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David C S Roberts

Publications and source records attributed to David C S Roberts.

At least 19 recordsLinked to original sources
PubMed2006

A single evoked afterdischarge produces rapid time-dependent changes in connexin36 protein expression in adult rat dorsal hippocampus.

Gap junctions between neurons contribute to synchronous neuronal firing and may play a role in the pathophysiology of epilepsy. We examined the expression of a number of gap junction subunits, including the neuronal gap junction forming protein connexin36 (Cx36), in the hippocampus at various time points following an electrically stimulated afterdischarge (AD) in freely-moving animals. Once recovered from electrode implantation, animals were tested with an escalating series of stimulations until an AD was evoked. Suprathreshold stimulation produced a brief AD with no convulsion. Groups of animals were sacrificed at 3, 12, and 24h post-stimulation, and connexin expression was assessed via semiquantitative immunoblotting. Compared to implanted non-stimulated controls, a significant decrease in Cx36 expression was observed in the stimulated dorsal hippocampus at 3h post-stimulation, which returned to control levels by 24h. No changes were seen in the ventral hippocampus. As well, no changes were seen in other selected connexin proteins including Cx26, Cx32, and Cx43, thought to be expressed primarily in glia, in either dorsal or ventral hippocampus. These data suggest that a relatively brief hypersynchronous neuronal discharge can produce rapid and specific changes in Cx36 expression, which may have implications for both normal brain function and the pathophysiology of epilepsy.

Action Potentials↗
PubMed2006

Involvement of adenosine A2A and dopamine receptors in the locomotor and sensitizing effects of cocaine.

Recent data indicate that cocaine locomotor responses may be influenced by dopamine (DA) neurotransmission and adenosine neuromodulation involving the A2A receptor (A2AR). Male Wistar rats were injected with MSX-3 (1-25 mg/kg; an antagonist of A2AR), CGS 21680 (0.05-0.2 mg/kg; an agonist of A2AR), SCH 23390 (0.125-0.25 mg/kg; an antagonist of DA D1/5R), raclopride (0.1-0.8 mg/kg; an antagonist of DA D2/3R), nafadotride (0.2-0.4 mg/kg; an antagonist of DA D3R) or 7-OH-PIPAT (0.01-1 mg/kg; an agonist of DA D3R) to verify the hypothesis that adenosine A2AR and DA receptors and their antagonistic interactions may control locomotor and sensitizing effects of cocaine. In well-habituated animals, MSX-3 (5 mg/kg) increased, while raclopride (0.4-0.8 mg/kg) decreased basal locomotor activation; the other drugs were inactive. The locomotor hyperactivation induced by acute cocaine (10 mg/kg) was enhanced by MSX-3 (5-25 mg/kg) or nafadotride (0.4 mg/kg), while CGS 21680 (0.2 mg/kg), SCH 23390 (0.25 mg/kg), raclopride (0.2-0.8 mg/kg) or 7-OH-PIPAT (0.1 mg/kg) decreased this effect of cocaine. Given during the development of sensitization (in combination with 5-daily cocaine, 10 mg/kg, injections), MSX-3 (5-25 mg/kg) increased, but CGS 21680 (0.2 mg/kg) and raclopride (0.8 mg/kg) reduced the locomotor response to a cocaine challenge dose (10 mg/kg) on day 10. When injected acutely with a cocaine challenge dose (on day 10), CGS 21680 (0.2 mg/kg), raclopride (0.2-0.8 mg/kg) or 7-OH-PIPAT (1 mg/kg) reduced, while MSX-3 (5 mg/kg) or nafadotride (0.4 mg/kg) enhanced the expression of cocaine sensitization. The present results show that adenosine A2ARs and DA D3Rs exert inhibitory actions on acute locomotor responses to cocaine and on the expression of cocaine sensitization, while DA D2Rs had an opposing role in such effects. Pharmacological stimulation of adenosine A2ARs protected against both the development and expression of cocaine sensitization, which may offer a therapeutic potential of A2AR agonists in the treatment of cocaine dependence. The results suggest an antagonistic role of A2ARs in D2R-mediated cocaine actions based at least in part on the existence of A2A/D2 heteromeric receptor complexes.

Analysis of Variance↗
PubMed2006

Discrete-trials heroin self-administration produces sensitization to the reinforcing effects of cocaine in rats.

RATIONALE: The prevalence of cocaine use in opioid-dependent individuals is reportedly high, and the associated negative health and social consequences are severe and well documented. Sensitization of the reinforcing effects of cocaine has been demonstrated following noncontingent opioid exposure in animals; however, no preclinical studies have investigated the impact of opioid self-administration on cocaine's reinforcing effects. OBJECTIVE: Experiments were designed to investigate whether access to heroin self-administration altered the subsequent reinforcing effects of cocaine. METHODS: Baseline responding for cocaine under a progressive ratio schedule was first established. Heroin was then self-administered under a 24-h discrete-trials procedure (DT5; access to heroin five times per hour). Subsequently, cocaine-maintained responding was reassessed. RESULTS: Here we demonstrate that 10 days of DT5 heroin self-administration (50 microg/kg per infusion) resulted in an increase in cocaine's reinforcing effects at several doses across the cocaine dose-effect curve (0.38-3.0 mg/kg per infusion). These increases were relatively long lasting, exceeding the time course of a mild withdrawal syndrome. CONCLUSIONS: The DT5x10-day history of heroin self-administration resulted in an upward shift in the cocaine dose-effect curve, suggesting that DT5 heroin self-administration produced an increase in potency and sensitization of the maximal effectiveness with which cocaine functions as a reinforcer. The present experiments contribute to a growing amount of preclinical evidence suggesting an impact of opioid exposure on the reinforcing effects of cocaine, which may partially explain the high incidence of cocaine use in opioid-dependent individuals.

Animals↗
PubMed2006

Rapid and persistent sensitization to the reinforcing effects of cocaine.

The development of drug addiction involves a transition from recreational use to compulsive drug seeking and taking, and this progression can occur rapidly with cocaine use. These data highlight the importance of early drug exposure and the development of drug dependence; however, little experimental attention has been paid to this phenomenon in animal models of drug abuse. The present experiments demonstrate a progressive and rapid sensitization to the reinforcing strength of cocaine assessed using a progressive ratio (PR) schedule in rats. The first experiment found that rats show increased breakpoints over a 2-week period following acquisition. Subsequent experiments examined the role of total cocaine intake during the initial exposure period and found that low intakes (20 mg/kg/day x 5 days) resulted in sensitization, whereas relatively higher intake (60 or 100 mg/kg/day x 5 days) suppressed the development of sensitization. In contrast, this higher level of intake (60 mg/kg/day x 5 days) only transiently suppressed the expression of sensitization. Examination of breakpoints maintained by various doses of cocaine revealed an upward and leftward displacement of the cocaine dose-effect curve, relative to nonsensitized animals. These studies describe a form of sensitization that occurs rapidly to the reinforcing effects of cocaine, and provide a model to study the potential impact of initial experience on the development of drug dependence.

Animals↗
PubMed2005

Extended cocaine self-administration and deprivation produces region-specific and time-dependent changes in connexin36 expression in rat brain.

Cocaine addiction is a disease that develops over time, and it is thought that drug-induced neuro-adaptations underlie the changes in behavior seen across the addictive process. While a number of alterations in synaptic transmission have been identified, little is currently known regarding cocaine's effects on gap junctional communication between neurons. Here we examine the effects of a cocaine self-administration regimen, previously shown to increase the reinforcing efficacy of cocaine, on the expression of the neuron-specific gap junction-forming protein connexin36 (C x 36). Using real-time RT-PCR and immunoblotting, we show that binge cocaine self-administration produces region-specific and time-dependent changes in C x 36 mRNA and protein expression in the nucleus accumbens, prefrontal cortex, and hippocampus. A number of changes in C x 36 were present 1 day and 7 days following self-administration, and C x 36 mRNA and protein appeared to be differentially regulated in a region-specific manner. C x 36 protein was significantly decreased in the prefrontal cortex 7 days following self-administration, a time point when behavioral sensitization to the reinforcing effects of cocaine is observed. These results suggest that changes in neuronal gap junction expression may be one mechanism by which cocaine self-administration produces enduring changes in behavior.

Animals↗
PubMed2005

Preclinical evidence for GABAB agonists as a pharmacotherapy for cocaine addiction.

A variety of studies indicate that GABA(B) receptor agonists may be useful in the treatment of addictive disorders. This brief review summarizes self-administration studies in rats which show that baclofen and other GABA(B) agonists may have specific effects on the reinforcing effects of cocaine. Preliminary clinical data with baclofen have also been encouraging. The obstacles and issues related to the use of GABA drugs in addiction therapy are briefly addressed.

Animals↗
PubMed2005

Effects of extended-access self-administration and deprivation on breakpoints maintained by cocaine in rats.

RATIONALE: Animal models that identify the effects of self-administration histories on subsequent patterns, levels of intake, and other aspects of reinforcement will help clarify the controlling variables of human drug use. OBJECTIVE: Identify the effects of extended-access to cocaine and 1 or 7 days of deprivation on cocaine-maintained breakpoints on a progressive ratio (PR) schedule of reinforcement. METHODS: Male, Sprague-Dawley rats were trained to self-administer intravenous cocaine (expt 1: 1.5 mg/kg per infusion; expt 2: 0.75 mg/kg per infusion), and then given various histories of self-administration and deprivation. Breakpoints, the number of infusions self-administered on a PR schedule, were assessed following the deprivation period. RESULTS: Rates of cocaine intake increased when access to cocaine was extended to 6 h/day. From day 1 to day 14, daily intake increased from 92 (+/-2.5) to 101 (+/-2.8) mg/kg in expt 1, and from 55 (+/-4) to 78 (+/-2.2) mg/kg in expt 2. Total intake across this 2-week period was approximately 1260 and 970 mg/kg in expts 1 and 2. Breakpoints were not different following this escalation period. The introduction of a 7-day deprivation period failed to alter breakpoints. CONCLUSIONS: There is dissociation between changes in rate of cocaine intake (or consumption) and breakpoints maintained on a PR schedule. Extended-access to cocaine produced increases in rate of intake without altering breakpoints. Depending on the experimental question, extended-access conditions may prove useful for studying changes in certain aspects of reinforcement, such as consumption, but not others, such as the strength of a drug as a reinforcer.

Animals↗
PubMed2005

Amphetamine withdrawal produces region-specific and time-dependent changes in connexin36 expression in rat brain.

Repeated amphetamine treatment produces a long-lasting augmentation of locomotor behavior in rats, a phenomenon known as behavioral sensitization. This process is thought to be a correlate of the addictive process in humans, and it is believed that there are drug-induced neuroadaptations that underlie these behavioral changes. One mechanism by which amphetamine can alter brain function is by affecting direct intercellular communication between neurons via gap junctions. The purpose of the present study was to examine the effect of an amphetamine treatment regimen known to produce changes in dye coupling between neurons, a functional correlate of gap junction function, on the expression of the neuronal gap junction-forming protein, connexin36. Here we report that withdrawal from an extended amphetamine regimen produces region-specific and time-dependent changes in connexin36 expression in rat nucleus accumbens and prefrontal cortex, brain regions known play roles in sensitization and addiction. This is, to our knowledge, the first demonstration of pharmacological manipulation of connexin36 in vivo.

Amphetamine↗
PubMed2005

Comparison of the reinforcing effects of cocaine and cocaine/heroin combinations under progressive ratio and choice schedules in rats.

The co-use of cocaine and heroin is relatively common, with a growing clinical and preclinical literature dedicated to investigating the factors underlying the phenomenon. Specifically, several studies have compared the reinforcing effects of the coadministration of cocaine and heroin, referred to commonly as 'speedball', to either drug alone. The present study assessed whether addition of heroin to a wide range of cocaine doses produces reinforcing effects greater than cocaine alone using both a progressive ratio (PR) schedule and a choice procedure. Patterns of coadministration of cocaine and heroin offered simultaneously were also assessed using double-lumen cannulas. Under the PR schedule, speedball combinations across a range of doses (0.38-3.0 mg/kg/inf cocaine+1.5-48 microg/kg/inf heroin) did not support higher break points than cocaine alone. When cocaine and heroin were made available concurrently (ie on two separate levers), rats self-administered cocaine exclusively. Using a choice procedure, however, a preference was demonstrated for some speedball combinations (eg 0.18 mg/kg/inf cocaine+50 microg/kg/inf heroin; 0.38 mg/kg/inf cocaine+50 microg/kg/inf heroin) over cocaine alone (0.75 mg/kg/inf). So while results obtained using the PR schedule do not support the hypothesis that speedball combinations are more reinforcing than cocaine alone, data from the choice procedure do support this hypothesis. These apparently discrepant results demonstrate that these models are measuring different aspects of drug reinforcement, and suggest that choice procedures in rats provide a useful tool to study speedball self-administration.

Animals↗
PubMed2005

Reduced dopamine terminal function and insensitivity to cocaine following cocaine binge self-administration and deprivation.

Despite large numbers of studies describing neuroadaptations caused by chronic cocaine exposure, there remains considerable uncertainty as to whether alterations in dopamine (DA) neurotransmission are responsible for progression into an addicted state. High-intake, 24-h access cocaine self-administration (SA, 10 days) followed by an extended (7 days), but not 1 day deprivation period produces an increased motivation to SA cocaine as measured by a progressive ratio protocol. Following binge cocaine SA and deprivation, the status of DA terminals in the nucleus accumbens (NAc) was investigated using microdialysis in freely moving rats and voltammetry in brain slices. At 1 and 7 days following binge cocaine SA, baseline extracellular DA concentrations in the NAc core were decreased by 40 and 55% of control levels, in the 1 and 7 day deprivation groups, respectively. Acute cocaine (1.5 mg/kg, i.v.) administration increased extracellular DA (350%) in the NAc core of naïve animals but failed to significantly increase DA at 1 or 7 days following binge cocaine SA. The shell of the NAc showed a similar lack of effect of cocaine. Analysis of DA terminals in brain slices showed that cocaine was markedly less effective in inhibiting DA uptake at 1 and 7 days of cocaine deprivation (max effect 40% of control). Electrically stimulated DA release was decreased at 1 day and further decreased at 7 days of deprivation (67 and 49% of control, respectively). The rate of DA uptake was increased (150% of control) following binge SA, irrespective of deprivation period. Finally, presynaptic autoreceptors were subsensitive at both time points, as measured by the ability of quinpirole, a D2-like DA receptor agonist, to inhibit DA release. Thus, the NAc was hypodopaminergic and DA terminals were less sensitive to cocaine following binge cocaine SA and deprivation.

Animals↗
PubMed2005

Sensitization of the reinforcing effects of self-administered cocaine in rats: effects of dose and intravenous injection speed.

Speed of drug onset is assumed to be an important determinant of the abuse liability of a drug. Studies in human and non-human primates suggest that the subjective and reinforcing effects of cocaine can be influenced by route of administration and/or speed of intravenous injection. Sensitization to the reinforcing effects of cocaine was studied in rats and the effects of various injection durations (i.e. speed of injection) on the development of sensitization was examined using a progressive ratio schedule. In addition, the effects of cocaine dose on sensitization and the effects of injection duration on the acute reinforcing effects of cocaine were examined. The initial study demonstrated that the development of sensitization (i.e. progressive increases in breakpoints) was dose-dependent. A robust sensitization of the reinforcing effects of cocaine was replicated in animals receiving cocaine at the highest rate (i.e. shortest duration; 5 s), but not in animals receiving the same dose over 25 or 50 s. Subsequent testing revealed that injection duration did not have profound effects on the acute reinforcing effects of cocaine (assessed by breakpoints or rate of responding on a fixed ratio schedule). These findings are similar to recent studies demonstrating that the development of sensitization, but not the acute responsivity, to cocaine's locomotor-activating effects are influenced by rate of intravenous injection. Taking these findings together, we hypothesize that the process of drug addiction involves both the acute reinforcing effects and the development of sensitization.

Animals↗
PubMed2004

Binge self-administration and deprivation produces sensitization to the reinforcing effects of cocaine in rats.

RATIONALE: Behavioral procedures that incorporate dynamic changes in drug-maintained behavior are needed to model the development of cocaine addiction in humans. OBJECTIVES: Because sensitization may occur to some aspects of drug administration during the addiction process, the objective of the present study was to define the critical features of self-administration histories that result in subsequent increases in the reinforcing efficacy of cocaine (measured using the progressive ratio (PR) schedule). METHODS: Animals were trained to self-administer cocaine on a fixed ratio (FR) schedule, baseline performance on a PR schedule was determined, and animals were given various histories of cocaine self-administration and drug deprivation. PR performance was reassessed following this experience. RESULTS: Cocaine self-administration under a discrete-trials procedure (24 h/day) for 10 days, followed by a 7-day deprivation period resulted in sensitization to the reinforcing effects of cocaine as assessed by the PR schedule (increases in maximal breakpoints maintained by cocaine with no change in sensitivity at lower doses). Similar levels of daily cocaine intake on a FR schedule (typically completed within 6 h) coupled with a deprivation period failed to produce changes in breakpoint. Providing access to cocaine during the "deprivation period" by repeated testing on a PR schedule prevented the sensitization. CONCLUSIONS: These data suggest that these self-administration-induced changes in breakpoint reflect sensitization, and show that a drug-free deprivation period is necessary, but not sufficient, to produce this increase.

Animals↗
PubMed2004

Effects of positive allosteric modulators of the GABAB receptor on cocaine self-administration in rats.

RATIONALE: Previous studies have strongly implicated a role for GABA(B) receptors in modulating the reinforcing effects of cocaine. OBJECTIVE: The purpose of the present study was to examine the efficacy of two novel positive allosteric modulators of the GABA(B) receptor, CGP7930 and GS39783, to decrease cocaine self-administration in rats responding under various schedules of reinforcement. METHODS: Rats were trained to self-administer cocaine under progressive ratio (PR), fixed ratio (FR) and discrete trials (DT) schedules of reinforcement, and the ability of CGP7930 and GS39783 to decrease cocaine-maintained responding was examined. RESULTS: On a PR schedule, CGP7930 markedly decreased break points maintained by 1.5 mg/kg per injection cocaine in a dose-dependent manner. GS39783 produced only modest decreases in cocaine-reinforced break points, with only the highest dose decreasing break points relative to baseline. On an FR1 schedule of reinforcement, both drugs decreased responding for a threshold dose of cocaine, but did not alter responding for higher doses of cocaine. In a DT procedure, 1.5 mg/kg per injection cocaine was made available during three 10-min trials each hour during 24-h sessions (DT3), engendering a circadian pattern of responding characterized by high numbers of infusions during the dark phase and low numbers of infusions during the light phase. Doses of 30 mg/kg CGP7930, 3.0 mg/kg GS39783 and 2.5 mg/kg baclofen significantly decreased cocaine-maintained responding when administered at the beginning of the dark phase of the cycle. Across all schedules, CGP7930 was more effective at decreasing cocaine self-administration than GS39783, a finding that may be due to differences in bioavailability between the two drugs. CONCLUSIONS: These findings suggest that positive allosteric modulators of the GABA(B) receptor may hold promise as potential pharmacotherapies for cocaine abuse and dependence.

Analysis of Variance↗
PubMed2004

Sensitization to the reinforcing effects of cocaine following binge-abstinent self-administration.

The process of addiction in humans involves a transition from recreational drug use to compulsive drug-taking. To understand or study this behavioral phenomenon from a neurobiological perspective, behavioral models that reflect this process are necessary. Data from typical (restricted access) self-administration procedures demonstrate a stable pattern of responding over time, and thus fail to capture the transitional phases of this process. Here we describe the development of a model that incorporates self-administration-induced changes in the reinforcing efficacy of cocaine, assessed using a progressive ratio schedule of reinforcement to probe the 'motivational' state of the animal. To date we have identified two necessary conditions for the development of this sensitization: extended access to cocaine and a deprivation period. This model, in conjunction with recently developed tools to characterize neurochemical and epigenetic changes, will provide a better understanding of the neurobiological bases of the addiction process.

Animals↗
PubMed2004

Fast onset of dopamine uptake inhibition by intravenous cocaine.

In vivo voltammetry in the nucleus accumbens of anesthetized rats was used to investigate the time of onset of dopamine uptake inhibition by intravenous cocaine. There is disagreement between behavioral and neurochemical studies concerning the time-course of cocaine effects. Because of the high temporal resolution of voltammetry, the processes of dopamine release and uptake could be temporally separated to make evaluation of cocaine effects on uptake easier to address. Within 4 s after intravenous cocaine administration (1.5 mg/kg) there was significant inhibition of dopamine uptake that reached a plateau in 20 s. The peak heights of electrically evoked dopamine signals were also rapidly increased by cocaine. The signals returned to baseline values within approximately 1 h. In parallel behavioral studies, locomotor activity was significantly increased within 5-6 s following intravenous infusion of cocaine. Here we demonstrate that intravenous cocaine administration begins inhibiting the uptake of dopamine within a few seconds. This is at least 10-fold faster than previous neurochemical estimates. The present findings may contribute to the understanding of the neurobiological mechanisms underlying the early behavioral responses to cocaine.

Animals↗
PubMed2003

Effect of HD-23, a potent long acting cocaine-analog, on cocaine self-administration in rats.

RATIONALE: "Agonist" therapy for drug addiction proposes that a long acting analog, with similar properties to the abused substance might serve as a useful therapeutic agent. HD-23 is a very long acting tropane analog that displays a neurochemical profile similar to cocaine. OBJECTIVE: To determine, using self-administration procedures and three different schedules of reinforcement, the effect of HD-23 on rate of cocaine intake (fixed ratio), the effect of HD-23 on the motivation to respond (progressive ratio) and the time course of HD-23 pretreatment (discrete trials). METHODS: Male Sprague-Dawley rats were implanted with chronically indwelling intravenous cannulae and trained to self-administer cocaine (1.5 mg/kg per infusion) on a fixed ratio schedule. After a stable baseline was established, separate groups of rats ( n=6-8) were given access to various doses of cocaine (0.37, 0.75, 1.5 or 3.0 mg/kg per injection) on a fixed ratio schedule during daily 3-h sessions, or to various doses of cocaine (0.18, 0.37, 0.75, 1.5 mg/kg per injection) on a progressive ratio schedule during daily 5-h sessions. A separate group of rats ( n=10) was tested using a discrete trials procedure; animals were given the opportunity to self-administer cocaine (1.5 mg/kg per injection) during 10-min trials which were initiated every 20 min throughout the day/night cycle. RESULTS: On the FR schedule, pretreatment with HD-23 (1.0 mg/kg) decreased the rate of cocaine intake. HD-23 shifted the dose-response curve on the PR schedule to the left. On the discrete trials schedule, animals displayed a circadian pattern of drug intake; pretreatment with HD-23 significantly increased cocaine intake for about 8 h during the light phase when the probability of responding would otherwise have been very low. Animals pretreated with HD-23 displayed a high probability of cocaine self-administration for about 14 h. CONCLUSIONS: The results are consistent with the idea that an acute pretreatment with the long-acting agonist, HD-23, augmented rather than diminished the motivation to self-administer cocaine.

Animals↗
PubMed2003

Beta-funaltrexamine affects cocaine self-administration in rats responding on a progressive ratio schedule of reinforcement.

Many studies have shown interactions between mu-opiates and the mesolimbic dopamine (DA) system. Mu-opiate receptor antagonists have been reported to either increase or decrease the rate of cocaine self-administration, and the interpretation of these data has been difficult. In an attempt to further characterize and localize the effect of opiate receptor blockade on the reinforcing effects of cocaine, the mu-opiate irreversible antagonist beta-funaltrexamine (betaFNA) was administered locally to different regions of the mesocorticolimbic system. Microinjection of betaFNA into the ventral tegmental area (VTA) or the nucleus accumbens (NAcc) had no effect on cocaine self-administration under a fixed ratio (FR) schedule of reinforcement. However, blockade of opiate receptors in both brain regions did attenuate responding for cocaine maintained by a progressive ratio (PR) schedule. Administration of betaFNA in the dorsal striatum had no effect under either schedule condition. The present findings suggest that endogenous opiate systems within the mesolimbic DA system modulate the reinforcing effects of cocaine; however, this modulation seems to be schedule dependent.

Animals↗