Increasing endocannabinoid levels in the ventral pallidum restore aberrant dopamine neuron activity in the subchronic PCP rodent model of schizophrenia

Abstract

Background: Schizophrenia is a debilitating disorder that affects 1% of the US population. While the exogenous administration of cannabinoids such as tetrahydrocannabinol is reported to exacerbate psychosis in schizophrenia patients, augmenting the levels of endogenous cannabinoids has gained attention as a possible alternative therapy to schizophrenia due to clinical and preclinical observations. Thus, patients with schizophrenia demonstrate an inverse relationship between psychotic symptoms and levels of the endocannabinoid anandamide. In addition, increasing endocannabinoid levels (by blockade of enzymatic degradation) has been reported to attenuate social withdrawal in a preclinical model of schizophrenia. Here we examine the effects of increasing endogenous cannabinoids on dopamine neuron activity in the sub-chronic phencyclidine (PCP) model. Aberrant dopamine system function is thought to underlie the positive symptoms of schizophrenia.

Methods: Using in vivo extracellular recordings in chloral hydrate-anesthetized rats, we now demonstrate an increase in dopamine neuron population activity in PCP-treated rats.

Results: Interestingly, endocannabinoid upregulation, induced by URB-597, was able to normalize this aberrant dopamine neuron activity. Furthermore, we provide evidence that the ventral pallidum is the site where URB-597 acts to restore ventral tegmental area activity.

Conclusions: Taken together, we provide preclinical evidence that augmenting endogenous cannabinoids may be an effective therapy for schizophrenia, acting in part to restore ventral pallidal activity.

Keywords: cannabinoids; hippocampus; phencyclidine; schizophrenia; ventral pallidum.

Figure 1.

Representative photomicrographs demonstrating cannula placements in the ventral pallidum (A), an electrode track in the VTA (B), and a stimulating electrode located in the ventral hippocampus (C). The left side of each panel depicts the approximate location based on the atlas of Paxinos and Watson (Paxinos and Watson, 2009).

Figure 2.

Acute URB-597 reverses aberrant dopamine neuron activity in the PCP-treated rat. (A) PCP-treated rats display increases in dopamine neuron population activity, which are reversed by systemic URB-597 administration. No changes in the average firing rate (B) or average percent burst firing (C) were observed. *significant difference from vehicle-treated saline rats; †significant difference from vehicle-treated PCP rats (two-way ANOVA).

Figure 3.

Chronic URB-597 reverses aberrant dopamine neuron activity in the PCP-treated rat. (A) PCP-treated rats display increases in dopamine neuron population activity, which are reversed by the chronic administration of URB-597. Small but significant alterations in the average firing rate were observed (B), with no effect on the average percent burst firing (C). *significant difference from vehicle-treated saline rats; †significant difference from vehicle-treated PCP rats; and #significant difference from URB-597–treated saline rats (two-way ANOVA).

Figure 4.

TTX inactivation of the vHipp reverses aberrant dopamine neuron activity in the PCP rat. Intra-vHipp TTX administration decreases dopamine neuron population activity (A) without affecting average firing rate (B) or burst firing (C) in PCP-treated rats. *Significant difference between groups (student’s t-test)

Figure 5.

Schematic demonstrating the aberrant vHipp regulation of dopamine neuron activity in the PCP model of schizophrenia. Aberrant vHipp activity drives the nucleus accumbens (NAc) that, in turn, inhibits spontaneous activity within the ventral pallidum (VP). This results in the disinhibition of VTA dopamine neurons and an increase in the number of spontaneously-active neurons.

Figure 6.

URB-597 inhibits the vHipp regulation of the VP. Stimulation of the vHipp induces a long-latency inhibition of spontaneous activity in VP neurons (A). This results in a decreased number of action potentials when compared to an equivalent pre-stimulus time (B). URB-597 attenuates this vHipp regulation of the VP. †main effect of treatment (two-way ANOVA); *significant difference between groups (Mann Whitney Rank Sum test).

Figure 7.

Intra-VP URB-597 reverses aberrant dopamine neuron activity in the PCP-treated rat. (A) The increase in dopamine neuron population activity observed in PCP-treated rats is not present following the direct administration of URB-597 into the VP (A). Consistent with the acute systemic administration of URB-597 detailed above, no effects were observed in either the average firing rate (B) or average percent burst firing (C). *significant difference from vehicle-treated saline rats (two-way ANOVA).