Pharmacotherapeutics directed at deficiencies associated with cocaine dependence: focus on dopamine, norepinephrine and glutamate

Abstract

Much effort has been devoted to research focused on pharmacotherapies for cocaine dependence yet there are no FDA-approved medications for this brain disease. Preclinical models have been essential to defining the central and peripheral effects produced by cocaine. Recent evidence suggests that cocaine exerts its reinforcing effects by acting on multiple neurotransmitter systems within mesocorticolimibic circuitry. Imaging studies in cocaine-dependent individuals have identified deficiencies in dopaminergic signaling primarily localized to corticolimbic areas. In addition to dysregulated striatal dopamine, norepinephrine and glutamate are also altered in cocaine dependence. In this review, we present these brain abnormalities as therapeutic targets for the treatment of cocaine dependence. We then survey promising medications that exert their therapeutic effects by presumably ameliorating these brain deficiencies. Correcting neurochemical deficits in cocaine-dependent individuals improves memory and impulse control, and reduces drug craving that may decrease cocaine use. We hypothesize that using medications aimed at reversing known neurochemical imbalances is likely to be more productive than current approaches. This view is also consistent with treatment paradigms used in neuropsychiatry and general medicine.

Fig. 1

Hypothetical dopamine (DA) synapse demonstrating deficiencies observed in cocaine-dependent individuals (see Table 1) and primary targets of potential pharmacotherapies to reverse these deficiencies. (1) SR-AMPH/SR-METH, modafinil and methylphenidate increase DA neurotransmission and DA levels that are low (2) in cocaine-dependent individuals. (3) Chronic methylphenidate may increase low levels of D2/D3 receptors and likely antagonize cocaine’s effects by occupying the DAT (4). (5) Prazosin and doxazosin target noradrenergic α1 receptors that control cocaine-induced DA neurotransmission and block cocaine-induced reinstatement of cocaine self-administration in animals. Preliminary studies in humans show that doxazosin also attenuates cocaine’s subjective effects. Disulfiram also alters central DA but its primary therapeutic effects are due to profound decreases in NE that would activate α1 receptors (5).

Fig. 2

Hypothetical noradrenergic (NE) synapse demonstrating dysregulated neurotransmission observed in cocaine-dependent individuals and primary targets of potential pharmacotherapies to ameliorate these abnormalities. (1) Disulfiram inhibits the enzyme DβH responsible for the conversion of DA to NE profoundly decreasing central NE that is presumably increased (2) in cocaine-dependent individuals since NET numbers (3) are also increased in parts of the brain involved in stress. SR-AMPH/SR-METH more potently increase NE (2) than DA and likely through chronic treatment produce tolerance to cocaine’s reinforcing effects. (4) Prazosin and doxazosin are NE α1 antagonists and block drug-induced reinstatement of cocaine-seeking. Disulfiram treatment, which depletes central NE, has similar effects to prazosin and doxazosin on reinstatement. Modafinil and methylphenidate also alter NE levels that may play a role in their therapeutic effects.

Fig. 3

Hypothetical glutamatergic (GLU) synapse with juxtaposed glial cell demonstrating abnormalities observed in cocaine-dependent individuals and primary targets of potential pharmacotherapies to address these deficits. (1) Normal GLU neurotransmission is compromised in cocaine-dependent individuals. Chronic cocaine down-regulates glial glutamate transporter-1 (GLT-1) and the cystine-glutamate exchanger (2) and disrupts mGluR2/3 and mGluR5 (3)(4) influence on GLU tone and neuroplasticity. N-acetylcysteine restores functional GLT-1 and the exchanger in turn, normalizing GLU tone by acting on mGluR2/3 and mGluR5. Modafinil also increases GLU neurotransmission and blocks reinstatement of cocaine seeking and reinstatement of drug-induced conditioning. Modafinil’s ability to block drug-induced conditioning is mediated by mGluR2/3 receptors. (5) Noradrenergic α1 receptors on GLU terminals in the NAc alter cocaine’s behavioral effects. Prazosin and doxazosin antagonists may exert their therapeutic effect partly by decreasing GLU in response to cocaine. Disulfiram treatment, which depletes central NE, may also reduce GLU influence on DA cells required for cocaine’s effects.