Involvement of Noradrenergic Neurotransmission in the Stress- but not Cocaine-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Role for β-2 Adrenergic Receptors

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate

Reduced Spontaneous Eye Blink Rates in Recreational Cocaine Users: Evidence for Dopaminergic Hypoactivity

Chronic use of cocaine is associated with a reduced density of dopaminergic D2 receptors in the striatum, with negative consequences for cognitive control processes. Increasing evidence suggests that cognitive control is also affected in recreational cocaine consumers. This study aimed at linking these observations to dopaminergic malfunction by studying the spontaneous eyeblink rate (EBR), a marker of striatal dopaminergic functioning, in adult recreational users and a cocaine-free sample that was matched on age, race, gender, and personality traits. Correlation analyses show that EBR is significantly reduced in recreational users compared to cocaine-free controls, suggesting that cocaine use induces hypoactivity in the subcortical dopamine system

Dopamine and inhibitory action control: evidence from spontaneous eye blink rates

The inhibitory control of actions has been claimed to rely on dopaminergic pathways. Given that this hypothesis is mainly based on patient and drug studies, some authors have questioned its validity and suggested that beneficial effects of dopaminergic stimulants on response inhibition may be limited to cases of suboptimal inhibitory functioning. We present evidence that, in carefully selected healthy adults, spontaneous eyeblink rate, a marker of central dopaminergic functioning, reliably predicts the efficiency in inhibiting unwanted action tendencies in a stop-signal task. These findings support the assumption of a modulatory role for dopamine in inhibitory action control