Abstract
Each of the co-authors worked with Athina Markou, at different stages of our careers
and in different capacities, to develop, optimize, and use animal models of drug addiction
and, more generally, mental health disorders such as anxiety, depression, and schizophrenia.
Here, we briefly summarize some of our work with Athina, primarily involving the use
of the intracranial self-stimulation and intravenous drug self-administration procedures.
This work established that excessive consumption of addictive drugs can induce profound
dysfunction in brain reward circuits. Such drug-induced reward deficits are likely
to play a key role in precipitating the emergence of compulsive drug-seeking behaviors.
We also summarize findings suggesting that perturbations in glutamatergic transmission
contribute to brain reward deficits in drug-dependent animals and that metabotropic
glutamate receptors are potential targets for the development of novel medications
to facilitate long-term drug abstinence and prevention of relapse.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The GABAB receptor-positive modulator GS39783 and the GABAB receptor agonist baclofen attenuate the reward-facilitating effects of cocaine: Intracranial self-stimulation studies in the rat.Neuropsychopharmacology. 2005; 30: 2065-2072
- Assessing antidepressant activity in rodents: Recent developments and future needs.Trends Pharmacol Sci. 2002; 23: 238-245
- Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents.Biol Psychiatry. 2003; 54: 49-58
- Non-nicotinic neuropharmacological strategies for nicotine dependence: Beyond bupropion.Drug Discov Today. 2003; 8: 1025-1034
- Nicotine potentiation of brain stimulation reward reversed by DH beta E and SCH 23390, but not by eticlopride, LY 314582 or MPEP in rats.Psychopharmacology (Berl). 2002; 160: 56-66
- The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice.Psychopharmacology (Berl). 2003; 167: 257-264
- Repeated administration of the GABAB receptor agonist CGP44532 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine-seeking in rats.Neuropsychopharmacology. 2005; 30: 119-128
- The GABAB receptor agonists baclofen and CGP44532 decreased nicotine self-administration in the rat.Psychopharmacology (Berl). 2004; 172: 179-186
- The gamma-aminobutyric acid type B receptor in depression and reward.Biol Psychiatry. 2018; 83: 963-976
- Positive reinforcement produced by electrical stimulation of the septal area and other regions of rat brain.J Comp Physiol Psychol. 1954; 47: 419-427
- Hypothalamic self-stimulation in three inbred strains of mice.Brain Res. 1974; 81: 159-167
- Intracranial self-stimulation in cats.J Comp Neurol. 1963; 121: 425-440
- Intracranial self-stimulation patterns in dogs.Physiol Behav. 1972; 8: 189-193
- Intracranial self-stimulation in man.Science. 1963; 140: 394-396
- Forebrain substrates of reward and motivation.J Comp Neurol. 2005; 493: 115-121
- Dorsal raphe neurons signal reward through 5-HT and glutamate.Neuron. 2014; 81: 1360-1374
- Sufficiency of mesolimbic dopamine neuron stimulation for the progression to addiction.Neuron. 2015; 88: 1054-1066
- A GABAergic projection from the centromedial nuclei of the amygdala to ventromedial prefrontal cortex modulates reward behavior.J Neurosci. 2016; 36: 10831-10842
- Activation of pedunculopontine glutamate neurons is reinforcing.J Neurosci. 2017; 37: 38-46
- Feeding and reward are differentially induced by activating GABAergic lateral hypothalamic projections to VTA.J Neurosci. 2016; 36: 2975-2985
- Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors.Cell. 2015; 160: 516-527
- Optogenetic activation of a lateral hypothalamic-ventral tegmental drive-reward pathway.PLoS One. 2016; 11: e0158885
- Intracranial self-stimulation thresholds: A model for the hedonic effects of drugs of abuse.Arch Gen Psychiatry. 1979; 36: 289-292
- Reward and detection thresholds for brain stimulation: Dissociative effects of cocaine.Brain Res. 1981; 209: 496-500
- Low dose cocaine self-administration transiently increases but high dose cocaine persistently decreases brain reward function in rats.Eur J Neurosci. 2003; 17: 191-195
- Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity.Neuropsychopharmacology. 2006; 31: 1203-1211
- Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction.Nat Neurosci. 2005; 8: 1442-1444
- The dark side of emotion: The addiction perspective.Eur J Pharmacol. 2015; 753: 73-87
- Negative reinforcement in drug addiction: The darkness within.Curr Opin Neurobiol. 2013; 23: 559-563
- A ‘crash’ course on psychostimulant withdrawal as a model of depression.Trends Pharmacol Sci. 2002; 23: 475-482
- Postcocaine anhedonia. An animal model of cocaine withdrawal.Neuropsychopharmacology. 1991; 4: 17-26
- An opponent-process theory of motivation. I. Temporal dynamics of affect.Psychol Rev. 1974; 81: 119-145
- An opponent-process theory of motivation. II. Cigarette addiction.J Abnorm Psychol. 1973; 81: 158-171
- The opponent-process theory of acquired motivation: The costs of pleasure and the benefits of pain.Am Psychol. 1980; 35: 691-712
- Neurobiological evidence for hedonic allostasis associated with escalating cocaine use.Nat Neurosci. 2002; 5: 625-626
- Transition from moderate to excessive drug intake: Change in hedonic set point.Science. 1998; 282: 298-300
- Conditioned withdrawal drives heroin consumption and decreases reward sensitivity.J Neurosci. 2006; 26: 5894-5900
- Decreased brain reward produced by ethanol withdrawal.Proc Natl Acad Sci U S A. 1995; 92: 5880-5884
- Differential effects of withdrawal from chronic amphetamine or fluoxetine administration on brain stimulation reward in the rat—interactions between the two drugs.Psychopharmacology (Berl). 1999; 145: 283-294
- A dysphoric-like state during early withdrawal from extended access to methamphetamine self-administration in rats.Psychopharmacology (Berl). 2013; 225: 753-763
- Dramatic decreases in brain reward function during nicotine withdrawal.Nature. 1998; 393: 76-79
- Withdrawal from chronic phencyclidine treatment induces long-lasting depression in brain reward function.Neuropsychopharmacology. 2003; 28: 1106-1116
- Conditioning of successive adaptive responses to the initial effects of drugs.Cond Reflex. 1973; 8: 193-210
- Conditioned narcotic withdrawal in humans.Science. 1977; 195: 1000-1002
- Conditioned nicotine withdrawal profoundly decreases the activity of brain reward systems.J Neurosci. 2005; 25: 6208-6212
- Cocaine vaccines: Antibody protection against relapse in a rat model.Proc Natl Acad Sci U S A. 2000; 97: 6202-6206
- The role of withdrawal in heroin addiction: Enhances reward or promotes avoidance?.Nat Neurosci. 2001; 4: 943-947
- Unlimited access to heroin self-administration: Independent motivational markers of opiate dependence.Neuropsychopharmacology. 2006; 31: 2692-2707
- Reinstatement of cocaine-reinforced responding in the rat.Psychopharmacology (Berl). 1981; 75: 134-143
- The reinstatement model of drug relapse: history, methodology and major findings.Psychopharmacology (Berl). 2003; 168: 3-20
- Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: Effects of conditioned cues and continuous access to cocaine.Psychopharmacology (Berl). 1998; 140: 331-344
- Dynamics of drug dependence. Implications of a conditioning theory for research and treatment.Arch Gen Psychiatry. 1973; 28: 611-616
- Drug addiction, dysregulation of reward, and allostasis.Neuropsychopharmacology. 2001; 24: 97-129
- Cellular and molecular mechanisms of drug dependence.Science. 1988; 242: 715-723
- Systemic nicotine stimulates dopamine release in nucleus accumbens: Re-evaluation of the role of N-methyl-D-aspartate receptors in the ventral tegmental area.J Pharmacol Exp Ther. 2000; 294: 458-465
- Nicotine-induced excitation of midbrain dopamine neurons in vitro involves ionotropic glutamate receptor activation.Synapse. 2000; 38: 1-9
- Long-term potentiation of excitatory inputs to brain reward areas by nicotine.Neuron. 2000; 27: 349-357
- N-methyl-D-aspartate receptor antagonism in the ventral tegmental area diminishes the systemic nicotine-induced dopamine release in the nucleus accumbens.Neuroscience. 1998; 82: 781-789
- The motivational valence of nicotine in the rat ventral tegmental area is switched from rewarding to aversive following blockade of the alpha7-subunit-containing nicotinic acetylcholine receptor.Psychopharmacology (Berl). 2003; 166: 306-313
- NMDA receptors regulate nicotine-enhanced brain reward function and intravenous nicotine self-administration: Role of the ventral tegmental area and central nucleus of the amygdala.Neuropsychopharmacology. 2009; 34: 266-281
- Group II metabotropic and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate glutamate receptors regulate the deficit in brain reward function associated with nicotine withdrawal in rats.J Pharmacol Exp Ther. 2003; 306: 1068-1076
- Habenular alpha5 nicotinic receptor subunit signalling controls nicotine intake.Nature. 2011; 471: 597-601
- Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors.Nature. 2005; 436: 103-107
- Metabotropic glutamate 2/3 receptors in the ventral tegmental area and the nucleus accumbens shell are involved in behaviors relating to nicotine dependence.J Neurosci. 2007; 27: 9077-9085
- Metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) microinfusions into the nucleus accumbens shell or ventral tegmental area attenuate the reinforcing effects of nicotine in rats.Neuropharmacology. 2011; 61: 1399-1405
- The role of cystine-glutamate exchange in nicotine dependence in rats and humans.Biol Psychiatry. 2009; 65: 841-845
- Cerebral cystine uptake: A tale of two transporters.Trends Pharmacol Sci. 2002; 23: 299-302
- Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse.Nat Neurosci. 2003; 6: 743-749
- N-acetylcysteine decreased nicotine self-administration and cue-induced reinstatement of nicotine seeking in rats: Comparison with the effects of N-acetylcysteine on food responding and food seeking.Psychopharmacology (Berl). 2013; 225: 473-482
- N-acetylcysteine decreased nicotine reward-like properties and withdrawal in mice.Psychopharmacology (Berl). 2016; 233: 995-1003
- Efficacy of N-acetylcysteine in the treatment of nicotine dependence: a double-blind placebo-controlled pilot study.Eur Addict Res. 2011; 17: 211-216
- Neuroadaptive changes in the mesocortical glutamatergic system during chronic nicotine self-administration and after extinction in rats.J Neurochem. 2008; 106: 943-956
- Reinstatement of nicotine seeking is mediated by glutamatergic plasticity.Proc Natl Acad Sci U S A. 2013; 110: 9124-9129
- Glutamate systems in cocaine addiction.Curr Opin Pharmacol. 2004; 4: 23-29
- Orally active metabotropic glutamate subtype 2 receptor positive allosteric modulators: Structure-activity relationships and assessment in a rat model of nicotine dependence.J Med Chem. 2012; 55: 9434-9445
- AZD8529, a positive allosteric modulator at the mGluR2 receptor, does not improve symptoms in schizophrenia: A proof of principle study.Schizophr Res. 2016; 172: 152-157
- Attenuation of nicotine-taking and nicotine-seeking behavior by the mGlu2 receptor positive allosteric modulators AZD8418 and AZD8529 in rats.Psychopharmacology (Berl). 2016; 233: 1801-1814
- The novel metabotropic glutamate receptor 2 positive allosteric modulator, AZD8529, decreases nicotine self-administration and relapse in squirrel monkeys.Biol Psychiatry. 2015; 78: 452-462
- Activation of group II metabotropic glutamate receptors in the nucleus accumbens shell attenuates context-induced relapse to heroin seeking.Neuropsychopharmacology. 2006; 31: 2197-2209
- Preferential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on conditioned reinstatement versus primary reinforcement: Comparison between cocaine and a potent conventional reinforcer.J Neurosci. 2004; 24: 4723-4727
- Group II metabotropic glutamate receptors (mGlu2/3) in drug addiction.Eur J Pharmacol. 2010; 639: 115-122
- The group II metabotropic glutamate receptor agonist, LY379268, inhibits both cocaine- and food-seeking behavior in rats.Psychopharmacology (Berl). 2006; 186: 143-149
- From bench to bedside: mGluR2 positive allosteric modulators as medications to treat substance use disorders.Psychopharmacology (Berl). 2017; 234: 1347-1355
Article Info
Publication History
Published online: February 21, 2018
Accepted:
February 14,
2018
Received in revised form:
February 14,
2018
Received:
November 17,
2017
Identification
Copyright
© 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
