Repeated Administration Of Psychostimulants Research Articles

Susceptibility to express amphetamine locomotor sensitization correlates with dorsolateral striatum bursting activity and GABAergic synapses in the globus pallidus

Repeated psychostimulant administration results in behavioral sensitization, a process that is relevant in the early phases of drug addiction. Critically, behavioral sensitization is not observed in all subjects. Evidence shows that differential neuronal activity in the dorsolateral striatum (DLS) accompanies the expression of amphetamine (AMPH) locomotor sensitization. However, whether individual differences in DLS activity previous to AMPH administration can predict the expression of locomotor sensitization has not been assessed. Here, we examined DLS neuronal activity before and after repeated AMPH administration and related it to the susceptibility of rats to sensitize. For that, single-unit recordings on DLS medium spiny neurons (MSNs) were carried out in freely moving male Sprague Dawley rats during repeated AMPH administration. We also examined differences in neurostructure that could accompany sensitization. We quantified the density of the inhibitory postsynaptic marker gephyrin (Geph) in the entopeduncular nucleus (EP) and globus pallidus (GP). A higher burst firing and a lower percentage of correlation between MSNs post-Saline firing rate vs. locomotion predicted the expression of locomotor sensitization. Moreover, during the AMPH challenge, we observed that burst firing decreased in sensitized rats, in contrast to non-sensitized rats in which burst firing was maintained. Finally, a higher Geph density on GP but not EP was observed in non-sensitized rats after AMPH challenge. These results indicate that initial differences in DLS burst firing might underlie the susceptibility to express locomotor sensitization and suggest that the potentiation of dorsal striatum indirect pathway could be considered a protective mechanism to locomotor sensitization.

The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement.

Reward-related behavior is complex and its dysfunction correlated with neuropsychiatric illness. Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been associated with different aspects of reward function, but it remains to be disentangled how distinct VTA DA neurons contribute to the full range of behaviors ascribed to the VTA. Here, a recently identified subtype of VTA neurons molecularly defined by NeuroD6 (NEX1M) was addressed. Among all VTA DA neurons, less than 15% were identified as positive for NeuroD6. In addition to dopaminergic markers, sparse NeuroD6 neurons expressed the vesicular glutamate transporter 2 (Vglut2) gene. To achieve manipulation of NeuroD6 VTA neurons, NeuroD6(NEX)-Cre-driven mouse genetics and optogenetics were implemented. First, expression of vesicular monoamine transporter 2 (VMAT2) was ablated to disrupt dopaminergic function in NeuroD6 VTA neurons. Comparing Vmat2lox/lox;NEX-Cre conditional knock-out (cKO) mice with littermate controls, it was evident that baseline locomotion, preference for sugar and ethanol, and place preference upon amphetamine-induced and cocaine-induced conditioning were similar between genotypes. However, locomotion upon repeated psychostimulant administration was significantly elevated above control levels in cKO mice. Second, optogenetic activation of NEX-Cre VTA neurons was shown to induce DA release and glutamatergic postsynaptic currents within the nucleus accumbens. Third, optogenetic stimulation of NEX-Cre VTA neurons in vivo induced significant place preference behavior, while stimulation of VTA neurons defined by Calretinin failed to cause a similar response. The results show that NeuroD6 VTA neurons exert distinct regulation over specific aspects of reward-related behavior, findings that contribute to the current understanding of VTA neurocircuitry.

Haloperidol attenuates Methylphenidate and Modafinil induced behavioural sensitization and cognitive enhancement.

Previous studies have demonstrated that repeated psychostimulant administration produces behavioural sensitization and cognitive tolerance. Brain dopaminergic system and the involvement of dopamine D2-receptors are considered to be important in psychostimulant-induced sensitization. Study designed to compared the motor activity by using familiar and novel enviroments and cognitive effects by water maze and passive avoidance test after long term administration of methylphenidate(at the dose 0.6mg/kg/day, 2.5mg/kg/day and 10mg/kg/day) and modafinil (50mg/kg/day, 64mg/kg/day and 75mg/kg/day) in rats. The effects of challenge dose of haloperidol (at the dose of 1mg/kg i.p.) has monitored to visualize any subsensitization or supersensitization of D2 receptors. We found that motor activity and cognitive performance was increased in all doses and sensitization effect was more pronounced after 13days of drug administration were greater at high than low and medium doses.Challenge dose of haloperidol attenuate motor activity in familiar and novel environment and impaired cognition in water maze and passive avoidance test in all treated rats. The effect of Haloperidol in high dose treated rats were however somewhat greater than low and medium dose treated rats following methylphenidate and modafinil administration. Increased response of haloperidol in methylphenidate treated rats can be explained in term of supersensitization of D2 receptors which is greater in high dose treated rats. The results show that the role of D2 receptors to develop side effects such as behavioural sensitization and cognitive tolerance by the long term administration of psychostimulants is of sufficient importance and helpful in understanding the mechanisms underlying the undesirable effects of psychostimulants.

Phasic mesolimbic dopamine signaling encodes the facilitation of incentive motivation produced by repeated cocaine exposure.

Drug addiction is marked by pathological drug seeking and intense drug craving, particularly in response to drug-related stimuli. Repeated psychostimulant administration is known to induce long-term alterations in mesolimbic dopamine (DA) signaling that are hypothesized to mediate this heightened sensitivity to environmental stimuli. However, there is little direct evidence that drug-induced alteration in mesolimbic DA function underlies this hypersensitivity to motivational cues. In the current study, we tested this hypothesis using fast-scan cyclic voltammetry to monitor phasic DA signaling in the nucleus accumbens core of cocaine-pretreated (6 once-daily injections of 15 mg/kg, i.p.) and drug-naive rats during a test of cue-evoked incentive motivation for food-the Pavlovian-to-instrumental transfer task. We found that prior cocaine exposure augmented both reward seeking and DA release triggered by the presentation of a reward-paired cue. Furthermore, cue-evoked DA signaling positively correlated with cue-evoked food seeking and was found to be a statistical mediator of this behavioral effect of cocaine. Taken together, these findings provide support for the hypothesis that repeated cocaine exposure enhances cue-evoked incentive motivation through augmented phasic mesolimbic DA signaling. This work sheds new light on a fundamental neurobiological mechanism underlying motivated behavior and its role in the expression of compulsive reward seeking.

Cocaine self‐administration‐induced sensitization of the dopamine system (LB621)

The ability of cocaine to bind to, and inhibit the dopamine transporter (DAT) mediates the reinforcing effects of the compound and is essential for the maintenance of self‐administration behaviors. As such, it is important to determine the changes in cocaine potency following cocaine self‐administration as they have important implications for 1.) how the DAT changes in response to repeated psychostimulant administration as well as 2.) changes in the reinforcing potential for drugs such as cocaine. Although sensitization paradigms, which result in sensitization of cocaine‐induced locomotor behavior and dopamine (DA) overflow following repeated 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) conditions can result in enhanced cocaine potency at the DAT in the nucleus accumbens immediately following self‐administration. However, traditional sensitization paradigms often show enhanced effects following withdrawal/abstinence periods. Here we aimed to determine a time‐course of IntA‐induced DA sensitization and how a seven‐day abstinence period influences these effects. We show that while three days of IntA is not sufficient to alter evoked DA release, a seven‐day abstinence period following IntA results in augmented release. Additionally, cocaine potency is enhanced following as little as 3‐day IntA and further augmented following an abstinence period. Further, IntA plus abstinence enhanced cocaine‐induced DA release as compared to all other groups, demonstrating that following abstinence, cocaine’s ability to increase DA release and inhibit uptake at the DAT, two separate mechanisms for increasing DA levels, is augmented. Thus, the enhanced cocaine potency and cocaine‐induced release following abstinence could enhance the reinforcing efficacy and facilitate drug‐seeking for cocaine following periods of abstinence/withdrawal.Grant Funding Source: Supported by NIH grants from NIDA [R01 DA024095, R01 DA03016, R01 DA14030, P50DA006634 (SRJ), T32 DA007246 and F31 DA031533 (ESC)]

Psychostimulant Abuse and Neuroinflammation: Emerging Evidence of Their Interconnection

During the past two decades, there has been a tremendous expansion of knowledge regarding the neurobiological effects of substance abuse and how these effects impact behavior. At the same time, there has been a profound change in our understanding of the way in which the central nervous system responds to noxious stimuli. Most often referred to as the innate immune response (IIR), this defense mechanism is activated by a number of agents (toxic, microbial, ischemic) and has been implicated in the progression of a number of neurodegenerative diseases. We review evidence that psychostimulants of abuse (cocaine, methamphetamine, ecstasy) are associated with activation of the IIR. We first present background on what is currently known about the IIR including some of the cellular elements involved (microglia, astrocytes, vascular endothelial cells), key receptor pathways, and primary inflammatory cytokines (IL-1β, IL-6, TNF-α). We then present a variety of protein and gene expression data taken from animal studies that show increased expression of various components of the IIR following acute or repeated psychostimulant administration. Collectively the data indicate an association of psychostimulant use with IIR activation in the brain even at exposures not traditionally associated with neurotoxicity. Thus, the gradually escalating deleterious effects of psychostimulant use could in part involve neuroinflammatory mechanisms. Finally, we offer one hypothesis of a possible mechanism by which psychostimulants result in IIR activation and discuss the potential therapeutic implications of these findings for treatment of the recovering addict.

Repeated administration of caffeine induces either sensitization or tolerance of locomotor stimulation depending on the environmental context

AbstractCaffeine is the psychostimulant substance consumed in greatest quantities in the world. The repeated administration of psychostimulants can either decrease or increase the drug effect, inducing tolerance or sensitization, respectively, depending on administration procedure. Not only the dose and regimen, but also the environment where drug is administered, seem to modulate the changes in locomotor activity following repeated psychostimulant administration. The purpose of the present study was to examine the influence of the environmental context on caffeine-induced psychomotor stimulation following repeated administration of this drug. Our results showed that repeated caffeine induced psychomotor sensitization when drug injections were paired with the environment in which the animals were subsequently tested, whereas tolerance occurred when the animals received repeated caffeine in an environment different from that where the tests were performed. In conclusion, the present results demonstrated that the environmental context where caffeine is administered is a key factor modulating the adaptations of the organism to drug effects.

Does prenatal methamphetamine exposure affect the drug-seeking behavior of adult male rats?

Methamphetamine (MA) is one of the most frequently used illicit drugs worldwide and also one of the most common drugs abused by pregnant women. Repeated administration of psychostimulants induces behavioral sensitization in response to treatment of the same or related drugs in rodents. The effect of prenatal MA exposure on sensitivity to drugs in adulthood is not yet fully determined. Because our most recent studies demonstrated that prenatal MA (5mg/kg) exposure makes adult rats more sensitive to acute injection of the same drug, we were interested whether the increased sensitivity corresponds with the increased drug-seeking behavior. The aim of the present study was to examine the effect of prenatal MA exposure on drug-seeking behavior of adult male rats tested in the conditioned place preference (CPP). The following psychostimulant drugs were used as a challenge in adulthood: MA (5mg/kg), amphetamine (5mg/kg) and cocaine (10mg/kg). All psychostimulant drugs induced increased drug-seeking behavior in adult male rats. However, while MA and amphetamine-induced increase in drug-seeking behavior did not differ based on the prenatal drug exposure, prenatally MA-exposed rats displayed tolerance effect to cocaine in adulthood. In addition, prenatally MA-exposed rats had decreased weight gain after administration of MA or amphetamine, while the weight of prenatally MA-exposed rats stayed unchanged after cocaine administration. Defecation was increased by all the drugs (MA, amphetamine and cocaine), while only amphetamine increased the tail temperature. In conclusion, our results did not confirm our hypothesis that prenatal MA exposure increases drug-seeking behavior in adulthood in the CPP test.

DECREASED AMPA GLuR2, BUT NOT GLuR3, mRNA EXPRESSION IN RAT AMYGDALA AND DORSAL HIPPOCAMPUS FOLLOWING MORPHINE‐INDUCED BEHAVIOURAL SENSITIZATION

1. Repeated administration of psychostimulants and micro-opioid receptor agonists elicits a progressive enhancement of drug-induced behavioural responses, a phenomenon termed behavioural sensitization. These changes in behaviour may reflect plastic changes requiring regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor function. 2. In the present study, rats were treated for 7 days with saline or morphine (10 mg/kg). After a washout period of either 24 h or 7 days, locomotion, oral stereotypy and state-dependent memory in a passive avoidance test were measured in the presence or absence of 6-cyano-7-nitroquinoxaline-2,3-dione disodium salt (CNQX; 3 mg/kg), an AMPA receptor antagonist. In order to evaluate the mechanism underlying the behavioural responses, quantitative real-time reverse transcription-polymerase chain reaction was used to evaluate mRNA expression of the AMPA receptor subunits GluR2 and GluR3 in the striatum, prefrontal cortex, hippocampus, hypothalamus and amygdala of animals treated repeatedly with morphine. 3. The results indicate that repeated morphine treatment followed by 7 days (but not 24 h) washout produces behavioural sensitization, as determined by locomotion, oral stereotypy and state-dependent memory. Blockade of AMPA receptors with CNQX on the test day did not alter these behavioural responses. In addition, repeated morphine treatment followed by 7 days (but not 24 h) washout decreased GluR2 mRNA expression in both the amygdala (by 50%) and hippocampus (by 35%). Repeated morphine treatment did not alter GluR3 mRNA expression in any brain area assessed. 4. These data imply that AMPA receptors are involved in the development (but not expression) phase of behavioural sensitization. The decreases in GluR2 mRNA expression in the amygdala and hippocampus may result in the formation of calcium-permeable AMPA receptors, which are believed to play an important role in behavioural sensitization.

The Roman High- and Low-Avoidance Rat Lines Differ in the Acquisition, Maintenance, Extinction, and Reinstatement of Intravenous Cocaine Self-Administration

The selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats for, respectively, rapid vs extremely poor acquisition of avoidant behavior in a shuttlebox has produced two phenotypes that differ in temperament traits, in mesocortical/mesolimbic dopamine system function, and in the behavioral and neurochemical responses to the acute and repeated administration of psychostimulants and opiates. The phenotypic traits of the RHA line predict higher susceptibility, compared with RLA rats, to the reinforcing properties of addictive substances like cocaine. The present study was designed to compare the acquisition, maintenance, reinstatement of drug-seeking after long-term extinction, and reacquisition of intravenous cocaine self-administration (SA) behavior in the Roman lines. Compared with RLA rats, the rates of responding during cocaine SA acquisition were higher, extinction from cocaine SA was prolonged, and drug-induced reinstatement of cocaine-seeking behavior was more robust in RHA rats. Moreover, only RHA rats reacquired extinguished lever-pressing activity when a low reinforcing dose of cocaine was available. These findings are consistent with the view that subjects with genetically determined high responsiveness to the acute and chronic (ie, sensitizing) effects of psychostimulants, such as RHA rats, also display a higher propensity to self -administer cocaine. Further comparative studies in the Roman lines, using SA paradigms that distinguish mere drug-taking from the compulsive and uncontrolled drug use that characterizes addiction in humans, may eventually help to characterize the relationships among genotype, temperament traits, and neurobiological mechanisms involved in the individual vulnerability to cocaine addiction.

The CB 1 cannabinoid receptor antagonist AM251 attenuates amphetamine-induced behavioural sensitization while causing monoamine changes in nucleus accumbens and hippocampus

Endogenous cannabinoids modulate the activity of dopamine reward pathways and may play a role in the development of behavioural sensitization to psychostimulants. Here, we investigated the effects of the CB 1 cannabinoid receptor antagonist AM251 on amphetamine-induced locomotor sensitization in mice. Furthermore, we measured post-mortem monoamine concentrations in nucleus accumbens and hippocampus after termination of the behavioural tests. The results can be summarized as follows: Mice pre-treated with AM251 (3 mg/kg; i.p.) showed less sensitivity to the psychomotor stimulant as well as locomotor sensitizing effects of amphetamine (2 mg/kg; i.p.) resembling previous results obtained with CB 1 receptor-deficient animals. Furthermore, the behavioural effects of AM251 were paralleled by increased dopamine concentration in nucleus accumbens and increased serotonin concentration/turnover rate in hippocampus, respectively. The present data indicate that under normal conditions activation of the CB 1 receptor facilitates those adaptive responses elicited by repeated psychostimulant administration and resulting in sensitization, possibly by reducing dopamine biosynthesis and serotonin turnover in the nucleus accumbens and hippocampus.

Changes in Proenkephalin mRNA expression in forebrain areas after amphetamine-induced behavioural sensitization

Acute and repeated psychostimulant administration induces a long-lasting enhanced behavioural response to a subsequent drug challenge, known as behavioural sensitization. This phenomenon involves persistent neurophysiological adaptations, which may lead to drug addiction. Brain dopaminergic pathways have been implicated as the main neurobiological substrates of behavioural sensitization, although other neurotransmitters and neuromodulators may also participate. In order to investigate a possible involvement of opioid systems in amphetamine (AMPH) behavioural sensitization, we studied the AMPH-induced changes in Proenkephalin (Pro-Enk) mRNA expression in forebrain areas in both drug-naïve and AMPH-sensitized rats. Male Sprague–Dawley rats were sensitized to AMPH by means of a single AMPH (1 mg/kg s.c.) injection and the same dose was injected 7 days later to assess the expression of sensitization. Pro-Enk mRNA levels were evaluated by in situ hybridization in coronal brain sections. AMPH injection induced an increase in Pro-Enk mRNA expression in the nucleus accumbens and the medial–posterior caudate-putamen in drug-naïve rats. Challenge with AMPH to rats injected 1 week earlier with AMPH induced motor sensitization and increased and decreased Pro-Enk mRNA expression in the prefrontal cortex and the anterior medial caudate-putamen, respectively. Our results suggest that alterations in cortical and striatal enkephalinergic systems could contribute to the expression of AMPH behavioural sensitization.

Exciting inhibition in psychostimulant addiction

Neuroplasticity induced in the nucleus accumbens by repeated psychostimulant administration is thought to underlie the vulnerability to relapse in addicts. Electrophysiological research presents a contradictory portrait of psychostimulant-induced neuroplasticity, reflecting both increases and decreases in excitatory transmission. Drug-induced adaptations of ionic conductances decrease the intrinsic excitability of individual nucleus accumbens spiny neurons but, in the context of the circuitry in which these neurons are embedded, such reduced intrinsic excitability increases the salience of excitatory drive that is elicited by drug-associated stimuli. Thus, we propose that reduced basal excitability, combined with enhanced excitatory drive by drug-associated stimuli, contributes to the two cardinal features of addiction: reduced responding to natural reward and enduring vulnerability to relapse.

Chronic treatment with a serotonin 2 receptor (5-HT 2R) agonist modulates the behavioral and cellular response to (+)-3,4-methylenedioxymethamphetamine [(+)-MDMA

3,4-Methylenedioxymethamphetamine [MDMA; ecstasy] evokes a multifaceted subjective experience in human users which includes stimulation, feelings of well-being, mood elevation, empathy towards others as well as distortions in time, sensation and perception. Aspects of this unique psychopharmacology of MDMA are thought to be related to its potent actions to release serotonin (5-HT) and indirectly stimulate the 5-HT 2A receptor (5-HT 2AR). In the present studies, we examined the interrelationship between down-regulation of 5-HT 2AR expression and the behaviorally stimulatory effects generated by acute administration of (+)-MDMA, the most potent enantiomer of (±)-MDMA. Male Sprague–Dawley rats were chronically treated with the preferential 5-HT 2AR agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) which has been shown to down-regulate expression of the 5-HT 2AR, but not the closely related 5-HT 2CR. While chronic DOI treatment did not alter the functional sensitivity of either the 5-HT 2AR or 5-HT 2CR, this regimen enhanced (+)-MDMA-evoked hyperactivity. Subsequent analysis of c-Fos and 5-HT 2AR immunoreactivity in brain sections demonstrated that DOI treatment decreased the number of (+)-MDMA-induced c-Fos immunopositive nuclei and 5-HT 2AR immunostaining in select cortical and striatal areas. These results indicate that chronic DOI exposure results in an enhanced behavioral response to (+)-MDMA and in a pattern of neuronal activation which resembles that seen in psychostimulant sensitization. These data also suggest that expression of the 5-HT 2AR in the NAc and PFC may play a role in the sensitivity to the locomotor-stimulating effects of (+)-MDMA and in the processes of neural regulation upon repeated psychostimulant administration.

Differential activation of dopamine release in the nucleus accumbens core and shell after acute or repeated amphetamine injections: A comparative study in the Roman high- and low-avoidance rat lines

The selectively bred Roman high- and low-avoidance rats differ in emotionality and responsiveness to the motor effects of acute and repeated psychostimulant administration. These lines also show drastic differences in the neurochemical responses of their mesolimbic dopamine systems to addictive drugs. The nucleus accumbens is critically involved in the locomotor activation produced by psychostimulants and in the augmentation of this effect observed upon repeated drug administration (i.e. behavioral sensitization), although there is not a general consensus as to whether the nucleus accumbens-core or the nucleus accumbens-shell is preferentially involved in such alterations. This study was designed to evaluate the effects of acute amphetamine (0.20mg/kg, s.c.) on dopamine output in the nucleus accumbens-shell and nucleus accumbens-core of the Roman lines under basal conditions (i.e. naïve rats) and after the repeated administration of amphetamine (1mg/kg, s.c.×10 days) or saline. We show that (1) in naïve rats, amphetamine caused a larger increment in dopamine output in the nucleus accumbens-shell vs the nucleus accumbens-core only in the Roman high-avoidance line; (2) repeated amphetamine elicits behavioral sensitization in Roman high-avoidance, but not Roman low-avoidance, rats; (3) in sensitized Roman high-avoidance rats, amphetamine provokes a larger increment in dopamine output in the nucleus accumbens-core, and an attenuated dopaminergic response in the nucleus accumbens-shell, as compared with Roman high-avoidance rats repeatedly treated with saline; and (4) such neurochemical changes are not observed in the mesoaccumbens dopaminergic system of the sensitization-resistant Roman low-avoidance line. We propose that (1) Roman high-avoidance and Roman low-avoidance rats differ in the vulnerability to develop psychostimulant sensitization, (2) the nucleus accumbens-core and nucleus accumbens-shell subserve distinct functional roles in this phenomenon, and (3) comparative studies in the Roman lines may provide insight into the influence of neural substrates and genetic background on the individual vulnerability to addiction.

Methamphetamine sensitization in nociceptin receptor knockout mice: locomotor and c- fos expression

The role of endogenous nociceptin in the development and expression of sensitization to repeated methamphetamine administration in a novel environment was studied in nociceptin receptor knockout mice. No differences in acute or sensitized locomotor responses were found in nociceptin receptor knockout mice. However, analysis of c- fos expression revealed significant interactions between chronic methamphetamine treatment and genotype in the nucleus accumbens and lateral septum. This was due to increased c- fos expression in chronically methamphetamine-treated nociceptin receptor knockout mice contrasted with reduced c- fos expression in chronically vehicle-treated nociceptin receptor knockout mice. Two further regions (nucleus accumbens core and ventromedial caudate putamen) showed significant interactions between genotype, chronic, and acute methamphetamine treatment due to accentuated c- fos expression in nociceptin receptor knockout mice sensitized and challenged with methamphetamine. These findings suggest endogenous nociceptin modulates the response of the central nervous system to repeated psychostimulant administration, although this is little reflected in locomotion.

Preweaning cocaine exposure alters brain glucose metabolic rates following repeated amphetamine administration in the adult rat

Developmental cocaine exposure produces long-term alterations in function of many neuronal circuits. This study examined glucose metabolic rates following repeated amphetamine administration in adult male and female rats pretreated with cocaine during postnatal days (PND) 11–20. PND11–20 cocaine increased the response to amphetamine in many components of the motor system and the dorsal caudate–putamen, in particular, and decreased the metabolic response in the hypothalamus. While amphetamine alone produced widespread increases in metabolism, there were no cocaine-related effects in the mesolimbic, limbic or sensory structures. These data suggest that a brief cocaine exposure during development can alter ontogeny and result in abnormal neuronal responses to repeated psychostimulant administration in adulthood.

Repeated cocaine injections have no influence on tyrosine hydroxylase activity in the rat nucleus accumbens core or shell

Numerous reports have demonstrated augmented cocaine-evoked release of dopamine in the nucleus accumbens of rats pre-treated with cocaine. However, the extent to which repeated cocaine injections affect basal levels of dopamine is unclear. There have been reports of increases, decreases, or no change in basal levels of extracellular accumbal dopamine resulting from repeated psychostimulant administration. The present study assessed the activity of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, in the nucleus accumbens following either acute or repeated cocaine administration. The in vivo microdialysis technique was used to measure accumulation of the dopamine precursor DOPA following intra-accumbal administration of the DOPA decarboxylase inhibitor NSD 1015 through the microdialysis probe. This method provides an estimate of tyrosine hydroxylase activity within the nucleus accumbens. Results indicate that neither acute nor repeated cocaine administration produced any change in DOPA accumulation in either the nucleus accumbens shell or core. These data indicate that dopamine synthesis is not altered by cocaine administration.

Repeated cocaine injections have no influence on tyrosine hydroxylase activity in the rat nucleus accumbens core or shell

Numerous reports have demonstrated augmented cocaine-evoked release of dopamine in the nucleus accumbens of rats pre-treated with cocaine. However, the extent to which repeated cocaine injections affect basal levels of dopamine is unclear. There have been reports of increases, decreases, or no change in basal levels of extracellular accumbal dopamine resulting from repeated psychostimulant administration. The present study assessed the activity of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, in the nucleus accumbens following either acute or repeated cocaine administration. The in vivo microdialysis technique was used to measure accumulation of the dopamine precursor DOPA following intra-accumbal administration of the DOPA decarboxylase inhibitor NSD 1015 through the microdialysis probe. This method provides an estimate of tyrosine hydroxylase activity within the nucleus accumbens. Results indicate that neither acute nor repeated cocaine administration produced any change in DOPA accumulation in either the nucleus accumbens shell or core. These data indicate that dopamine synthesis is not altered by cocaine administration.

Brain circuitry and the reinstatement of cocaine-seeking behavior.

Recent studies have attempted to identify the neuroanatomical substrates underlying primed reinstatement of drug-seeking behavior. Identification of neuronal substrates will provide a logical rationale for designing pharmacological interventions in treating drug relapse. The objective was to identify brain circuitry that is shared between cue-, drug- and stress-primed reinstatement, as well as identifying aspects of brain circuitry that are distinct for each stimulus modality. The resulting circuit offers theoretical interpretations for consideration in future studies. Aspects of the circuitry mediating reinstatement can be identified with reasonable confidence. The role of the basolateral amygdala in cue-primed reinstatement, the role of the ventral tegmental area in drug-primed reinstatement and the role of adrenergic innervation of the extended amygdala in stress-primed reinstatement are well characterized. Also, all three modes for priming reinstatement may converge on the anterior cingulate cortex and have a final common output through the core of the nucleus accumbens. Lacunae in our understanding of the circuit were identified, especially with regard to how stress priming is conveyed from the extended amygdala to the shared anterior cingulate accumbens core circuit. The proposed convergence of priming stimuli into the glutamatergic projection from anterior cingulate to the accumbens core combined with the changes in glutamate transmission and signaling that accompany repeated psychostimulant administration points to the potential value of pharmacological agents that manipulate glutamate release or postsynaptic glutamate receptor signaling and trafficking in treating primed relapse in addicts.