Neurobiological Effects

Binge/Intoxication Stage

Psychostimulants increase dopamine release in a phasic manner at a level 10 times the normal release of dopamine. Thus, drug-induced synaptic plasticity in the nucleus accumbens (ventral striatum) and dorsal striatum exaggerates the cue-induced drug seeking outlined above. In humans, positron emission tomography (PET) imaging studies have confirmed that all major classes of drugs increase dopamine in the nucleus accumbens (ventral striatum) and dorsal striatum, and the drug-induced increases in dopamine in the striatum are proportional to the intensity of the subjective experience of euphoria or “high” (for further reading, see Volkow et al., 2009). Human studies also show that prefrontal cortex regions become activated when cocaine abusers are exposed to craving-inducing stimuli (either drugs or cues), thus supporting the concept of the plasticity of the neurocircuitry.

Repeated treatments with amphetamine or cocaine in animals increase dendritic spine density and the number of branched spines in the nucleus accumbens and prefrontal cortex, which can last for weeks. Multiple cellular mechanisms have been identified to account for this structural plasticity. Previously silent synapses that involve the expression of N-methyl-D-aspartate receptors are observed with repeated psychostimulant administration in the shell of the nucleus accumbens, and withdrawal and protracted abstinence involve the overexpression of AMPA receptors. Drugs that block AMPA receptors also block the cue-induced reinstatement of cocaine-seeking behavior, linking this synaptic plasticity with incentive salience (Box 4.14; for further reading, see Grueter et al., 2012).

Figure 4.13 Sagittal section through a representative rodent brain illustrating the pathways and receptor systems implicated in the acute reinforcing actions of cocaine and amphetamines. Cocaine and amphetamines activate release dopamine in the nucleus accumbens and amygdala via direct actions on dopamine terminals. The blue arrows represent the interactions within the extended amygdala system hypothesized to have a key role in psychostimulant reinforcement. AC, anterior commissure; AMG, amygdala; ARC, arcuate nucleus; BNST, bed nucleus of the stria terminalis; Cer, cerebellum; C-P, caudate putamen; DMT, dorsomedial thalamus; FC, frontal cortex; Hippo, hippocampus; IF, inferior colliculus; LC, locus coeruleus; LH, lateral hypothalamus; N Acc., nucleus accumbens; OT, olfactory tract; PAG, periaqueductal gray; RPn, reticular pontine nucleus; SC, superior colliculus; SNr, substantia nigra pars reticulata; VP, ventral pallidum; VTA, ventral tegmental area. [From Koob GF, Le Moal M, 2006. Neurobiology of Addiction. Academic Press, London.]

BOX 4.14

SYNAPTIC PLASTICITY

Synaptic plasticity is the capacity for continuous alteration of the neural circuits and synapses of the living brain and nervous system in response to experience or injury. Plasticity includes long-term potentiation (LTP) and has been observed at the cellular level in the ventral tegmental area and nucleus accumbens with repeated psychostimulant exposure. LTP occurs when neurons are turned on and take longer than usual to turn off. Cellular plasticity also includes changes in synaptic strength (signals may be stronger or weaker than normal) that require activation of N-methyl-D-aspartate glutamate receptors from excitatory inputs that originate in prelimbic cortical areas and do not depend on dopamine receptors (for further reading, see Thomas and Malenka, 2003).

The acute reinforcing actions of cocaine, amphetamines, and methamphetamine are mediated by the release of dopamine in the terminal areas of the mesocorticolimbic dopamine system (Figure 4.13). Lesions of the mesocorticolimbic dopamine system with 6-hydroxydopamine block the reinforcing effects of cocaine and D-amphetamine, assessed by drug self-administration. Rats that are trained to self-administer cocaine or amphetamine intravenously and then subjected to 6-hydroxydopamine lesions of the nucleus accumbens show an extinction-like response pattern that consists of a high level of responding (lever-presses) at the beginning of the test session followed by a gradual decline over subsequent sessions and a long-lasting decrease in responding (Table 4.5, Figure 4.14). Lesions of the dorsal striatum do not block cocaine self-administration. Much of the work on the acute reinforcing effects of psychostimulants has focused on the medial subregion of the nucleus accumbens, termed the shell of the nucleus accumbens (see Introduction to the Neuropsychopharmacology). Early in vivo microdialysis studies in awake, freely moving animals showed preferential activation of dopamine in the shell of the nucleus accumbens with administration of all drugs of abuse (for further reading, see Di Chiara 2002). Injections of a dopamine D1 receptor antagonist directly into the shell of the nucleus accumbens, central nucleus of the amygdala, and bed nucleus of the stria terminalis also decrease the reinforcing effects of cocaine and block the motivation to work for intravenous cocaine (that is, animals are not willing to press a lever as many times to receive a drug injection). Knockout studies show that D1 receptors, D2 receptors, and the dopamine transporter play important roles in psychostimulant actions (for example, D1 knockout mice do not self-administer cocaine; Table 4.6). Thus, the mesocorticolimbic dopamine system is clearly critical for psychostimulant activation and reinforcement, and it also plays a major role in the reinforcing actions of other drugs of abuse (for further reading, see Koob, 1992). The heterogeneity of connectivity within subregions of the nucleus accumbens, for example, suggests that the nucleus accumbens shell may provide a link between the terminals of the mesocorticolimbic dopamine system and other forebrain areas involved in psychostimulant reinforcement.

TABLE 4.5

Effects of Specific Lesions of the Midbrain Dopamine Systems on Behavior

System

Effect

Mesocorticolimbic and nigrostriatal dopamine systems

_ Parkinsonian-like symptoms
_ Spontaneous activity
_ Eating
_ Drinking
_ Performance in conditioned avoidance task

Mesocorticolimbic dopamine system

_ Amphetamine-induced locomotor activity
_ Cocaine-induced locomotor activity
_ Cocaine self-administration
_ D-amphetamine self-administration

Nigrostriatal dopamine system

_ D-amphetamine-induced stereotypy

Dorsal striatum

_ Locomotor activity
_ Amphetamine-induced stereotyped behavior

Nucleus accumbens

_ Cocaine self-administration
_ Amphetamine self-administration

More specifically, the reinforcing effects of psychostimulants involve output systems that engage striatal–pallidal–thalamic–cortical loops that have been hypothesized to interact within the topographical connections of the basal ganglia (seeIntroduction to the Neuropsychopharmacology). While the initial acute reinforcing actions of psychostimulants engage the ventral part of the basal ganglia, such as the shell of the nucleus accumbens, as drug self-administration becomes more habit-like (a more regular and stereotyped pattern), the dorsal part of the basal ganglia becomes engaged. Some have argued that these circuits play a key role in the compulsive-like responding associated with psychostimulant addiction (for further reading, see Everitt and Wolf, 2002; Belin and Everitt, 2008).

Individual differences in response to psychostimulant drugs are determined by many factors, but a key factor is activation of the hypothalamic–pituitary–adrenal (HPA) axis and the release of glucocorticoids. In normal situations and during the rodent’s active period in the light/dark cycle, glucocorticoids increase dopaminergic function, especially in mesocorticolimbic regions. The interaction between glucocorticoids and the mesocorticolimbic dopamine system may have a significant impact on the vulnerability to self-administer psychostimulant drugs. Rats that have a high initial propensity to explore a novel environment also have a high initial corticosterone response (corticosterone is the rodent equivalent to human cortisol) and are much more likely to self-administer psychostimulant drugs. Additionally, rats with normal initial sensitivity that receive repeated injections of corticosterone acquire cocaine self-administration at a much lower dose than rats that receive vehicle injections. Corticosterone administration causes rats that would not initially self-administer amphetamine at low doses to self-administer the drug (Figure 4.15; for further reading, see Piazza and Le Moal, 1996).

Figure 4.14 Effect of 6-hydroxydopamine lesions of the nucleus accumbens on cocaine self-administration in rats. The data-points represent mean (± SEM) daily intake for each group. One group received the monoamine oxidase inhibitor pargyline (50 mg/kg) prior to 6-hydroxydopamine treatment (filled triangles). Another group received both pargyline and the tricyclic antidepressant desmethylimipramine (25 mg/kg) prior to 6-hydroxydopamine (filled circles). The control group received pargyline and desmethylimipramine prior to vehicle infusions (rather than 6-hydroxydopamine infusions) into the nucleus accumbens. Cocaine was not available for self-administration until day 5 post-lesion. A significant difference was found between the two lesion groups and the control group. No difference was observed between the 6-hydroxydopamine groups. These data show that removal of dopaminergic terminals in the mesocorticolimbic dopamine system in the nucleus accumbens with a neurotoxin that selectively destroys monoamine axons and terminals causes rats to stop taking cocaine. In other words, the rats extinguished their drug seeking behavior although cocaine was readily available (see Animal Models for a definition of extinction). [From: Roberts DCS, Koob GF, Klonoff P, Fibiger HC. Extinction and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the nucleus accumbens. Pharmacology Biochemistry and Behavior, 1980, (12), 781–787.]

Electrophysiological recordings in awake, freely moving animals during intravenous cocaine self-administration have identified several types of neurons in the nucleus accumbens that respond to drug infusion and reinforcement, and these studies emphasize the key role of the nucleus accumbens in the acute reinforcing actions of cocaine and, by extrapolation, psychostimulants in general. One group of neurons in the nucleus accumbens shows anticipatory neuronal responses, as if the neurons “sense” the coming reinforcement. Another group of neurons increases or decreases firing following the response to cocaine and represents a direct effect of reinforcement. Much data have been generated with in vivo electrophysiology to show that neuronal firing in the nucleus accumbens can also follow the acquisition, extinction, and maintenance of cocaine self-administration.

TABLE 4.6

Dopamine Receptor Subtype-Specific Knockouts and Psychostimulant-Induced Behavior in Mice

Locomotor Response

Dopamine Receptor
Knockout

Rewarding Effects

_ Amphetamine
_ Cocaine
_ Amphetamine sensitization
_ Cocaine sensitization

icon

_ Amphetamine-induced conditioned place preference
_ Cocaine-induced conditioned place preference
_ Amphetamine self-administration
_ Cocaine self-administration

_ Amphetamine
_ Cocaine

icon

_ Cocaine self-administration (descending limb)

_ Amphetamine
_ Cocaine

icon

No significant effects

_ Amphetamine
_ Cocaine
_ Amphetamine sensitization

icon

_ Methamphetamine-induced conditioned place preference

No significant effects

icon

No significant effects

In humans, acute infusions of cocaine have been shown to selectively increase brain metabolic activity in reward structures in functional magnetic resonance imaging studies. In cocaine-dependent subjects who were abstinent for 18 h, the brain was imaged for 5 min before and 13 min after infusion of either cocaine or saline while the subjects rated their subjective feelings of rush, high, low, and craving. The high only appeared in the drug group, followed by dysphoria 11 min post-infusion, whereas peak craving occurred 12 min post-infusion. Prior to both infusions (saline and cocaine), within 5 min a positive signal change was observed in the ventral region of the nucleus accumbens and subcallosal cortex. After the cocaine infusion, the signal increased in some areas, such as the nucleus accumbens, subcallosal cortex, caudate putamen, thalamus, insula, hippocampus, cingulate, lateral prefrontal cortex, temporal cortex, ventral tegmentum, and pons. The signal actually decreased in some subjects in the amygdala, temporal pole, and medial frontal cortex. Saline infusion produced a limited set of significant activation, such as frontal and temporal-occipital cortices, to match some of the activation seen in the cocaine group. The activation correlated with the degree of emotional ratings (Figure 4.16; for further reading, see Koob and Le Moal, 2006).

Figure 4.15 Corticosteroids and behavioral effects of psychostimulants. (A) Effects of adrenalectomy on cocaine self-administration in rats. Animals were trained to self-administer cocaine by nosepoking and then subjected to several doses of cocaine. Adrenalectomy produced a flattening of the dose-effect function, with decreases in cocaine intake at all doses. (B) Corticosterone-induced changes in extracellular concentrations of dopamine in rats bred for either high-responsiveness (HR) or low-responsiveness (LR) to stress and psychostimulant drugs. High-responding animals that drank the corticosterone solution (100 mg/ml) in the dark period showed a faster and higher increase in nucleus accumbens dopamine than low-responding animals. These data show that removal of the adrenal glands and the source of circulating glucocorticoids block the reinforcing effects of cocaine and that the glucocorticoid corticosterone increased the release of dopamine measured by in vivo microdialysis in rats selected for a high response to novelty. Thus, glucocorticoids facilitate the dopaminergic response to cocaine and its consequent reinforcing effects. [Panel A. Modified from: Deroche V, Marinelli M, Le Moal M, Piazza PV. Glucocorticoids and behavioral effects of psychostimulants: II. Cocaine intravenous self-administration and reinstatement depend on glucocorticoid levels. Journal of Pharmacology and Experimental Therapeutics, 1997, (281), 1401–1407.] [Panel B. From: Piazza PV, Rouge-Pont F, Deroche V, Maccari S, Simon H, Le Moal M. Glucocorticoids have state-dependent stimulant effects on the mesencephalic dopaminergic transmission. Proceedings of the National Academy of Sciences USA, 1996, (93), 8716–8720.]

Withdrawal/Negative Affect Stage

Cocaine withdrawal in animal studies is characterized by significant motivational changes measured by changes in reward thresholds but few physical or somatic symptoms. Elevations in brain reward thresholds reflect decreases in reward (that is, more stimulation is required for the individual to sense the stimulus as rewarding). During an acute 12 h binge of intravenous cocaine self-administration in rats that were tested for brain reward thresholds, a dose-dependent elevation in these thresholds in the medial forebrain bundle occurred when the self-administration session ended (Figure 4.17). Rats that had access to cocaine for 48 h showed elevations in thresholds that lasted for 5 days after cocaine self-administration ended. Similar results have been observed with cocaine and D-amphetamine. Elevations in brain reward thresholds (decreased reward) temporally preceded and were highly correlated with escalation in cocaine intake with extended access (Figure 4.18). Post-session elevations in reward thresholds failed to fully return to baseline levels in rats that had extended access to cocaine before the onset of each subsequent self-administration session, thereby progressively deviating more and more from baseline levels. These results provide compelling evidence that brain reward dysfunction occurs with escalated cocaine intake.

Figure 4.16 Summary of limbic and paralimbic brain regions that correlate with euphoria (red) vs. regions that correlate with craving (green). Above these schematics are indications of the brain regions (yellow) predicted to be active after an infusion of cocaine. Two other brainstem monoaminergic regions, potentially encompassed in pontine activation seen in a baseline vs. post-infusion comparison, are illustrated in blue. This pontine activation correlated with behavioral ratings of “rush.” [From: Breiter HC, Gollub RL, Weisskoff RM, Kennedy DN, Makris N, Berke JD, Goodman JM, Kantor HL, Gastfriend DR, Riorden JP, Mathew RT, Rosen BR, Hyman SE. Acute effects of cocaine on human brain activity and emotion. Neuron, 1997, (19), 591–611.]

With cocaine and amphetamines, the neurochemical basis of the motivational significance of withdrawal involves both a decrease in the function of neurotransmitters related to reward function and recruitment of brain stress systems. Dopamine and serotonin release in the basal forebrain (e.g., nucleus accumbens), measured by in vivo microdialysis, decreases during withdrawal in animal studies. Animals that underwent escalation of drug intake had enhanced sensitivity to the mixed D1/D2 receptor antagonist cis-flupenthixol, with a leftward shift of the dose-response function, suggesting that escalation in cocaine self-administration may be mediated, at least partially, by decreased function of dopamine receptors or transduction mechanisms. The initial “crash” experienced immediately after a binge by human cocaine users may reflect a decrease in extracellular dopamine that can persist for months after chronic high-dose use.

Figure 4.17 Intracranial self-stimulation thresholds in rats following 3–48 h of cocaine self-administration at several time-points post-cocaine (0, 1, 3, 6, 12, 24, 48, and 72 h). Data are expressed as a percent change from baseline threshold levels. Asterisks (*) indicate statistically significant differences between the control and experimental groups. These data show that animals that are allowed extended access to cocaine show elevations in reward thresholds measured by intracranial self-stimulation (see Animal Models for details of intracranial self-stimulation). These increases can be interpreted as dysphoric-like effects and clearly are dose-related. More self-administration is associated with a greater increase in thresholds and longer duration of the increase in thresholds. [From: Markou A, Koob GF. Post-cocaine anhedonia: an animal model of cocaine withdrawal. Neuropsychopharmacology, 1991, (4), 17–26.]

Chronic cocaine administration decreased dopamine neuron firing in the mesocorticolimbic system, consistent with results from microdialysis studies during acute withdrawal. The change in dopamine transmission is dose- and time-dependent. Decreases in neuronal excitability and firing rates in the nucleus accumbens also predominate with repeated cocaine self-administration. Interestingly, nucleus accumbens neurons that increase firing in response to limited or intermittent cocaine self-administration show a resistance to decreased firing during a prolonged, continuous self-administration session. A decrease in ventral tegmental area and nucleus accumbens nondrug-reward-related activity occurs with repeated cocaine administration, consistent with neuropharmacological studies of decreased nondrug (e.g., food) reward with repeated administration.

Few human imaging studies have been done during acute withdrawal from drugs of abuse. However, imaging studies of protracted or prolonged withdrawal, once the signs and symptoms of acute withdrawal have subsided, have documented hypofunction in dopamine pathways, reflected by decreases in D2 receptor expression and decreases in dopamine release, which may contribute to the hypohedonia (i.e., decreased sensitivity to rewarding stimuli) and amotivation reported by subjects with addiction during protracted withdrawal (Figure 4.19).

At the molecular level, the dysphoria and motivational symptoms of withdrawal from cocaine appear to result from downstream signal transduction adaptations in response to excessive drug intake. Early studies in rats demonstrated that chronic cocaine administration (15 mg/kg twice daily for 14 days) upregulated the cyclic adenosine monophosphate (cAMP) pathway in the nucleus accumbens for 16 h after the last injection. Stimulation of protein kinase A (PKA; which activates cAMP response element binding protein [CREB] in the nucleus accumbens) decreased cocaine self-administration. Elevated CREB levels in the nucleus accumbens also decreased cocaine self-administration. Blockade of PKA activity and CREB antagonism in the nucleus accumbens increased cocaine reward in the form of conditioned place preference and increased self-administration.

Figure 4.18 Relationship between elevations in intracranial self-stimulation (ICSS) reward thresholds and cocaine intake escalation. (A) Percentage change from baseline ICSS thresholds. (B) Number of cocaine injections earned during the first hour of each session. Rats were first prepared with bipolar electrodes in either the right or left posterior lateral hypothalamus. One week after surgery, they were trained to respond for electrical brain stimulation. ICSS thresholds (measured in μA) were then assessed. During the screening phase, the rats tested for self-administration were allowed to self-administer cocaine during only 1 h on a fixed-ratio 1 schedule of reinforcement, after which two balanced groups with the same weight, cocaine intake, and ICSS reward thresholds were formed. During the escalation phase, one group had access to cocaine self-administration for only 1 h per day (short access or ShA rats), and the other group had access for 6 h per day (long-access or LgA rats). ICSS reward thresholds were measured in all rats twice per day, 3 h and 17–22 h after each daily self-administration session (ShA and LgA rats). Each ICSS session lasted approximately 30 min. Asterisks (∗) indicate a significant difference from drug-naive or ShA rats. These data show that the overall increase over days in thresholds associated with extended access to cocaine parallels the overall increase over days in drug taking (termed escalation; see Animal Models) associated with extended access. Notice that the increases in thresholds are generally greater 17–22 h after each daily self-administration session compared with 3 h after each daily session and that rats with short access do not show an overall increase in reward thresholds. [From: Ahmed SH, Kenny PJ, Koob GF, Markou A. Neurobiological evidence for hedonic allostasis associated with escalating cocaine use. Nature Neuroscience, 2002, (5), 625–626.]

CREB regulates dynorphin gene expression in vitro and in vivo. Elevated CREB in the nucleus accumbens produces dysphoria-like responses and increases dynorphin expression, and dynorphin is a neuropeptide associated with decreased function of the mesocorticolimbic dopamine system. Psychostimulants also increase the expression of the opioid peptide dynorphin in the nucleus accumbens. Elevated CREB in the nucleus accumbens increased the aversion to cocaine in a conditioned place preference test and produced a depression-like profile in the forced swim test. This “depressive” state in rodents was reversed by a κ opioid receptor antagonist (κ is one of the three opioid receptors: κ preferentially binds the opioid dynorphin, δ preferentially binds the opioid enkephalin, and μ preferentially binds the opioid endorphin; see Opioids). These results suggest that CREB and dynorphin in the nucleus accumbens contribute to the dysphoria associated with withdrawal from chronic cocaine (see Introduction to the Neuropsychopharmacology; Figure 4.20).

Figure 4.19 Brain imaging of a normal control subject and cocaine abuser tested 1 and 4 months after the last cocaine use. The images correspond to the four sequential planes where the basal ganglia are located. The color scale has been normalized to the injected dose. Notice the lower uptake of the image tracer in the cocaine abuser compared with the normal control. Notice also the persistence of the decreased uptake even 4 months after cocaine discontinuation. BNL, Brookhaven National Laboratory; SUNY, State University of New York. [From: Volkow ND, Fowler JS, Wang GJ, Hitzemann R, Logan J, Schlyer DJ, Dewey SL, Wolf AP, Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers, Synapse, 1993, (14),169–177.]

Much research has focused on a monoamine deficiency hypothesis to explain the decreased reward (and by extrapolation, dysphoria in humans) associated with acute psychostimulant withdrawal, but more recent theories have invoked the activation of other brain systems that may act in opposition to brain reward systems. At least two neuropeptide systems, dynorphin (see above) and corticotropin-releasing factor (CRF; see below), are recruited during acute cocaine withdrawal and may contribute to the negative emotional state.

Stressors and the state of stress contribute to acute withdrawal, protracted abstinence, and vulnerability to relapse. As noted above, the HPA axis is activated during psychostimulant dependence and acute withdrawal, and its dysregulation can persist long after the acute withdrawal period. An acute binge of cocaine dramatically increases adrenocorticotropic hormone (ACTH), corticosterone, and CRF in the hypothalamus. In a parallel fashion, brain CRF function outside of the HPA axis in the extended amygdala is activated during acute withdrawal and may mediate the behavioral aspects of stress associated with abstinence. Rats treated repeatedly with cocaine show significant anxiety-like responses following the cessation of chronic administration that are reversed by intracerebroventricular administration of a CRF receptor antagonist. CRF levels increase in the central nucleus of the amygdala during acute withdrawal from drugs of abuse in rodents, and animals that self-administer cocaine continuously for 12 h show a time-related increase in CRF in the amygdala (Figure 4.21). The opioid peptide dynorphin has also been implicated in the anti-reward, dysphoric-like effects of withdrawal from repeated cocaine exposure, in which dynorphin levels increase in the nucleus accumbens and then in turn decrease dopamine release.

Figure 4.20 Regulation of CREB by drugs of abuse. The figure shows a dopamine (DA) neuron in the ventral tegmental area (VTA) innervating a class of γ-aminobutyric acid (GABA) projection neurons from the nucleus accumbens (NAc) that expresses dynorphin (DYN). Dynorphin constitutes a negative feedback mechanism in this circuit: dynorphin, released from terminals of the NAc neurons, acts on κ-opioid receptors located on nerve terminals and cell bodies of the dopamine neurons to inhibit their functioning. Chronic exposure to cocaine or opiates upregulates the activity of this negative feedback loop through upregulation of the cAMP pathway, activation of CREB, and induction of dynorphin. cAMP, cyclic adenosine monophosphate; CREB, cyclic adenosine monophosphate response element binding protein; DR, dopamine receptor; OR, opioid receptor. [Modified from: Carlezon WA Jr, Nestler EJ, Neve RL. Herpes simplex virus-mediated gene transfer as a tool for neuropsychiatric research. Critical Reviews in Neurobiology, 2000, (14), 47–67; see also Nestler EJ. Molecular basis of long-term plasticity underlying addiction. Nature Reviews Neuroscience, 2001, (2),119–128.]

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