Behavioral Actions Of Cocaine Research Articles

Cocaine Receptor Identified as BASP1

Cocaine exerts its behavioral actions mainly through inhibition of dopamine reuptake. However, cocaine is a weak and non-selective inhibitor of the monoamine transporters. In addition, many dopamine reuptake inhibitors do not produce psychotropic effects in drug-experienced volunteers. On the other hand, previous evidence indicates more potent effects of cocaine. For example, low nanomolar cocaine regulates dopamine D2 receptor signaling. In planarians, low nanomolar levels of cocaine produces environmental place conditioning. These signaling and behavioral actions of cocaine could not be mediated through the inhibition of monoamine transporters. Furthermore, previous a study describes 16 nM cocaine binding in rat striatal synaptosomes suggesting the existence of a high-affinity receptor for cocaine. However, the identity of such receptor is unknown.

The SERT Met172 Mouse: An Engineered Model To Elucidate the Contributions of Serotonin Signaling to Cocaine Action.

Cocaine abuse and addiction remain highly prevalent and, unfortunately, poorly treated. It is well-known that essential aspects of cocaine's addictive actions involve the drug's ability to block the presynaptic dopamine (DA) transporter (DAT), thereby elevating extracellular levels of DA in brain circuits that subserve reward, reinforcement, and habit. Less well appreciated are the multiple DA-independent actions of cocaine, activities that we and others believe contribute key pieces to the puzzle of cocaine addiction, treatment, and relapse. In particular, a significant body of work points to altered serotonin (5-HT) signaling as one such component, not surprising given that, relative to DAT, cocaine acts as potently to block the 5-HT transporter (SERT) as to block DAT, and thereby elevates extracellular 5-HT levels throughout the brain when reward-eliciting DA elevations occur. To elucidate the contribution of SERT antagonism to the actions of cocaine, we engineered a mouse model that significantly reduces cocaine potency at SERT without disrupting the expression or function of SERT in vivo. In this short Perspective, we review the rationale for development of the SERT Met172 model, the studies that document the pharmacological impact of the Ile172Met substitution in vitro and in vivo, and our findings with the model that demonstrate serotonergic contributions to the genetic, physiological, and behavioral actions of cocaine.

WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine

Wiskott-Aldrich syndrome protein (WASP) family verprolin homologous protein 1 (WAVE1) regulates actin-related protein 2/3 (Arp2/3) complex-mediated actin polymerization. Our previous studies have found WAVE1 to be inhibited by Cdk5-mediated phosphorylation in brain and to play a role in the regulation of dendritic spine morphology. Here we report that mice in which WAVE1 was knocked out (KO) in neurons expressing the D1 dopamine receptor (D1-KO), but not mice where WAVE1 was knocked out in neurons expressing the D2 dopamine receptor (D2-KO), exhibited a significant decrease in place preference associated with cocaine. In contrast to wild-type (WT) and WAVE1 D2-KO mice, cocaine-induced sensitized locomotor behavior was not maintained in WAVE1 D1-KO mice. After chronic cocaine administration and following withdrawal, an acute cocaine challenge induced WAVE1 activation in striatum, which was assessed by dephosphorylation. The cocaine-induced WAVE1 dephosphorylation was attenuated by coadministration of either a D1 dopamine receptor or NMDA glutamate receptor antagonist. Upon an acute challenge of cocaine following chronic cocaine exposure and withdrawal, we also observed in WT, but not in WAVE1 D1-KO mice, a decrease in dendritic spine density and a decrease in the frequency of excitatory postsynaptic AMPA receptor currents in medium spiny projection neurons expressing the D1 dopamine receptor (D1-MSNs) in the nucleus accumbens. These results suggest that WAVE1 is involved selectively in D1-MSNs in cocaine-evoked neuronal activity-mediated feedback regulation of glutamatergic synapses.

Epac Signaling Is Required for Cocaine-Induced Change in AMPA Receptor Subunit Composition in the Ventral Tegmental Area.

Exchange protein directly activated by cAMP (Epac) and protein kinase A (PKA) are intracellular receptors for cAMP. Although PKA and its downstream effectors have been studied extensively in the context of drug addiction, whether and how Epac regulates cellular and behavioral effects of drugs of abuse remain essentially unknown. Epac is known to regulate AMPA receptor (AMPAR) trafficking. Previous studies have shown that a single cocaine exposure in vivo leads to an increase in GluA2-lacking AMPARs in dopamine neurons of the ventral tegmental area (VTA). We tested the hypothesis that Epac mediates cocaine-induced changes in AMPAR subunit composition in the VTA. We report that a single cocaine injection in vivo in wild-type mice leads to inward rectification of EPSCs and renders EPSCs sensitive to a GluA2-lacking AMPAR blocker in VTA dopamine neurons. The cocaine-induced increase in GluA2-lacking AMPARs was absent in Epac2-deficient mice but not in Epac1-deficient mice. In addition, activation of Epac with the selective Epac agonist 8-CPT-2Me-cAMP (8-CPT) recapitulated the cocaine-induced increase in GluA2-lacking AMPARs, and the effects of 8-CPT were mediated by Epac2. We also show that conditioned place preference to cocaine was impaired in Epac2-deficient mice and in mice in which Epac2 was knocked down in the VTA but was not significantly altered in Epac1-deficient mice. Together, these results suggest that Epac2 is critically involved in the cocaine-induced change in AMPAR subunit composition and drug-cue associative learning. Addictive drugs, such as cocaine, induce long-lasting adaptions in the reward circuits of the brain. A single intraperitoneal injection of cocaine leads to changes in the composition and property of the AMPAR that carries excitatory inputs to dopamine neurons. Here, we provide evidence that exchange protein directly activated by cAMP (Epac), a cAMP sensor protein, is required for the cocaine-induced changes of the AMPAR. We found that the effects of cocaine were mimicked by activation of Epac but were blocked by genetic deletion of Epac. Furthermore, cocaine-cue associative learning was impaired in mice lacking Epac. These findings uncovered a critical role of Epac in regulating the cellular and behavioral actions of cocaine.

Discovery of Drugs to Treat Cocaine Dependence: Behavioral and Neurochemical Effects of Atypical Dopamine Transport Inhibitors

Stimulant drugs acting at the dopamine transporter (DAT), like cocaine, are widely abused, yet effective medical treatments for this abuse have not been found. Analogs of benztropine (BZT) that, like cocaine, act at the DAT have effects that differ from cocaine and in some situations block the behavioral, neurochemical, and reinforcing actions of cocaine. Neurochemical studies of dopamine levels in brain and behavioral studies have demonstrated that BZT analogs have a relatively slow onset and reduced maximal effects compared to cocaine. Pharmacokinetic studies, however, indicated that the BZT analogs rapidly access the brain at concentrations above their in vitro binding affinities, while binding in vivo demonstrates apparent association rates for BZT analogs lower than that for cocaine. Additionally, the off-target effects of these compounds do not fully explain their differences from cocaine. Initial structure-activity studies indicated that BZT analogs bind to DAT differently from cocaine and these differences have been supported by site-directed mutagenesis studies of the DAT. In addition, BZT analog-mediated inhibition of uptake was more resistant to mutations producing inward conformational DAT changes than cocaine analogs. The BZT analogs have provided new insights into the relation between the molecular and behavioral actions of cocaine and the diversity of effects produced by dopamine transport inhibitors. Novel interactions of BZT analogs with the DAT suggest that these drugs may have a pharmacology that would be useful in their development as treatments for cocaine abuse.

Blockade of melanocortin transmission inhibits cocaine reward

Melanocortins and the melanocortin-4 receptor (MC4-R) are enriched in the nucleus accumbens, a brain region that has been implicated in the rewarding action of cocaine and other drugs of abuse. In the present study we use a number of rat behavioral models to show that infusion of a melanocortin peptide antagonist into the nucleus accumbens blocks the reinforcing, incentive motivational, and locomotor sensitizing effects of cocaine. We also show that locomotor responses to repeated cocaine exposure are completely blocked in MC4-R null mutant mice and reduced in Agouti mice that overexpress an endogenous inhibitor of melanocortins in the brain. The results also demonstrate that cocaine administration increases the expression of MC4-R in the nucleus accumbens and striatum, and that MC4-R is co-localized with prodynorphin in medium spiny neurons in the nucleus accumbens. Together, these findings indicate that the behavioral actions of cocaine are dependent on activation of MC4-R, and suggest that upregulation of this receptor by drug exposure may contribute to sensitization of these behavioral responses. Modulation of cocaine reward is a novel action of the melanocortin-MC4-R system and could be targeted for the development of new medications for cocaine addiction.

Cocaine-induced hypophagia and hyperlocomotion in rats are attenuated by prazosin

The present studies examined the effects of antagonizing α 1-adrenoceptors via systemic administration of prazosin on the behavioral actions of cocaine in rats, including induction of locomotion and suppression of eating. In Experiment 1, locomotor activity was monitored in automated chambers for 80 min in adult male rats pretreated with the α 1-adrenoceptor antagonist prazosin (0, 0.5, or 2 mg/kg, i.p.) and then treated (i.p.) with either 0, 10, 20, or 40 mg/kg cocaine hydrochloride. Cocaine dose-dependently increased total distance traveled and the number of stereotypy counts, and significantly decreased rest time. Each dose of prazosin produced a significant attenuation of the locomotor effects of a limited range of cocaine doses (i.e. 10 and/or 20 mg/kg cocaine, but not 40 mg/kg cocaine). Prazosin alone did not alter any measure of locomotion. In Experiment 2, eating and drinking were monitored for 60 min in male rats pretreated with prazosin (0, 1, and 2 mg/kg, i.p.) and then treated with 0, 10, 20, or 40 mg/kg (i.p.) cocaine. Rats pretreated with vehicle exhibited a dose-dependent suppression of eating, but not drinking, to cocaine. The impact of prazosin on cocaine-induced hypophagia paralleled that noted for locomotion in that administration of prazosin significantly attenuated the hypophagic action of 20 mg/kg cocaine, but not that of 40 mg/kg cocaine. These findings confirm earlier studies noting a partial role for α 1-adrenoceptors in the locomotor stimulant actions of cocaine and extend those findings to the feeding-inhibitory actions of cocaine.

Cocaine actions, brain levels and receptors in selected lines of mice

The effects of cocaine (15 mg/kg IP) versus IP saline on open-field behaviors were evaluated using a crossover design in long-sleep (LS) and short-sleep (SS) mice. Under treatment order 1, mice received saline injection on day 1 followed 24 h later by cocaine (saline-cocaine, S-C). Under treatment order 2, animals received cocaine on day 1 and saline on day 2 (cocaine-saline, C-S). Immediately following injection, animals were placed into an automated open-field apparatus with behavioral samples taken at 5-min intervals for 30 min. The behaviors measured were distance traveled, stereotypy and time spent in proximity to the margins of the test apparatus (thigmotaxis). Cocaine increased locomotor activity in both lines of mice, with S-C producing more pronounced initial activation than C-S in LS mice. Compared to S-C, C-S also increased thigmotaxis, an effect more pronounced in SS mice. In a separate experiment, brain cocaine levels were measured in brains of adapted and nonadapted LS and SS mice 5 min following injection of 15 mg/kg cocaine. Regardless of order, SS mice had significantly higher brain cocaine levels than did LS mice. Mazindol and cocaine binding studies in the forebrain indicated higher Bmax values for both ligands in LS compared to SS mice. The results of this study indicate that genetically based differences in cocaine receptors as well as treatment order contribute to behavioral actions of cocaine.

Genetic Determinants of Suceptability to the Rewarding and Other Behavioral Actions of Cocaine

The role of genotype as a determinant of biologically based inter-individual differences in vulnerability to substance abuse has received little systematic investigation except in the case of alcohol. This report describes the use of an animal model, the inbred mouse, to identify and to characterize variants with inherently altered susceptibilities to the rewarding and other behavioral actions of cocaine. Among a battery of nine inbred strains chosen solely for their genetic diversity, genetic polymorphisms commonly occurred which altered the potency and/or efficacy of cocaine to induce conditioned place preference, oral self-administration, motor activity activation, seizures and lethality. These changes in cocaine sensitivity generally were of a behavior-specific and pharmacodynamic nature. One strain, DBA/2J, found to be markedly hyporesponsive to the rewarding action of cocaine, also was hyporesponsive to the rewarding effects of amphetamine, etonitazene, phencyclidine, caffeine and procaine. We speculate that this strain has an inherent generalized appetitive defect. The frequent occurrence and large magnitude of inherent phenotypic changes in cocaine responsiveness which we have identified among inbred mouse strains now permits an analytical genetic study of processes underlying cocaine-mediated reinforcement.