Cocaine Increases Dopaminergic Neuron and Motor Activity via Midbrain α1 Adrenergic Signaling

Abstract

Cocaine reinforcement is mediated by increased extracellular dopamine levels in the forebrain. This neurochemical effect was thought to require inhibition of dopamine reuptake, but cocaine is still reinforcing even in the absence of the dopamine transporter. Here, we demonstrate that the rapid elevation in dopamine levels and motor activity elicited by cocaine involves α1 receptor activation within the ventral midbrain. Activation of α1 receptors increases dopaminergic neuron burst firing by decreasing the calcium-activated potassium channel current (SK), as well as elevates dopaminergic neuron pacemaker firing through modulation of both SK and the hyperpolarization-activated cation currents (Ih). Furthermore, we found that cocaine increases both the pacemaker and burst-firing frequency of rat ventral-midbrain dopaminergic neurons through an α1 adrenergic receptor-dependent mechanism within the ventral tegmental area and substantia nigra pars compacta. These results demonstrate the mechanism underlying the critical role of α1 adrenergic receptors in the regulation of dopamine neurotransmission and behavior by cocaine.

A new exposure model to evaluate smoked illicit drugs in rodents: A study of crack cocaine

“…We found that crack induced hyperlocomotion, as previously reported by other groups using different inhalational crack-cocaine models (Areal et al, 2015). Many hypotheses of the exact mechanism of action by which cocaine promotes locomotor activity changes exist, including midbrain α1 adrenergic signaling (Goertz et al, 2014), dopamine D3 receptors (Galaj, Ananthan, Saliba, & Ranaldi, 2014), and a cocaine-andamphetamine-regulated transcript (CART) peptide (Job, Perry, Shen, & Kuhar, 2014). The present model demonstrated the efficacy of the Table 2 Food consumption and body weight gain of rats exposed to the smoke of 250 mg of crack cocaine or air twice daily for 28 days.…”

Specificity and impact of adrenergic projections to the midbrain dopamine system

“…Inhibition of firing rate is also evoked by the β adrenoceptor agonist, isoproterenol (Aghajanian and Bunney, 1977; White and Wang, 1984). Contrary to the inhibitory effects of α 2 and β adrenoceptors, activation of α1 adrenoceptors by phenylephrine increased both firing rate and burst firing of DA neurons (Goertz et al, 2015). …”

“…Two conductances are affected by α 1 adrenoceptors activation, calcium-activated potassium channel currents are decreased and hyperpolarization-activated cation currents are increased. Acting on theses conductances, NE increased intra-burst frequency of aspartate-evoked burst firing (Goertz et al, 2015). …”

“…Similarly, NE and UK14304 activate a non-specific cationic conductance that produced a small inward current (Cathala et al, 2002). In conjunction, these two postsynaptic actions render DA neurons more excitable and might play a role in the transition to burst firing observed with systemic administration of α 2 antagonists (Grenhoff and Svensson, 1988; Grenhoff and Svensson, 1989) These action of α 2 adrenoceptors may also synergize with the postsynaptic activation of α 1 adrenoceptors (Goertz et al, 2015). …”

Gene Set Enrichment Analysis (GSEA) of Upregulated Genes in Cocaine Addiction Reveals miRNAs as Potential Therapeutic Agents

“…Another study has revealed that a α1 receptor mediates the increase in dopamine levels elicited by cocaine [3].…”