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1.
Neuropsychopharmacology ; 38(12): 2508-14, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23800967

ABSTRACT

Cue-induced cocaine craving intensifies, or 'incubates', during the first few weeks of abstinence and persists over extended periods of time. One important factor implicated in cocaine addiction is the endogenous opioid ß-endorphin. In the present study, we examined the possible involvement of ß-endorphin in the incubation of cocaine craving. Rats were trained to self-administer cocaine (0.75 mg/kg, 10 days, 6 h/day), followed by either a 1-day or a 30-day period of forced abstinence. Subsequent testing for cue-induced cocaine-seeking behavior (without cocaine reinforcement) was performed. Rats exposed to the drug-associated cue on day 1 of forced abstinence demonstrated minimal cue-induced cocaine-seeking behavior concurrently with a significant increase in ß-endorphin release in the nucleus accumbens (NAc). Conversely, exposure to the cue on day 30 increased cocaine seeking, while ß-endorphin levels remained unchanged. Intra-NAc infusion of an anti-ß-endorphin antibody (4 µg) on day 1 increased cue-induced cocaine seeking, whereas infusion of a synthetic ß-endorphin peptide (100 ng) on day 30 significantly decreased cue response. Both intra-NAc infusions of the δ opioid receptor antagonist naltrindole (1 µg) on day 1 and naltrindole together with ß-endorphin on day 30 increased cue-induced cocaine-seeking behavior. Intra-NAc infusion of the µ opioid receptor antagonist CTAP (30 ng and 3 µg) had no behavioral effect. Altogether, these results demonstrate a novel role for ß-endorphin and the δ opioid receptor in the development of the incubation of cocaine craving.


Subject(s)
Cocaine-Related Disorders/metabolism , Drug-Seeking Behavior , Nucleus Accumbens/metabolism , Receptors, Opioid, delta/metabolism , beta-Endorphin/metabolism , Animals , Cocaine/pharmacology , Cues , Drug-Seeking Behavior/drug effects , Male , Rats , Rats, Sprague-Dawley , Self Administration , beta-Endorphin/chemistry , beta-Endorphin/pharmacology
2.
Addict Biol ; 16(2): 251-60, 2011 Apr.
Article in English | MEDLINE | ID: mdl-20731634

ABSTRACT

Drug addiction is a chronic brain disorder, characterized by the loss of the ability to control drug consumption. The neurobiology of addiction is traditionally thought to involve the mesocorticolimbic system of the brain. However, the hippocampus has received renewed interest for its potential role in addiction. Part of this attention is because of the fact that drugs of abuse are potent negative regulators of neurogenesis in the adult hippocampus and may as a result impair learning and memory. We investigated the effects of different dosages of contingent cocaine on cell proliferation and neurogenesis in the dentate gyrus of the hippocampus and on working memory during abstinence, using the water T-maze test, in adult rats. We found that cocaine, in addition to the changes it produces in the reward system, if taken in high doses, can attenuate the production and development of new neurons in the hippocampus, and reduce working memory.


Subject(s)
Central Nervous System Stimulants/toxicity , Cocaine-Related Disorders/physiopathology , Cocaine/toxicity , Dentate Gyrus/drug effects , Dopamine Uptake Inhibitors/toxicity , Hippocampus/drug effects , Memory, Short-Term/drug effects , Neurogenesis/drug effects , Animals , Cell Division/drug effects , Cell Division/physiology , Cocaine-Related Disorders/psychology , Dentate Gyrus/physiopathology , Dose-Response Relationship, Drug , Hippocampus/physiopathology , Male , Maze Learning/drug effects , Maze Learning/physiology , Memory, Short-Term/physiology , Neurogenesis/physiology , Rats , Rats, Sprague-Dawley , Self Administration , Substance Withdrawal Syndrome/physiopathology
3.
Eur J Neurosci ; 30(3): 485-92, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19614746

ABSTRACT

Anhedonia and lack of motivation are core symptoms of depression. In contrast, hyper-motivation and euphoria characterize intoxicated states. In order to explore the relationship between these two behavioral states we examined cocaine self-administration tasks in an animal model of depression [Flinders Sensitive Line (FSL) rats]. We found that FSL rats exhibit sub-sensitivity in their cocaine-seeking behavior, which was normalized following a chronic treatment with the antidepressant desipramine. However, when the cocaine dosage was increased, FSL rats demonstrated a similar cocaine-seeking behavior to that of controls. In light of dopamine's central role in modulating cocaine reinforcement, we examined dopaminergic neurotransmission in the nucleus accumbens, a brain region implicated in the rewarding and hedonic effects of substances of misuse. FSL rats exhibited low but dose-dependent increases in extracellular levels of dopamine in the nucleus accumbens after acute intravenous cocaine injection. Furthermore, by using the dopamine transporter blocker GBR-12909 we were able to demonstrate that the low extracellular dopamine levels, observed in FSL rats, were a consequence of low dopamine release in the nucleus accumbens, as opposed to the possibility of increased uptake. Treatment of FSL rats with the antidepressant desipramine raised cocaine- and GBR-12909-induced dopamine release to the level of controls. This treatment also resulted in increased cocaine-seeking behavior.


Subject(s)
Antidepressive Agents/pharmacology , Depression/drug therapy , Dopamine/metabolism , Nucleus Accumbens/drug effects , Animals , Autoradiography , Behavior, Addictive/drug therapy , Behavior, Addictive/metabolism , Behavior, Addictive/physiopathology , Behavior, Animal/drug effects , Cocaine/pharmacology , Depression/metabolism , Depression/physiopathology , Disease Models, Animal , Dopamine Uptake Inhibitors/pharmacology , Microdialysis , Nucleus Accumbens/metabolism , Rats
4.
Prog Neurobiol ; 86(1): 1-21, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18602444

ABSTRACT

Although drugs of abuse have different acute mechanisms of action, their brain pathways of reward exhibit common functional effects upon both acute and chronic administration. Long known for its analgesic effect, the opioid beta-endorphin is now shown to induce euphoria, and to have rewarding and reinforcing properties. In this review, we will summarize the present neurobiological and behavioral evidences that support involvement of beta-endorphin in drug-induced reward and reinforcement. Currently, evidence supports a prominent role for beta-endorphin in the reward pathways of cocaine and alcohol. The existing information indicating the importance of beta-endorphin neurotransmission in mediating the reward pathways of nicotine and THC, is thus far circumstantial. The studies described herein employed diverse techniques, such as biochemical measurements of beta-endorphin in various brain sites and plasma, and behavioral measurements, conducted following elimination (via administration of anti-beta-endorphin antibodies or using mutant mice) or augmentation (by intracerebral administration) of beta-endorphin. We suggest that the reward pathways for different addictive drugs converge to a common pathway in which beta-endorphin is a modulating element. Beta-endorphin is involved also with distress. However, reviewing the data collected so far implies a discrete role, beyond that of a stress response, for beta-endorphin in mediating the substance of abuse reward pathway. This may occur via interacting with the mesolimbic dopaminergic system and also by its interesting effects on learning and memory. The functional meaning of beta-endorphin in the process of drug-seeking behavior is discussed.


Subject(s)
Conditioning, Psychological/physiology , Reinforcement, Psychology , Substance-Related Disorders/psychology , beta-Endorphin/physiology , Animals , Behavior, Animal , Conditioning, Psychological/drug effects , Euphoria/drug effects , Humans , beta-Endorphin/pharmacology
5.
Eur J Neurosci ; 18(7): 2093-8, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14622243

ABSTRACT

Neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), may play a role in drug-induced biochemical and behavioural adaptations that characterize addiction. We found that GDNF mRNA levels are lower in the striatum of rats that chronically self-administered cocaine. Therefore, we examined the effect of transplanted cells used as a biodelivery system for GDNF on cocaine self-administration in rats. A human astrocyte-like cell line, which produces and excretes GDNF, was transplanted into the striatum and nucleus accumbens of rats. These rats showed a significantly lower number of active lever presses in the cocaine self-administration paradigm compared with control rats. Moreover, rats that received a chronic infusion of GDNF via a micro-osmotic pump also exhibited weak cocaine self-administration. Therefore, we conclude that exogenous augmentation of GDNF repositories may be useful in suppressing cocaine self-administration.


Subject(s)
Cocaine-Related Disorders/prevention & control , Cocaine/administration & dosage , Dopamine Uptake Inhibitors/administration & dosage , Nerve Growth Factors/metabolism , Neuroglia/transplantation , Self Administration , Animals , Cell Line/virology , Corpus Striatum/drug effects , Gene Expression Regulation/drug effects , Glial Cell Line-Derived Neurotrophic Factor , Humans , Immunohistochemistry , Infusion Pumps , Male , Nerve Growth Factors/therapeutic use , Neuroglia/metabolism , Neuroglia/virology , Nucleus Accumbens/drug effects , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Simian virus 40/metabolism , Time Factors
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