Effects of alprazolam and cannabinoid-related compounds in an animal model of panic attack.

Selective stimulation of carotid chemoreceptors by intravenous infusion of low doses of potassium cyanide (KCN) produces short-lasting escape responses that have been proposed as a model of panic attack. In turn, preclinical studies suggest that facilitation of the endocannabinoid system attenuate panic-like responses. Here, we compared the effects of cannabinoid-related compounds to those of alprazolam, a clinically effective panicolytic, on the duration of the escape reaction induced by intravenous infusion of KCN (80µg) in rats. Alprazolam (1, 2, 4mg/kg) decreased escape duration at doses that did not alter basal locomotor activity. URB597 (0.1, 0.3, 1mg/kg; inhibitor of anandamide hydrolysis), WIN55,212-2 (0.1, 0.3, 1mg/kg; synthetic cannabinoid), arachidonoyl-serotonin (1, 2.5, 5mg/kg; dual TRPV1 and anandamide hydrolysis inhibitor), and cannabidiol (5, 10, 20, 40mg/kg; a phytocannabinoid) did not decrease escape duration. Alprazolam also prevented the increase in arterial pressure evoked by KCN, while bradycardia was unchanged. This study reinforces the validity of the KCN-evoked escape as a model of panic attack. However, it does not support a role for the endocannabinoid system in this behavioral response. These results might have implications for the screening of novel treatments for panic disorder.

Long-lasting marked inhibition of periaqueductal gray-evoked defensive behaviors in inescapably-shocked rats.

Clinical evidence suggests that depression and trauma predispose the subject to panic. Accordingly, here we examined the late effects of uncontrollable stress, a presumptive model of depression and/or traumatic disorder, on panic-like behaviors evoked by electrical stimulation of the dorsal periaqueductal gray (DPAG). Changes in anxiety and depression were also assessed in the elevated plus-maze (EPM) and forced-swimming test (FST), respectively. Rats with electrodes in the DPAG were subjected to a 7-day shuttle-box one-way escape yoked training with foot-shocks either escapable (ES) or inescapable (IS). The day after the end of one-way escape training, rats were trained in a two-way escape novel task (test-session) to ascertain the effectiveness of uncontrollable stress. DPAG stimulations were carried out in an open field, both before the escape training and 2 and 7 days after it, and EPM and FST were performed on the 8th and 10th days afterwards, respectively. Controls were either trained with fictive shocks (FS) or subjected to intracranial stimulations only. Although the ES rats performed significantly better than the IS group in the two-way escape task, groups did not differ with respect to either the anxiety or depression scores. Unexpectedly, however, IS rats showed a marked attenuation of DPAG-evoked freezing and flight behaviors relative to both the ES and FS groups, 2 and 7 days after one-way escape training. The conjoint inhibition of passive (freezing) and active (flight) defensive behaviors suggests that IS inhibits a DPAG in-built motivational system that may be implicated in depressed patients' difficulties in coping with daily-life stress.

Elevated T-maze evaluation of anxiety and memory effects of NMDA/glycine-B site ligands injected into the dorsal periaqueductal gray matter and the superior colliculus of rats.

Rat behaviors in the elevated T-maze (ETM) were evaluated following tectum microinjections of either glycine (GLY, 1, 10, 80 and 120 nmol) or d-serine (D-SER, 160 and 320 nmol), the putative endogenous agonists of GLY-B site at NMDA receptor, or the respective antagonist 7-chloro-kynurenic acid (7CK, 8 nmol). ETM performance was appraised by two validated scores of anxiety, i.e., the inhibitory avoidance duration (AD) and risk assessment behavior, and two scores derived from a newly developed approach to inhibitory avoidance learning curves, i.e., the learning median number of trials (T50) and avoidance variability (standard deviation of learning curve). Effects on aversive memory consolidation were assessed through changes in the AD measured 48 h after the full-acquisition of inhibitory avoidance. Drug effects were compared to those of vehicle. In most cases, microinjection of GLY-B site agonists into the dorsal periaqueductal gray (dPAG) produced increases in AD, which were compatible with an increase in anxiety. However, neither the intra-periaqueductal injection of 80 nmol GLY, nor that of 160 nmol D-SER, increased the AD. On the other hand, these microinjections invariably produced a parallel left shift in avoidance learning curves, thereby reducing the T50 but not the variability. Effects of 120 nmol GLY on AD and T50 were both antagonized by a previous microinjection of 7CK into the dPAG. The inverse relationship of AD and T50 suggests that increases in the anxiety level reduce the number of trials required for the acquisition of inhibitory avoidance. The above data also suggest the higher consistency and drug sensitivity of T50 as compared to the AD. In turn, whereas the microinjection of 120 nmol GLY into the superior colliculus (SC) did not affect the T50, it increased the AD. On the other hand, there was an increase in avoidance variability following the microinjection of either 120 nmol GLY into the SC or 8 nmol 7CK into the dPAG. Therefore, the GLY-B receptors within these structures seem to play opposite roles on avoidance variability. In contrast, neither of these treatments changed T50. Finally, whereas the risk assessment was solely decreased by the microinjection of GLY into the SC, the aversive memory was only impaired by the microinjection of 7CK into the dPAG. Overall, these data suggest that NMDA/GLY-B receptors of dPAG mediate both anxiety and aversive memory, while those in the SC are most likely involved with attention and visuomotor components of risk assessment behavior.