Brain Structures and Functions Relevant to the Three Stages of the Addiction Cycle

Withdrawal/Negative Affect Stage - Extended Amygdala

The withdrawal/negative affect stage involves key elements of the extended amygdala. The extended amygdala consists primarily of three structures: the central nucleus of the amygdala, bed nucleus of the stria terminalis, and a transition zone in the nucleus accumbens shell (for those interested in learning more about the anatomy of this structure, see Alheid et al., 1995). The extended amygdala can also be divided into two major divisions: central division and medial division. These two divisions have important anatomical structural differences and dissociable afferent and efferent connections.

The central division of the extended amygdala includes the central nucleus of the amygdala, central sublenticular extended amygdala, lateral bed nucleus of the stria terminalis, and a transition area in the medial and caudal portions of the nucleus accumbens (Figure 2.21). These structures in the central division have similar morphology (structure), immunohistochemistry (proteins associated with neurotransmission), and connectivity, and they receive afferent connections from limbic cortices, the hippocampus, the basolateral amygdala, the midbrain, and the lateral hypothalamus. The efferent connections from this complex include the posterior medial (sublenticular) ventral pallidum, ventral tegmental area, various brainstem projections, and a considerable projection to the lateral hypothalamus. The extended amygdala includes major components of the brain stress systems associated with the negative reinforcement of dependence. The central division has also been found to receive cortical information and regulate the hypothalamic-pituitary-adrenal stress axis.

Figure 2.20 Simplified schematic of converging acute actions of drugs of abuse on the ventral tegmental area (VTA) and nucleus accumbens (NAc). Drugs of abuse, despite diverse initial actions, produce some common effects on the VTA and NAc. Stimulants directly increase dopaminergic transmission in the NAc. Opiates do the same indirectly: they inhibit γ-aminobutyric acid (GABA) interneurons in the VTA, which disinhibits VTA dopamine neurons. Opiates also directly act on opioid receptors on NAc neurons, and opioid receptors, like dopamine (DA) D2 receptors, signal via Gi proteins. Hence, the two mechanisms converge within some NAc neurons. The actions of the other drugs remain more conjectural. Nicotine seems to activate VTA dopamine neurons directly by stimulating nicotinic cholinergic receptors on those neurons and indirectly by stimulating its receptors on glutamatergic nerve terminals that innervate dopamine cells. Alcohol, by promoting GABAA receptor function, may inhibit GABAergic terminals in the VTA and hence disinhibit VTA dopamine neurons. It may similarly inhibit glutamatergic terminals that innervate NAc neurons. Many additional mechanisms (not shown) are proposed for alcohol. Cannabinoid mechanisms seem complex, and they involve the activation of cannabinoid CB1 receptors (which, like D2 and opioid receptors, are Gi-linked) on glutamatergic and GABAergic nerve terminals in the NAc and on NAc neurons themselves. Phencyclidine (PCP) may act by inhibiting postsynaptic NMDA glutamate receptors in the NAc. Finally, there is some evidence that nicotine and alcohol may activate endogenous opioid pathways and that these and other drugs of abuse (such as opiates) may activate endogenous cannabinoid pathways (not shown). PPT/LDT, peduncular pontine tegmentum/lateral dorsal tegmentum. [Modified with permission from Nestler EJ. Is there a common molecular pathway for addiction? Nature Neuroscience, 2005, (8), 1445-1449.]

The medial division of the extended amygdala consists of the medial bed nucleus of the stria terminalis, medial nucleus of the amygdala, and medial sublenticular extended amygdala. It appears to be more involved in sympathetic (fight-or-flight) and physiological responses and receives olfactory information. Most motivational experimental manipulations that modify the reinforcing effects of drugs of abuse through both positive and negative reinforcement appear to do so by impacting the central division : central nucleus of the amygdala and lateral bed nucleus of the stria terminalis.

Negative reinforcement occurs when the removal of an aversive event increases the probability of a response. In the case of addiction, negative reinforcement involves the removal of a negative emotional state associated with withdrawal, such as dysphoria, anxiety, irritability, sleep disturbances, and hyperkatifeia. Such negative emotional states are thought to derive from two sources: within-system changes and between-system changes.

Figure 2.21 Brain regions recruited during the withdrawal/negative affect stage of the addiction cycle. [Modified with permission from Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology Reviews, 2010, (35), 217-238 (erratum: 35: 1051).]

Within-system neuroadaptations in the reward system. During the development of dependence, the brain systems in the ventral striatum that are important for the acute reinforcing effects of drugs of abuse, such as dopamine and opioid peptides, become compromised and begin to contribute to a negative reinforcement mechanism, in which the drug is administered to restore the decreased function of the reward systems. Within-system changes within medium spiny neurons in the nucleus accumbens during acute withdrawal include decreased long-term potentiation, increased trafficking of AMPA receptors to the surface of neurons, increased adenylate cyclase activity, and increased CREB phosphorylation. Some of these changes may precede or drive between-system neuroadaptations. Neurochemical evidence of within-system neuroadaptations includes the observation that chronic administration of all drugs of abuse decreases the function of the mesocorticolimbic dopamine system. Decreases in neuronal firing rate in the mesocorticolimbic dopamine system and decreases in serotonergic neurotransmission in the nucleus accumbens occur during drug withdrawal. Decreases in the firing of dopamine neurons in the ventral tegmental area have also been observed during withdrawal from opioids, nicotine, and ethanol. Imaging studies in drug-addicted humans have also consistently shown long-lasting decreases in the number of dopamine D2 receptors in drug abusers compared with controls. Additionally, drug abusers have reduced dopamine release in response to a pharmacological challenge with drugs. Decreases in the number of dopamine D2 receptors, coupled with the decrease in dopaminergic activity in cocaine, nicotine, and alcohol abusers, results in decreased sensitivity of reward (incentive salience) circuits to stimulation by natural reinforcers. These findings suggest an overall reduction of the sensitivity of the dopamine component of reward circuitry to natural reinforcers and other drugs in drug-addicted individuals (Figure 2.22).

Between-system neuroadaptations in the extended amygdala. The neuroanatomical substrates for many of the motivational effects of drug dependence may also involve between-system neuroadaptations that occur in the ventral striatum and extended amygdala, which includes neurotransmitters associated with the brain stress systems involved in the negative reinforcement of dependence. Several neurotransmitters localized to the extended amygdala, such as CRF, norepinephrine, and dynorphin, are activated during states of stress and anxiety and during drug withdrawal (Figure 2.22). Antagonists of these neurochemical systems selectively block drug self-administration in dependent animals, suggesting a key role for these neurotransmitters in the ventral striatum and extended amygdala in the negative reinforcement associated with drug dependence.

To summarize the roles of positive and negative reinforcement in addiction, the brain reward (incentive salience) system is implicated in both the positive reinforcement produced by drugs of abuse and the negative reinforcement produced by dependence, mediated by dopamine in the ventral striatum. Neuropharmacological studies in animal models of addiction have provided evidence of the dysregulation of specific neurochemical mechanisms in specific positive reinforcement (reward) systems in the ventral striatum (dopamine, opioid peptides, and GABA). Importantly, however, brain stress systems (CRF, dynorphin, and norepinephrine) are also recruited in the extended amygdala to contribute to the negative motivational state associated with drug abstinence, which in turn drives an additional source of negative reinforcement in drug addiction.

Figure 2.22 Diagram of the hypothetical "within-system" and "between-system" changes that lead to the "dark side" of addiction. (Top) Circuitry for drug reward with major contributions from mesolimbic dopamine and opioid peptides that converge on the nucleus accumbens. During the binge/intoxication stage of the addiction cycle, the reward circuitry is excessively engaged. (Middle) Such excessive activation of the reward system triggers "within-system" neurobiological adaptations during the withdrawal/negative affect stage, including activation of cyclic adenosine monophosphate (cAMP) and cAMP response element binding protein (CREB), downregulation of dopamine D2 receptors, and decreased firing of ventral tegmental area (VTA) dopaminergic neurons. (Bottom) As dependence progresses and the withdrawal/negative affect stage is repeated, two major "between-system" neuroadaptations occur. One is activation of dynorphin feedback that further decreases dopaminergic activity. The other is recruitment of extrahypothalamic norepinephrine (NE)-corticotropin-releasing factor (CRF) systems in the extended amygdala. Facilitation of the brain stress system in the prefrontal cortex is hypothesized to exacerbate the between-system neuroadaptations while contributing to the persistence of the dark side into the preoccupation/anticipation stage of the addiction cycle. [Taken with permission from Koob GF. Negative reinforcement in drug addiction: the darkness within. Current Opinion in Neurobiology, 2013, (23), 559-563.]

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