstatement was attenuated by pretreatment with U69593. The data indicate that the ability of U69593 to decrease drug seeking is not restricted to subjects experienced with cocaine self-administration. Self-administration history does, however, determine the effect of U69593 on amphetamine-produced drug seeking.

Active cocaine immunization attenuates the discriminative properties of cocaine.

Anticocaine antibody, resulting from immunization with the cocaine-keyhole-limpet-hemocyanin (KLH) conjugate, weakened the ability of cocaine to act as a discriminative stimulus in rats. Subjects were given extensive training to discriminate 5.0 mg/kg of cocaine from saline prior to immunization. Several weeks following immunization with cocaine-KLH, subjects failed to reliably discriminate cocaine from saline. Nonimmunized control rats retained the ability to discriminate cocaine from saline throughout the experiment. These results further demonstrate that active immunization is effective in blunting cocaine effects. Immunized subjects were able to discriminate 20 mg/kg of cocaine, however, suggesting that anticocaine antibody may be overwhelmed by large cocaine doses.