| Slidelist | References | Glossary | Questions and Answer Session | Reading & Papers | Bio

OVERVIEW: The goal of this lecture is to describe the neurobiological mechanisms underlying reward/reinforcement and the role of these mechanisms in drug addiction and its attendant phenomena - including craving, rebound dysphoria, and relapse. We will describe the neuroanatomy, neurophysiology, and neurochemistry of the brain's reward/reinforcement circuits. We will describe laboratory paradigms for studying the role of brain reward mechanisms in addiction - including intracranial drug self-administration in lab animals, electrical brain-stimulation reward, and in vivo brain microdialysis and microelectrochemistry. We will describe genetic variation in brain reward activation by addicting drugs, and the neurobiology of drug craving. We will note the implications of addictive drug action on brain reward mechanisms for the development of rational pharmacotherapies for drug addiction at the human level.

KEY CONCEPTS:

• Drug addiction is as old as recorded history. References to drug (including, of course, alcohol) addiction and dependence are found in the earliest written and oral records of virtually every society and culture on earth.

• Although Chemical Abstracts lists millions of chemicals only a few score of these are addictive.

• Addictive drugs have in common that they are voluntarily self-administered by laboratory animals (often avidly) and that they facilitate the functioning of the pleasure/reward/reinforcement circuitry of the brain.

Fig. 2. Opioid antagonist (naloxone)-induced blockade of pentobarbital-enhanced brain pleasure/reward. "p <.001 " indicates a statistically significant difference at greater than the 0.001 level of probability. "p<.02" indicates a statistically significant difference at greater than the 0.02 level of probability. "N.S." ("not significant") indicates the lack of a statistically significant difference.

• The core pleasure/reward/reinforcement circuitry of the mammalian brain consists of an "in series" circuit containing at least three fundamental neural elements: 1) a descending, myelinated, moderately fast-conducting tract originating in the anterior bed nuclei of the medial forebrain bundle, projecting caudally through the medial forebrain bundle to synapse on dopaminergic neurons in the ventral tegmental area; 2) an ascending dopaminergic tract originating in the ventral tegmental area, projecting rostrally through the medial forebrain bundle to synapse on enkephalinergic neurons in the nucleus accumbens; and 3) a descending enkephalinergic tract originating in the nucleus accumbens and projecting to the ventral pallidum (see Fig. 3).

• The "second-stage" dopaminergic fibers in this pleasure/reward/reinforcement circuitry appear to be the crucial addictive-drug-sensitive component. All addictive drugs have in common that they enhance (some directly, some indirectly, some even transsynaptically) dopaminergic function at crucial dopamine pleasure/reward synapses in the nucleus accumbens (e.g., Fig. 4). Congruent with the findings using electrophysiological measures of brain reward thresholds (see above), in vivo neurochemical measurements show that the enhanced synaptic dopamine levels at nucleus accumbens pleasure/reward synapses produced by addicting drugs is attenuated by opioid antagonists (e.g., Fig. 5).

• Anatomic projections into this core pleasure/reward/reinforcement circuit from the amygdala appear crucial in mediating the phenomenon of craving. The amygdala and other nearby deep temporal lobe structures such as the subiculum may also be crucial in mediating relapse to drug-taking after successful cessation of drug self-administration. Stress and post-drug-use dysphoria (e.g., Fig. 6) also are known to be triggers for relapse to drug-taking in both laboratory animals and humans.

Figure 3. Schematic diagram of the brain-reward circuitry of the mammalian (laboratory rat) brain, with sites at which various abusable substances appear to act to enhance brain-reward and thus to induce drug-taking behavior and possibly drug-craving. ICSS, descending, myelinated, moderately-fast-conducting component of the brain-reward circuitry that is preferentially activated by electrical intracranial self-stimulation., DA subcomponent of the ascending mesolimbic dopaminergic system that appears preferentially activated by abusable substances: Raphé brain stem serotonergic raphé nuclei LC, locus coeruleus; VTA ventral tegmental area; Acc, nucleus accumbens; VP, ventral pallidum; ABN, anterior bed nuclei of the medial forebrain bundle; AMYG, amydala; FCX frontal cortex: 5HT, serotonergic (5-Hydroxytryptamine) fibers, which originate in the anterior raphé nuclei and project to both the cell body region (ventral tegmental area) and terminal projection field (nucleus accumbens) of the DA reward neurons; NE, noradrenergic fibers, which originate in the locus coeruleus and synapse into the general vicinity of the ventral mesencephalic DA cell fields of the ventral tegmental area; GABA, GABAerqic inhibitory fiber systems synapsing upon the locus coeruleus noradrenergic fibers, the ventral tegmental area, and the nucleus accumbens, as well as the GABAergic outflow from the nucleus accumbens; Opioid, endogenous opioid peptide neural systems synapsing into both the ventral tegmental DA cell fields and the nucleus accumbens DA terminal projection loci; ENK, enkephalinergic outflow from the nucleus accumbens; DYN, dynorphinergic outflow from the nucleus accumbens; GLU, glutamatergic neural systems originating in frontal cortex and synapsing in both the ventral tegmental area and the nucleus accumbens.

Fig. 4. Enhanced extracellular synaptic dopamine in nucleus accumbens pleasure/reward synapses produced by the addicting drug morphine.

Fig. 5. Enhanced extracellular synaptic dopamine in nucleus accumbens pleasure/reward synapses produced by D⁹-tetrahydrocannabinol (THC), the addicting constituent of marijuana and hashish, and attenuation of same by the opioid antagonist naloxone (NAL). "p<.001" indicates a statistically significant difference at greater than the 0.001 level of probability. "p<.01" indicates a statistically significant difference at greater than the 0.01 level of probability. "p<.05" indicates a statistically significant difference at greater than the 0.05 level of probability.
 

Fig. 6. Enhanced brain reward following acute systemic administration of D⁹-tetrahydrocannabinol ("THC," the addicting constituent of marijuana and hashish) (top panel), and diminished brain reward (dysphoria) during withdrawal from THC (bottom panel). Enhanced brain reward is measured as a left-shift, and diminished brain reward as a right-shift, in mean rate-frequency electrical brain stimulation reward functions in the medial forebrain bundle axons of the ventral tegmental area (dopaminergic nucleus A10). In the above figure, THC significantly shifts the reward function curve to the left (enhanced brain reward), while withdrawalfrom THC significantly shifts the reward function curve to the right (diminished brain reward).

• For some classes of addicting drugs (e.g., opiates such as heroin or morphine), tolerance to the euphoric effects develops with chronic use (see Fig. 7). In fact, with chronic use, the post-use dysphoria comes to dominate the hedonic tone of the brain's pleasure/reward circuits. Under these circumstances, the addict no longer uses drugs to get "high," but simply to get back to normal ("get straight" in street parlance).

• The brain circuits mediating the pleasurable effects of addictive drugs are anatomically, neurophysiologically, and neurochemically different from those mediating the physical dependence produced by some addictive drugs. Some addicting drugs (e.g., cocaine) are intensely addicting while producing no physical dependence whatever.

Fig. 7. Tolerance to the euphorigenic effects of morphine with repeated administration. Enhancement of brain reward is measured as a decrease in electrical brain-stimulation reward threshold in the ventral tegmental area (dopaminergic nucleus A10). Inhibition of brain reward is measured as a increase in electrical brain-stimulation reward threshold in the ventral tegmental area (dopaminergic nucleus A10).

• There are important genetic variations in vulnerability to drug addiction, at both the laboratory animal and human levels (see Figs. 8 and 9).

Fig. 9. Genetic variation in the neurochemical substrates of the enhanced brain reward seen following acute systemic administration of D⁹-tetrahydrocannabinol ("D⁹-THC, " the addicting constituent of marijuana and hashish). In vivo brain microdialysis is used to measure dopamine release at pleasure/reward synapses in the nucleus accumbens. In addictive-drug-neutral Sprague-Dawley rats, D⁹-THC enhances synaptic dopamine in nucleus accumbens pleasure/reward synapses only modestly. In addictive-drug-preferring Lewis rats, D⁹-THC robustly enhances synaptic dopamine in nucleus accumbens pleasure/reward synapses. "x" indicates statistical significance of comparisons of individual samples with pre-injection dopamine levels (x = p < 0.05, xx = p < 0.01).

Vulnerability to drug addiction correlates with a hypo-dopaminergic dysfunctional state within the core pleasure/reward/reinforcement circuitry of the brain (see Fig. 10).
 
 

Figure 10.

 Schematic summary of similar biochemical manifestations of the 'drug-addicted' and 'drug-preferring' state. (A) (Normal state) depicts a control VTA neuron projecting to the NAcc. Shown in the VTA cell are tyrosine hydroxylase (TH), dopamine (DA), presynaptic dopamine receptors (D₂ coupled to G-proteins (Gi), and neurofilaments (NFs). Shown in the NAcc are, in addition to TH and DA, dopamine receptors (D₁ and D₂), G-proteins (Gi and Gs), components of the intraceIlular cyclic AMP system (AC, adenylate cyclase; PKA, cAMP-dependent protein kinase; and possible substrates for the kinase-ion channels and the nuclear transcription factors, CREB, fos and jun), as well as major inputs and outputs of this region (VP, ventral pallidum; HP, hippocampus; AMYG, amygdala; OLF, olfactory cortex; CTX, other cortical regions). (B) (Drug-addicted, drug-preferring state) depicts a VTA neuron projecting to the NAcc after chronic morphine or cocaine, or from a Lewis (drug-preferring) rat versus Fischer (F344) rat. In the drug-addicted or drug-preferring animal, TH levels are increased in the VTA, and decreased in the NAcc (due to either decreased phosphorylation as for morphine and cocaine, or decreased enzyme levels as in Lewis versus Fischer rats). In addition, NF levels are decreased in the VTA in the drug-addicted and drug-preferring state. This decrease in NFs may be associated with alterations in neuronal structure, decreases in axonal caliber, and/or decreases in axonal transport rate in these cells, as indicated in the figure. Such a decrease in axonal transport, demonstrated for chronic morphine,²⁷ could account for the lack of correspondingly increased levels of TH in dopaminergic terminals in the NAcc. Decreased TH implies decreased dopamine synthesis, and may result in lower dopaminergic transmission to the NAcc. In the NAcc of the drug-addicted or drug-preferring state, Gi is decreased, and adenylate cyclase and cAMP-dependent protein kinase activities are increased, changes that could account for the D₁ receptor supersensitivity observed electrophysiologically. It should be noted that alterations in dopaminergic transmission probably influence many cell types within the NAcc, as well as other nerve terminals in the NAcc. Similarly, altered local dopaminergic transmission in the VTA could also influence other nerve terminals in this brain region. Thus, biochemical alterations in the mesolimbic dopamine system could potentially lead to altered neuronal function in many other brain regions as well.

• Knowledge of the neuroanatomy, neurophysiology, neurochemistry, and neuropharmacology of addictive drug action in the brain is currently producing a variety of strategies for pharmacotherapeutic treatment of drug addiction, some of which seem promising (see Figs. 11 and 12).

Fig. 11. Effects of CTDP-30,640 - a slow-onset long-acting dopamine reuptake blocker being explored at AECOM as a potential anti-cocaine-addiction medication - on intravenous cocaine self-administration in laboratory rats.

^{Fig. 12. Effects of g -vinyl-GABA - a GABA-transaminase inhibitor being explored at AECOM as a potential anti-cocaine-addiction medication - on acquisition (upper panel, Table 1) and on expression (lower panel, Table 2) of cocaine-seeking behavior in laboratory rats. The GABAergic strategy for development of anti-cocaine-addiction medications at AECOM is based on the important functional regulation of the brain's dopaminergic pleasure/reward circuits by the neurotransmitter GABA (g -amino-butyric acid) (see Fig. 3 above).}
 
 

^REFERENCES:

^{Ahmed, S.H. & Koob, G.F. Transition from moderate to excessive drug intake: change in hedonic set point. Science 282:298-300 (1998).}

^{Gardner, E.L. Brain reward mechanisms. In Lowinson, J.H., Ruiz, P., Millman, R.B. & Langrod, J.G. (Eds), Substance Abuse: A Comprehensive Textbook, 3rd ed. Baltimore: Williams & Wilkins, pp.51-85 (1997).}

^{Gardner, E.L. (Ed) The Neurobiology of Drug Addiction/Dependency. Seminars in the Neurosciences. London: Academic Press (1993).}

^{Gardner, E.L. & David, J. The neurobiology of chemical addiction. In Elster, J. & Skog, O.-J.
(Eds), Getting Hooked: Rationality and the Addictions. Cambridge, England: Cambridge University Press, pp.93-136 (1999).}

^{Gardner, E.L. & Lowinson, J.H. Drug craving and positive/negative hedonic brain substrates activated by addicting drugs. Seminars in the Neurosciences 5:359-368 (1993).}

^{Koob, G.F. & Le Moal, M. Drug abuse: hedonic homeostatic dysregulation. Science 278:52-58(1997).}

^{Kornetsky, C. Brain-stimulation reward: a model for the neuronal bases for drug-induced euphoria. National Institute on Drug Abuse Research Monograph Series 62:30-50 (1985).}

^{Wise, R.A. & Rompre, P.-P. Brain dopamine and reward. Annual Review of Psychology 40:191-225 (1989).}

^{Wise, R.A. Neurobiology of addiction. Current Opinion in Neurobiology 6:243-251 (1996).}

^{Wise, R.A. Addictive drugs and brain stimulation reward. Annual Review of Neuroscience 19:319-340 (1996).}

^{Wise, R.A. Drug activation of brain reward pathways. Drug and Alcohol Dependence 51:13-22(1998).}