Role of the cAMP Pathway and CREB in the Nucleus Accumbens

As stated earlier, the mesolimbic dopamine system is a major neural substrate for the motivational and rewarding effects of opiates. This occurs via two mechanisms (3). Opiates increase dopaminergic transmission to the NAc by activating VTA dopamine neurons. This occurs indirectly through opiate inhibition of GABAergic interneurons within the VTA that inhibit the dopamine neurons. Opiates also act directly on opioid receptors expressed by NAc neurons. The rewarding effects of other drugs of...

Implications for Addiction to Cannabinoids 81 Tolerance

Tolerance to cannabinoids developed in all species studied, with varying duration and onset, depending, for example, on the parameter studied (72,180-184). In humans, development of tolerance to the psychoactive effects of marijuana is clearly seen with heavy (daily) use, but usually not with casual or moderate use (72,185). Tolerance to ANA has been shown in animal studies (50,51). The behavioral tolerance is accompanied, analogous to other classes of drugs, by a decrease in CB1 receptors in...

Findings from an Animal Model with Long Term Alcohol Self Administration with Repeated Deprivation Phases

Involvement of Opioidergic Systems in the Alcohol Deprivation Effect A first pathway that may induce alcohol craving and relapse due to the mood-enhancing, positive-reinforcing effects of alcohol consumption and that seems to involve opioidergic systems was studied in long-term voluntary alcohol-drinking rats that had repeated deprivation phases. In particular, the role of opioid receptors on the alcohol deprivation effect was studied. Three different types of opioid receptors have been...

Craving and Reinforcement

Addictive potential of marijuana was long thought to be very weak or absent (72). However, although addictive behaviors such as compulsive drug seeking (due to craving) is rarely induced by marijuana use, preparations containing higher D9-THC concentrations, such as hashish, have been shown to induce addictive behaviors, especially in populations at risk (188-189). Hence one may speculate that marijuana, as obtained at the turn of the millenium, may be addictive as well, since it often contains...

Clinical Interest in Enkephalin Degrading Enzyme Inhibitors in Opioid Addiction Treatment

Addiction involves the compulsive seeking of the drug (craving), caused both by its reinforcing or rewarding effects and by the unpleasant experience (i.e., abstinence syndrome) produced by the sudden interruption of its consumption. It is important to emphasize that, in contrast to tolerance or physical dependence, which could be explained by events occurring at the receptor level, addiction is more complicated. Thus, psychological, environmental, and social factors can strongly influence its...

The Mesocorticolimbic DA System Pharmacological Neuroadaptation to Nicotine Exposure

The mesocorticolimbic DA system has been the object of intense research in the field of drug addiction because 1. It is a relevant component of the reward system (16). 2. It is involved in stimulus-reward learning and in the incentive motivational effects of drugs (19,20). 3. When exposed to chronic treatment with addictive drugs, it is the site of neuroadaptive changes, such as sensitization or dysregulation associated with negative emotional states (19,21,68,69). Midbrain DA neurons contain...

Overview of Cannabinoids and Cannabinoid Receptors

Cannabinoids are a group of approx 60 terpinophenolic 21-carbon-containing compounds present in plants of the Cannabis genus, particularly C. sativa and C. indica. Although cannabis preparations have been used for centuries for medicinal, recreational, or religious purposes, it was not until the mid-1960s that the primary psychoac- tive ingredient was determined to be (-)-irans-D9-tetrahydrocannabinol (THC) (18,19). Subsequently, highly potent and selective synthetic cannabinoid agonists,...

Abrupt Cannabinoid Withdrawal

The sudden termination of chronic treatment with cannabinoids in several different laboratory animal models has not produced uniform results. Kaymakcalan treated rhesus monkeys for 36 d with THC and observed aggressiveness, hyperirritability, tremors, yawning, photophobia, hallucinatory behavior, and anorexia upon abrupt treatment termination (52). This syndrome appeared 12 h after THC was discontinued and lasted for 5 d. Another approach is to determine whether withdrawal can be measured by...

The Other Side of the Coin Relevance of Nicotine Withdrawal and the Negative Reinforcing Effects of Nicotine in Self

Difficulties in giving up the habit of smoking are often reported to be also related to the nicotine withdrawal syndrome, that is, increase nervousness, frustration, anger, and desire to smoke (7,28). Nicotine withdrawal syndrome can also be seen in rats passively infused with high doses of nicotine and then acutely treated with mecamylamine (29,30). Stress, depression, and other negative affective states, and peripheral signs induced by nicotine withdrawal, have been suggested to be the basis...

References

NIAAA. (2000) 10th Special Report to the U.S. Congress on Alcohol and Health. Public Health Service, U.S. Department of Health and Human Services, Washington, DC. 2. Tabakoff, B. and Hoffman, P. L. (1988) A neurobiological theory of alcoholism, in Theories on Alcoholism (Chaudron, C. D. and Wilkinson, D. A., eds.), Addiction Research Foundation, Toronto, Canada, pp. 29-72. 3. Crabbe, J. C. and Cunningham, C. L. (1999) Drug and alcohol dependence-related behaviors, in Handbook of Molecular...

Ethanol Induced Behavioral Sensitization

Repeated administration of psychoactive drugs can have neuroadaptive consequences that lead either to a decrease (tolerance or desensitization) or an increase (sensitization) of their behavioral effects. Sensitization processes have been implicated in the development of compulsive drug use. One of the most prominent theories on the significance of drug-induced sensitization, proposed by Robinson and Berridge (26), posits that compulsive drug-seeking behavior is a result of a progressive...

Effects of Cannabinoids on Endogenous Opioid Peptides

Biochemical studies have revealed that cannabinoid administration can increase the release of several endogenous peptides, which can contribute to the acute and chronic pharmacological responses induced by these compounds. Thus, acute intrathecal administration of THC and other cannabinoid agonists has been reported to enhance in vivo the extracellular levels of endogenous dynorphins in the spinal cord (48,61,62,70,101,). These dynorphins seem to play an important role in the antinociception...

Chronic Nicotine Administration Produces AchR Upregulation

Recent reports consistently indicate that 3H-nicotine binding, but not 125I-D-bungarotoxin binding, is upregulated in human postmortem prefrontal cortex, hippocampus, entorhinal cortex, and, to a lesser extent, striatum of smokers when compared with age-matched controls (60-62). Interestingly, nicotine binding is normalized in ex-smokers, confirming the reversibility of the upregulation of 3H-nicotine-binding sites observed in rodent brain following chronic passive nicotine administration...

Similar Neuroanatomical Sites are Involved in Cannabinoid and Opioid Antinociception

Supraspinal, spinal, and peripheral mechanisms seem to be involved in the antinociceptive properties of cannabinoid agonists. Thus, intracerebreventricular (29,49,50), intrathecal (29,39,75), and local peripheral administration of cannabinoids (37,75) are able to induce potent antinociceptive responses. Studies using local administration of cannabinoid agonists in various brain structures have identified the central areas involved specifically in cannabinoid antinociception. Thus,...

Locomotor Response to Psychostimulants

Acute Injection of Psychostimulants Locomotor response to drugs is an interesting parameter, as it constitutes an unconditioned response to drugs that correlates well with drug self-administration (7). Studies on the role of corticosterone in drug-induced locomotor activity are consistent, showing a facilitatory effect of this hormone. This has been shown over a wide range of drug doses and with different methods of manipulating HPA activity. Suppression of glucocorticoids by...

Glucocorticoids and the Dopamine System

Here we will review several observations suggesting that glucocorticoid hormones could facilitate drug-related behaviors by acting on the dopamine system. 5.2.1. Glucocorticoids and Dopamine-Dependent Responses to Drugs The first evidence of dopamine involvement in the interaction between glucocorti-coids and psychostimulants probably comes from studies investigating changes in behavioral effects of centrally injected psychostimulants. Thus, the locomotor response induced by the injection of...

Methodological Aspects of Intravenous Nicotine Self Administration in Experimental Animals

Initially, nicotine self-administration was successfully developed in subhuman primates (34,35). Some early works also described different protocols in rats (36-40). It was only during late 1980s that Corrigalll and Coen (1989) developed reliable schedules of iv nicotine self-administration in rats (41), which were replicated and used by other groups (42-44). Under these specific methodological conditions, rats acquire stable self-administration. Critical schedule parameters are 1. The short...

Effects of Chronic Cannabinoid Administration on Molecular Signaling Pathways

Most of the studies employing chronic cannabinoid agonist treatment followed by subsequent examination of the molecular effects of this treatment have not concurrently measured cannabinoid dependence via antagonist-precipitated withdrawal. Indeed, many of these studies report correlation either with cannabinoid tolerance (i.e., the decrease in agonist potency or effectiveness with repeated administration) or have not directly measured any physiological or behavioral endpoint. Nonetheless, the...

Modulation of Psychostimulant Induced Sensitization by KOR Ligands Role of the Mesoprefrontal and Mesolimbic DA Systems

The systemic administration of KOR agonists with cocaine prevents the sensitization that develops to the locomotor activating and conditioned reinforcing effects of this psychostimulant (113-116). KOR agonists also prevent changes in basal and cocaine-evoked DA levels in the NAc that are associated with the induction and long-term expression of sensitization (117,118). As discussed above, quantitative dialysis studies have shown that repeated administration of KOR agonists produces changes in...

Notes on Neuroadaptation to Nicotine Exposure of Neurotransmitter Systems Other Than DA

Are all the positive reinforcing effects of nicotine mediated only by meso-corticolimbic DA Some discrepancies in the experiments cited above, and evidence of neuroadaptation in other neurotransmitter systems, may open some alternatives. Two examples follow. 1. A cDNA microarray experiment reveals effects on biochemical pathways whose changes have not been related to DA effects (e.g., EGRF) (113). 2. In rats, cocaine self-administration completely downregulates c-fos expression in the nucleus...

Lisa M Monteggia and Eric J Nestler

Addiction is characterized by compulsive drug seeking and taking despite adverse consequences. Addiction is a gradual process, which occurs in most individuals only after repeated drug exposure. Thus, it appears that individuals addicted to drugs undergo time-dependent alterations or neuroadaptations in the brain that occur during a course of repeated drug administration. Chronic drug intake produces these neuroadaptations in neuronal cell types located within specific brain regions. These...

Participation of Opioid Mechanisms in Cannabinoid Antinociception

CB1 and CB2 cannabinoid agonists induce antinociceptive responses that have been revealed in several animal species, including mouse, rat, rabbit, cat, dog, and monkeys (22). These antinociceptive properties have been shown in several acute behavioral models of nociception thermal models such as the radiant heat tail flick (23), tail immersion (24), and the hot plate (23-25), mechanical models evaluating motor (26) or reflex responses (27), chemical tests such as the abdominal constrictions...

Withdrawal

Drug abstinence following chronic drug exposure results in the development of a withdrawal syndrome that comprises two components, a negative emotional state and physical somatic and vegetative signs of withdrawal 4,95 . The negative emotional state results in dysphoria, anxiety, and irritability, is considered a source of negative reinforcement, and is produced by most drugs of abuse, including opioids. It has been proposed that both the positive reinforcing effect of the drug reward and the...