1 MOLECULAR BIOLOGY OF DRUG ADDICTION Sylvane Desrivières, SGDP Centre
Reward 2 Humans, as well as other organisms engage in behaviours that are rewarding The pleasurable feelings provide positive reinforcement so that the behaviour is repeated. Reward = appetitive stimulus that when given to a human or other animal alters its behaviour by producing positive reinforcement There are natural rewards as well as artificial rewards, such as drugs.
Natural Rewards 3 Food Water Sex Nurturing Pleasure feelings Reinforcement of the behaviour Repetition of the behaviour
The reward system of the brain 4 The mesolimbic and mesocortical dopamine (DA) pathways: - originate in the ventral tegmental area (VTA) - send ascending projections to the nucleus accumbens (NAc) and other limbic structures, such as the prefrontal cortex (PFC)
5 Discovery of the brain reward pathway Self-stimulation experiments pioneered by James Olds and Peter Milner (1954) PFC Electrical stimulus in NAc Rewarding feeling (positive reinforcement) NAc VTA Seeking behaviour The reward pathway is strongly activated by drugs of abuse and is implicated i n their rewarding psychological properties
6 ADDICTION A state in which an organism engages in a compulsive behaviour, even when faced with negative consequences Behaviour is reinforcing (rewarding or pleasurable) Loss of control in limiting intake
7 ACUTE EFFECTS OF DRUGS OF ABUSE Interactions with molecular and cellular targets
Addictive drugs and their protein targets in the brain 8 Reinforcing drugs target different proteins, all involved in synaptic transmission Drug Drug receptor Receptor signaling mechanism Opiates (morphine-like drugs including heroin) μ and δ opioid receptors (agonist) G i (inhibitory guanine nucleotide-binding protein) Psychostimulants (cocaine, amphetamine) Dopamine transporter (antagonist-cocaine; reverse transport-amphetamine) G i and G s (stimulatory G proteins) Cannabinoids (marijuana) CB 1 cannabinoid receptor (agonist) G i Nicotine Neuronal nicotinic Ach receptor (agonist) Ligand-gated ion channels Alcohol N-methyl-d-aspartate (NMDA) type glutamate receptors (antagonist) GABA A receptors (agonist) Glycine receptors (agonist) Serotonin (5-HT 3 ) receptor (agonist) Neuronal nicotinic Ach receptor (agonist) Others Ion channels and others
Reinforcing drugs stimulate the release of dopamine in the NAc 9 Di Chiara & Imperato, PNAS 85, 5274 (1988)
10 All reinforcing drugs induce release of dopamine in the NAc How?
11 Reinforcing drugs use different mechanisms to increase dopamine release in the NAc Opiates (heroin), alcohol and cannabinoids (marijuana): GABA transmission in the VTA => disinhibition of dopamine neurons => dopamine release Alcohol Nicotine: Excites dopamine cells directly Projection towards NAc or PFC Psychomotor stimulants (cocaine, amphetamines): interact with the DA transporter (DAT) => extracellular dopamine levels. VTA neuron GABAergic interneuron Opiates, cannabinoids, and alcohol can also act directly on the NAc, in a dopamineindependent manner Neuron, Volume 69, Issue 4, 650-663, 24 February 2011
Other regions than NAc contribute to the development of Addiction 12 Maintenance of cue-activated drug taking (habit driven) Establishment of cue-activated drug seeking and taking behaviours (motivation driven) Transition between initial, motivation-driven drug seeking to habit-driven drug taking is accompanied by switch in brain circuitry: NAc => Striatum
13 LONG-TERM EFFECTS OF DRUGS OF ABUSE
The brain of a drug abuser adapts to counteract the effects of the drug 14 Dopamine transporter levels measured by positron emission tomography scans following administration of [(11)C]d-threo-methylphenidate (a dopamine transporter ligand) Nora D. Volkow et al. Am J Psychiatry 2001;158:377-382
The life cycle of addiction 15 Acute drug intake Chronic drug intake Short-term abstinence Long-term abstinence Minutes to hours Days to years Hours to days Days to years Reinforcement, reward Tolerance Sensitisation Dependence Withdrawal Craving Relapse Mesolimbic dopaminergic?other (e.g., serotonergic) Receptor adaptations camp pathway CREB FosB Glutamatergic GABAergic Dopaminergic & 5HTergic CRF Synaptic remodeling (e.g., learning & memory) CRF, glucocorticoids Adapted from Science. 1997 Oct 3;278(5335):58-63
16 TOLERANCE A state in which an organism no longer responds to a drug A higher dose is required to achieve the same effect
17 DEPENDENCE A state in which an organism functions normally only in the presence of a drug Manifested as a physical disturbance when the drug is removed (withdrawal)
18 NEURO-ADAPTATIONS FOLLOWING CHRONIC DRUG USE Molecular mechanisms underlying opiate addiction
Acute effects of Opiates 19 locus coeruleus Opiates acutely inhibit neurons by: -opioid receptor = Morphine or DAMGO a. Increasing the conductance of a G protein-coupled inwardly-rectifying potassium channel (GIRK-type K+ channel) (+) GIRK-type K + channels => neural excitability Other pathways a. Inhibiting the cyclic AMP (camp) / protein kinase A (PKA) pathway analgesia, sedation, nausea, euphoria, respiration, constricted pupils, bowel motility
20 Mechanisms of tolerance to chronic morphine Receptor adaptations Desensitisation = loss of a biological response to a ligand despite its continuous presence Receptor downregulation (internalisation/degradation) Receptor internalisation and degradation Adapted from Science 1997:Vol. 278. pp. 58-63
21 Mechanisms of tolerance during chronic morphine Perturbed downstream signalling Perturbed downstream signalling Adapted from Science 1997:Vol. 278. pp. 58-63
22 Up-regulation of the camp pathway by chronic morphine alters gene expression via the transcription factor CREB Science 1997:Vol. 278. pp. 58-63
Molecular and cellular mechanisms of opiates and cocaine action in the VTA NAc pathway 23 Consequences: aversion, withdrawal-induced disphoria Nature Reviews Neuroscience 2, 119-128 (February 2001)
24 PERMANENT CHANGES INDUCED BY DRUGS OF ABUSE Drug-Evoked Synaptic Plasticity
25 Synaptic plasticity Synaptic plasticity is the experience-dependent change in connectivity between neurons. By strengthening the connection between two neurons, the ability of the presynaptic cell to activate the postsynaptic cell is enhanced. This type of synaptic regulation forms the basis of synaptic plasticity. It is believed to underlie learning and memory. Addictive drugs modify synaptic transmission in the mesocorticolimbic DA system by hijacking mechanisms normally used for synaptic plasticity.
26 Dendritic spine small membranous protrusion that receives input from a single synapse of an axon (A). The ultrastructure of the synapse found on the dendrites of most principal neurons in the brain, including the medium spiny neurons of the striatum. very "plastic : change in shape, volume, and number in small time courses V M Ho et al. Science 2011;334:623-628 Published by AAAS
27 Repeated exposure to drugs of abuse produces long-lasting changes in the structure of dendrites and dendritic spines Repeated drug exposure Acute response to drugs Use-dependent plasticity leading to sensitised responses to drugs and environmental cues Nature Reviews Neuroscience 2, 119-128 (February 2001) Adapted from Robinson, T. E. and Kolb, B., Eur. J. Neurosci. 11; 1598 1604, 1999
Synaptic plasticity measured using the AMPAR/NMDAR ratio 28 Nature Reviews Neuroscience 8, 844-858 (November 2007)
29 Commonly abused drugs trigger synaptic plasticity Whole-cell voltage clamp recording NMDA receptor mediated synaptic current AMPA receptor mediated synaptic current AMPA/NMDA ratio => in excitatory synaptic strength
Longer-Lasting Molecular and Cellular Adaptations as consequence of psychoactive drug use 30 Stable changes in transcription factor activity (CREB, Fos, ) Stable changes in gene expression Changes in neurotransmission Changes in structure and number of synaptic connections formed by individual neurons
31 Summary Acute effects Chronic drug intake Despite the diversity of their molecular mechanisms, psychoactive drugs converge on the activation of the mesolimbic dopamine system This involves increased firing of DA neurons in the VTA and subsequent increase of DA release in the NAc. hedonic effects of drugs of abuse, contribute to their reinforcing properties Molecular and cellular mechanisms of adaptation occur as consequence of chronic drug intake development of tolerance and dependence Permanent cellular alterations (synaptic plasticity) might also be involved contributes to the risk of relapse even after long periods of abstinence