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Serge H Ahmed

Publications and source records attributed to Serge H Ahmed.

12 recordsLinked to original sources
PubMed2006

Heroin-induced reinstatement is specific to compulsive heroin use and dissociable from heroin reward and sensitization.

Increased drug availability can precipitate a rapid transition to compulsive drug use in both vulnerable humans and laboratory animals. Recent studies have shown that despite equivalent levels of psychomotor sensitization, only rats with prolonged, but not limited, access to cocaine self-administration respond to the priming effects of cocaine on drug seeking, as measured in a within-session reinstatement model of drug craving. In this model, drug seeking is first extinguished and then reinstated by non-contingent presentations of the drug alone in the absence of response-contingent stimuli. Here, we assessed the generality of this observation in rats with daily short (1 h, ShA) vs long access (6 h, LgA) to i.v. heroin self-administration. As expected, heroin intake by LgA rats (n=24) increased over time to become excessive compared to heroin intake by ShA rats (n=24). After escalation, LgA rats tended to be less sensitive to heroin-induced locomotion (7.5-30 microg, i.v.) than ShA rats. In contrast, only LgA rats, not ShA rats, responded to the priming effects of heroin, as measured by the ability of heroin alone (7.5-30 microg, i.v.) to reinstate extinguished drug-seeking behavior. Finally, during the course of heroin intake escalation, a large proportion of LgA rats developed self-injury (mostly targeting the nails and digit tips of the forepaws), a negative consequence not seen in ShA rats. This study reproduces and extends previous research on compulsive cocaine use by showing that heroin-induced reinstatement is also specific to compulsive drug use and dissociable from heroin-induced reward and psychomotor sensitization.

Animals↗
PubMed2006

Dissociation of psychomotor sensitization from compulsive cocaine consumption.

The transition from drug use to drug addiction is associated with a process of escalation, whereby drug use becomes excessive and difficult to control. Several mechanisms have been advanced to explain escalating patterns of drug use as opposed to nonescalating patterns. Although current evidence favors hedonic tolerance, there remains some dispute about the contribution of behavioral sensitization to cocaine intake escalation. Here, we concurrently assessed the ability of cocaine to induce psychomotor sensitization and drug-seeking behavior in animals with 1-h (short access or ShA) vs 6-h (long access or LgA) access to intravenous (i.v.) cocaine self-administration. As expected, cocaine intake by LgA rats escalated over time and became excessive compared to cocaine intake by ShA rats, which remained low and stable. Despite escalated levels of cocaine consumption, however, LgA rats were not more sensitized to cocaine than ShA rats. The dose-effect function for cocaine-induced locomotion (0.125-1 mg, i.v.) was shifted to the left in LgA rats by the same amount as in ShA rats after cocaine self-administration. In contrast, LgA rats were much more responsive than ShA rats to the motivational effects of cocaine, as measured by the ability of i.v. cocaine to reinstate extinguished drug-seeking behavior. This study demonstrates a dissociation of psychomotor sensitization from the change in motivation underlying the transition to compulsive cocaine consumption, and therefore suggests that responsiveness to the motivational effects of the drug, not psychomotor sensitization, would represent a specific behavioral marker of the transition to and maintenance of compulsive cocaine use.

Animals↗
PubMed2005

Imbalance between drug and non-drug reward availability: a major risk factor for addiction.

Laboratory animals self-administer most, though not all, drugs of abuse. Recent evidence shows that with increased drug availability, most laboratory rats develop all the major behavioral signs of addiction, including: 1) drug intake escalation, 2) increased motivation for the drug, 3) difficulty to abstain, 4) decreased reward function, and 5) inflexible drug use. The large prevalence of addicted rats may suggest that they are particularly vulnerable to develop compulsive drug use. I review evidence showing that this apparent vulnerability results in large part from the lack of positive (i.e., alternative non-drug rewards) and negative (i.e., costs) incentives capable of turning animals away from the pursuit of drugs. In particular, most animals seem to take drugs and eventually become addicted, not because drugs are intrinsically addictive, but more likely because drugs are the only significant sources of reward available in the laboratory. Laboratory animals would therefore represent more of a model of high-risk human groups than of the general population. Consequently, they should be more suited for searching factors that protect from, rather than predispose to, drug addiction. Reconsidering the environmental background of drug self-administration experiments in laboratory animals raises intriguing implications for understanding the initial demand for drug consumption and the transition to drug addiction, and for extrapolation from laboratory animals to humans.

Animals↗
PubMed2005

Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction.

By using high-density oligonucleotide arrays, we profiled gene expression in reward-related brain regions of rats that developed escalated cocaine intake after extended access to cocaine (6 h per day). Rats allowed restricted daily access to cocaine (only 1 h) that displayed a stable level of cocaine intake and cocaine naive rats were used for controls. Four analysis methods were compared: Affymetrix microarray suite 4 and microarray suite 5, which use perfect-match-minus-mismatch models, and dchip and rma, which use perfect-match-only models to generate expression values. Results were validated by RT-PCR in individual animals from an independent replication of the experiment. A small number of genes was associated with escalated cocaine intake (ESC genes). Unexpectedly, of the brain regions examined [prefrontal cortex, nucleus accumbens, septum, lateral hypothalamus (LH), amygdala, and ventral tegmental area], the LH was the most transcriptionally responsive in escalation of cocaine intake. Most of the ESC genes identified are also expressed during synaptogenesis and synaptic plasticity and include genes that code for several presynaptic and postsynaptic proteins involved in neurotransmission. These results suggest that LH intrinsic circuitry undergoes a structural reorganization during escalation of cocaine use. This remodeling of LH circuitry could contribute to the chronic deficit in reward function that has been hypothesized to drive the transition to drug addiction. Results also support the value of using multiple analysis strategies to identify the most robust changes in gene expression and to compensate for the biases that affect each strategy.

Animals↗
PubMed2005

Transition to drug addiction: a negative reinforcement model based on an allostatic decrease in reward function.

RATIONALE: The transition from initial drug use to drug addiction has been proposed to result from an allostatic decrease in reward function driven by an overactivation of brain antireward processes. OBJECTIVES: How decreased reward function explains compulsive drug use is not entirely clear at present, and is still a subject for debate. METHODS: We present a quantitative model of cocaine self-administration that integrates pharmacokinetic, pharmacodynamic, and motivational factors to address this question. The model assumes that reward system responsivity is a homeostatically regulated process where the desired level of responsivity (called the reward set point) is initially different from the baseline level. The reduction or correction of this difference or error in reward function would drive cocaine self-administration. RESULTS: Theoretical data obtained by computer simulation fit the experimental data obtained in animals self-administering cocaine (i.e., the within-session pattern of self-injections, the shape and curvature of the dose-injection function, the nonlinear relationship between drug intake and regulated drug effects). Importantly, simulation of an allostatic decrease in reward system responsivity exacerbates the initial error that drives self-administration, thereby increasing both the intake of, and the motivation for, the drug. This allostatic change manifests as a vertical shift in the dose-injection function similar to that seen in animals with escalating cocaine self-administration. CONCLUSIONS: The present model provides a satisfactory explanation of escalated drug intake and suggests a novel negative reinforcement view of addiction based on an allostatic decrease in reward function.

Adaptation, Physiological↗
PubMed2005

Mesolimbic dopamine drives the diurnal variation in opiate-induced feeding.

Brain opioid peptides modulate feeding behavior and opiate drugs have powerful orexigenic effects in mammals. Recent studies have shown that opiate-induced eating depends, though not exclusively, on mu-opioid receptors located in the ventral striatum. Here we report that morphine orexigenic effects vary with the time of day according to a biphasic pattern. The effects first increase and then decrease during the light phase, with the peak effect occurring in the middle of this phase. This diurnal profile is shifted toward the dark phase after dopamine deafferentation of the ventral striatum. Consequently, the peak effect of morphine is delayed and occurs just before the dark phase. This finding suggests that mesolimbic dopamine transmission contributes to the neural mechanisms that normally drive the circadian timing of opioid-dependent feeding.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

The transition from controlled to compulsive drug use is associated with a loss of sensitization.

Rats provided limited daily access to cocaine (1 h) maintain stable levels of drug self-administration over time while those switched to longer access (6 h or more) exhibit escalating patterns of drug intake. These results are reminiscent of human recreational and compulsive drug-taking behavior, respectively. We found that the brains of cocaine-self-administering rats were also qualitatively different in subjects having experienced 6-h (Coc6h) daily access compared to 1-h (Coc1h) access. Fourteen days after an eight-day protocol of cocaine self-administration, all subjects received one infusion of cocaine. Coc1h animals showed enhanced c-Fos reactivity in dopaminergic mesocorticolimbic brain regions and a sensitized locomotor response to IV cocaine. In contrast, both the neural and behavioral sensitization to cocaine was diminished in Coc6h animals. These data suggest that the transition to escalating patterns of drug use is associated with neuroadaptive changes that counteract those initially associated with controlled stable patterns of drug use.

Animals↗
PubMed2004

Neurobiological mechanisms in the transition from drug use to drug dependence.

Drug addiction is a chronic relapsing disorder characterized by compulsive drug intake, loss of control over intake, and impairment in social and occupational function. Animal models have been developed for various stages of the addiction cycle with a focus in our work on the motivational effects of drug dependence. A conceptual framework focused on allostatic changes in reward function that lead to excessive drug intake provides a heuristic framework with which to identify the neurobiologic mechanisms involved in the development of drug addiction. Neuropharmacologic studies in animal models have provided evidence for the dysregulation of specific neurochemical mechanisms in specific brain reward and stress circuits that provide the negative motivational state that drives addiction. The allostatic model integrates molecular, cellular and circuitry neuroadaptations in brain motivational systems produced by chronic drug ingestion with genetic vulnerability, and provides a new opportunity to translate advances in animal studies to the human condition.

Adaptation, Physiological↗
PubMed2003

Changes in response to a dopamine receptor antagonist in rats with escalating cocaine intake.

RATIONALE AND OBJECTIVES: Prolonged access to cocaine self-administration (long access or LgA) produces an escalation in drug intake not observed with limited access to the drug (short access or ShA). The present study tested the hypothesis that escalating use of cocaine is associated with chronic alterations in dopamine neurotransmission. METHODS: After escalation of cocaine self-administration, ShA and LgA rats were challenged with different subcutaneous doses of cis-flupenthixol (10-270 micro g/kg), a highly selective dopamine receptor antagonist. RESULTS: In both groups, increasing doses of cis-flupenthixol first produced an increase in the number of cocaine injections and then a dramatic suppression of behavior. This biphasic dose-effect function-which replicates previous findings from this laboratory-was shifted to the left in LgA rats relative to ShA rats, thereby decreasing the threshold dose at which behavior was completely suppressed. CONCLUSIONS: These data support the hypothesis that alterations in dopamine neurotransmission contribute to escalation of cocaine self-administration.

Animals↗
PubMed2003

Escalation of cocaine self-administration does not depend on altered cocaine-induced nucleus accumbens dopamine levels.

Previous studies showed that prolonged access to cocaine or heroin self-administration (long access, or LgA) produces an escalation in drug intake not observed with limited access to the drug (short access, or ShA). The present experiment employed in vivo microdialysis to test the role of alterations in drug pharmacokinetics and/or efficacy in increasing dopamine (DA) levels in the nucleus accumbens (NAcc) during cocaine intake escalation. In experiment 1, both ShA and LgA rats were challenged with passive intravenous administration of cocaine (0.125-1 mg/injection). Regardless of the doses tested, there was no difference between groups in the ability of cocaine to increase NAcc DA levels and no group differences in the temporal profile of dialysate cocaine levels. In experiment 2, cocaine and DA concentrations were measured during cocaine self-administration. Self-administration produced sustained increases of DA in the NAcc with LgA rats maintaining greater steady levels of DA (750% of baseline) than ShA rats (400% of baseline). The difference in the LgA versus ShA rats was not due to differences in the efficacy of cocaine to elevate DA levels, or in the rate of cocaine metabolism, but was directly related to the amount of self-administered cocaine. These findings show that changes in cocaine efficacy or pharmacokinetics do not play a critical role in cocaine intake escalation.

Animals↗
PubMed2002

Neurobiological evidence for hedonic allostasis associated with escalating cocaine use.

A paradoxical aspect of the transition to drug addiction is that drug users spend progressively more time and effort to obtain drug hedonic effects that continually decrease with repeated experience. According to the hedonic allostasis hypothesis, increased craving for and tolerance to the hedonic effects of drugs result from the same chronic alteration in the regulation of brain reward function (allostasis). Here we show in rats that repeated withdrawals from prolonged cocaine self-administration produces a persistent decrease in brain reward function that is highly correlated with escalation of cocaine intake and that reduces the hedonic impact of cocaine.

Animals↗