Drug addiction as dopamine-dependent associative learning disorder

Chiara, G. Di

doi:10.1016/s0014-2999(99)00372-6

Cited by 510 publications

(331 citation statements)

References 123 publications

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“…Recent brain microdialysis studies have confirmed that this effect does not undergo tolerance with repeated exposure (Di Chiara 1999). DA release in the accumbens shell is also phasically activated by the presentation of novel natural rewards, but this effect rapidly undergoes habituation, and is absent on second and subsequent presentations (Di Chiara 1999;Schultz 1997;Suri and Schultz 1999). Signals predictive of the later presentation of natural rewards maintain their ability to elicit phasic release of DA in the accumbens shell Schultz 1997;Suri and Schultz 1999); however, this process does not operate during the acquisition of place conditioning, as the reward is present immediately the animal is exposed to the apparatus on conditioning trials.…”

Section: Differential Effects Of Acpc On Place Conditioning With Drugmentioning

confidence: 96%

“…As noted above, a common feature of drugs of abuse, with the exception of diazepam, is that they increase extracellular levels of DA in the nucleus accumbens shell, either by activating DA cell firing or by blocking reuptake of released DA. Recent brain microdialysis studies have confirmed that this effect does not undergo tolerance with repeated exposure (Di Chiara 1999). DA release in the accumbens shell is also phasically activated by the presentation of novel natural rewards, but this effect rapidly undergoes habituation, and is absent on second and subsequent presentations (Di Chiara 1999;Schultz 1997;Suri and Schultz 1999).…”

Section: Differential Effects Of Acpc On Place Conditioning With Drugmentioning

confidence: 99%

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Selective Blockade of Drug-induced Place Preference Conditioning by ACPC, a Functional NDMA-receptor Antagonist

Papp

Gruca

Willner

2002

Neuropsychopharmacology

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ACPC (1-aminocyclopropanecarboxylic acid) is a partial agonist at the strychnine-insensitive glycine receptor site on the NMDA receptor complex, and a functional NMDA antagonist. A series of experiments was conducted to assess the effects of ACPC in a biased place conditioning paradigm. As previously reported, ACPC itself did not support either appetitive or aversive place conditioning. However, co-administration of ACPC (200 mg/kg) blocked the acquisition of place preferences conditioned using a variety of psychoactive drugs (amphetamine, cocaine, nomifensine, diazepam, morphine, nicotine). No tolerance was seen to this effect following two weeks of chronic ACPC administration. Overall, ACPC did not affect the expression of place conditioning when administered immediately before the post-conditioning test. However, these effects appeared somewhat variable between drugs, and further analysis showed that ACPC did block the expression of preferences conditioned with some drugs (diazepam, morphine, nicotine), but not others (amphetamine, cocaine, nomifensine). The effects of ACPC could not be accounted for by state dependence, as ACPC blocked morphine and cocaine place preferences when administered during both the acquisition and the expression phase of conditioning. In contrast to the blockade by ACPC of drug-induced place preferences, ACPC had no effect on the acquisition of place preferences conditioned using a variety of natural non-drug reinforcers (food, sucrose, social interaction, novelty). ACPC also had no effect on the acquisition of drug-induced place aversions (naloxone, picrotoxin The treatment of drug addiction has two targets: cessation or reduction of use, and maintenance of those gains. During the maintenance phase, a number of factors have been identified that predispose to relapse. These include stimuli associated with drug taking (O'Brien et al. 1998). The place preference conditioning procedure has been used extensively as an animal model for investigating the rewarding properties of drug-conditioned stimuli. In this procedure, 27 , NO . 5 the animal experiences the effects of a drug while confined in a distinctive environment; subsequently the animal is offered a choice between the drug-paired environment and an environment that has been experienced in the drug-free state. Subject to certain methodological considerations, a preference for the drug-paired environment is interpreted to mean that the environment has acquired secondary reinforcing properties as a consequence of its pairing with a primary reinforcer. Drugs that support the development of a conditioned place preference (CPP) are generally those that are abused by people (e.g. psychostimulants, opioids, benzodiazepines, alcohol, nicotine), while drugs that do not support CPP are typically not abused (e.g. neuroleptics, antidepressants, antihistamines) (Carr et al. 1989;Schechter and Calcagnetti 1993;Calcagnetti and Schechter 1998;Tzschentke 1998). In addition to drug rewards, CPP can also be used to study the reinforcing prop...

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Section: Differential Effects Of Acpc On Place Conditioning With Drugmentioning

confidence: 96%

Section: Differential Effects Of Acpc On Place Conditioning With Drugmentioning

confidence: 99%

Selective Blockade of Drug-induced Place Preference Conditioning by ACPC, a Functional NDMA-receptor Antagonist

Papp

Gruca

Willner

2002

Neuropsychopharmacology

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“…It is perplexing that both thalamic and dopaminergic inputs are required to generate the cholinergic pause response, but neither seems to be responsible for generating it by direct synaptic action. It is possible, however, that dopaminergic and thalamostriatal afferents control some cholinergic patterns in a more complex manner than presently appreciated, just as the relationship between reward-based learning and the firing of DA neurons is complex (Schultz et al, 1997;Di Chiara, 1999;Spanagel and Weiss, 1999;Waelti et al, 2002).…”

Section: Neurophysiological Influences Over the Firing Of Cholinergicmentioning

confidence: 99%

“…The mesolimbic dopaminergic system is important for the acquisition of behaviors that are reinforced by the salient drives of the environment or by the inappropriate stimuli of addictive drugs. Many recent studies of addiction have focused on dopaminergic signaling to forebrain structures, particularly the prefrontal cortex and the nucleus accumbens (NAc) in the ventral striatum (Di Chiara 1999;Berke and Hyman, 2000;Wise, 2000;Dani and De Biasi, 2001). The link between nicotine addiction and DA signaling in the striatum indicates the potency of the nicotinic-dopaminergic interaction.…”

Section: Introductionmentioning

confidence: 99%

Cholinergic interneuron characteristics and nicotinic properties in the striatum

2002

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ABSTRACT:The neostriatum (dorsal striatum) is composed of the caudate and putamen. The ventral striatum is the ventral conjunction of the caudate and putamen that merges into and includes the nucleus accumbens and striatal portions of the olfactory tubercle. About 2% of the striatal neurons are cholinergic. Most cholinergic neurons in the central nervous system make diffuse projections that sparsely innervate relatively broad areas. In the striatum, however, the cholinergic neurons are interneurons that provide very dense local innervation. The cholinergic interneurons provide an ongoing acetylcholine (ACh) signal by firing action potentials tonically at about 5 Hz. A high concentration of acetylcholinesterase in the striatum rapidly terminates the ACh signal, and thereby minimizes desensitization of nicotinic acetylcholine receptors. Among the many muscarinic and nicotinic striatal mechanisms, the ongoing nicotinic activity potently enhances dopamine release. This process is among those in the striatum that link the two extensive and dense local arbors of the cholinergic interneurons and dopaminergic afferent fibers. During a conditioned motor task, cholinergic interneurons respond with a pause in their tonic firing. It is reasonable to hypothesize that this pause in the cholinergic activity alters action potential dependent dopamine release. The correlated response of these two broad and dense neurotransmitter systems helps to coordinate the output of the striatum, and is likely to be an important process in sensorimotor planning and learning.

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“…The dopamine (DA) system is an obvious starting point in the search for neuroadaptations responsible for the addictive process. Pharmacological, neurochemical, and lesion experiments indicate that cocaine acts as an indirect agonist at DA synapses by blocking the reuptake of DA into the presynaptic terminal in the nucleus accumbens (NAc) and other projection areas of the ventral tegmental area (Heikkila et al, 1975;Ritz et al, 1987, Roberts et al, 1977Koob et al, 1994;Volkow et al, 1997;Bardo, 1998;Di Chiara, 1999). Despite the evidence for the role of DA neurotransmission in the acute reinforcing effects of cocaine, it remains to be determined whether changes in the physiology of this system account for motivational changes associated with cocaine addiction.…”

Section: Introductionmentioning

confidence: 99%

Reduced Dopamine Terminal Function and Insensitivity to Cocaine Following Cocaine Binge Self-Administration and Deprivation

Mateo

Läck

Morgan

et al. 2005

Neuropsychopharmacol

122

139

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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. Highintake, 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.

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Drug addiction as dopamine-dependent associative learning disorder

Cited by 510 publications

References 123 publications

Selective Blockade of Drug-induced Place Preference Conditioning by ACPC, a Functional NDMA-receptor Antagonist

Selective Blockade of Drug-induced Place Preference Conditioning by ACPC, a Functional NDMA-receptor Antagonist

Cholinergic interneuron characteristics and nicotinic properties in the striatum

Reduced Dopamine Terminal Function and Insensitivity to Cocaine Following Cocaine Binge Self-Administration and Deprivation

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