Brain-Derived Neurotrophic Factor Signaling Modulates Cocaine Induction of Reward-Associated Ultrasonic Vocalization in Rats

Abstract

Cocaine exhibits high liability for inducing addictive behaviors, but the mechanisms of neuroplasticity underlying the behavioral effects remain unclear. As a crucial mediator of neuroplasticity in diverse functional models, brain-derived neurotrophic factor (BDNF) could contribute to the mechanisms of addictionrelated neuroplasticity. Here, we addressed the hypothesis that cocaine increases synaptic dopamine, which induces BDNF protein expression to initiate addiction-related behavior in the rat. An enzyme-linked immunosorbent assay was used to measure BDNF protein expression in rat striatal tissues. For behavioral readout, we used a noninvasive measurement system to measure the emission of 50-kHz ultrasonic vocalization (USV), a response that correlates with electrical brain stimulation and conditioned place preference behavior in rodents. A single injection of cocaine significantly increased BDNF protein expression, but this effect was not further augmented by repeated cocaine administration. A single administration of cocaine elicited significant and dose-related USV responses, and the magnitude of the behavior increased with repeated drug administration. R-(ϩ)-7- 3,4,5-tetrahydro-1H-3-benzazepine (SCH23390), but not raclopride, significantly attenuated cocaine-induced BDNF protein expression, whereas either the D 1 -like or D 2 -like receptor antagonist blocked cocaine-induced USV behavior. Furthermore, significant USV behavior was elicited by the nonselective dopamine agonist, apomorphine, but not by agonists that are selective for D 1 -like or D 2 -like receptors. Intracerebroventricular injection of the neurotrophin TrkB receptor inhibitor, K252a, blocked cocaine-induced USV behavior but not locomotor activity. These results suggest that neurotrophin signaling downstream of dopamine receptor function probably constitutes a crucial link in cocaine induction of USV behavior and may contribute to the mechanisms underlying the development of addiction-related behaviors.

Acute Cocaine Induces Fast Activation of D1 Receptor and Progressive Deactivation of D2 Receptor Striatal Neurons:In VivoOptical Microprobe [Ca2+]iImaging

“…For the groups in Exp3 (Table 1), the mice were injected (ip) with either D1R antagonist (a bolus dose of 0.075mg/kg SCH23390, Sigma Aldrich) or D2R antagonist (a bolus dose of 3mg/kg raclopride, Sigma Aldrich), which were administrated ip at 30min before cocaine injection in the Drd1-EGFP transgenic mice and Drd2-EGFP transgenic mice, respectively. We chose SCH23390 and raclopride since these are validated antagonists for D1R and D2R respectively, and we selected doses that have been commonly used in preclinical studies (Doherty et al, 2008; Lange et al 2011; Choleris et al 2011; Williams et al 2010). …”

α- and β-Adrenergic Receptors Differentially Modulate the Emission of Spontaneous and Amphetamine-Induced 50-kHz Ultrasonic Vocalizations in Adult Rats

“…Acute IP cocaine administration reportedly increases 50-kHz call rate (Williams and Undieh, 2010). Previous studies using IV cocaine have been performed in the context of self-administration (and its anticipation) and sensitization (Barker et al, 2010;Browning et al, 2011;Maier et al, 2010).…”

“…In addition, AMPH has been shown to modify the 50-kHz call 'profile' (ie, the relative proportion of different call subtypes), preferentially increasing trills and decreasing flat calls (Wright et al, 2010). Cocaine administration is also reported to promote 50-kHz calling (Barker et al, 2010;Browning et al, 2011;Maier et al, 2010;Mu et al, 2009;Williams and Undieh, 2010), and a recent report shows a preferential increase in FM 50-kHz calls in response to intraperitoneal (IP) cocaine (Meyer et al, 2011). However, whether intravenous (IV) cocaine mimics the AMPH-induced shift in the call profile has not been reported.…”

Brain-Derived Neurotrophic Factor Controls Cannabinoid CB1 Receptor Function in the Striatum

“…5B-D). cocaine exposure can both increase (Williams and Undieh, 2010) or decrease (Angelucci et al, 2007) BDNF levels. Our neurophysiological data show that BDNF contrasts the effects of cocaine on CB 1 R (GABA) sensitivity in the striatum, thus suggesting that DA-mediated CB 1 R (GABA) upregulation can be mediated by a negative effect on striatal BDNF levels.…”