We report that intra-PLC modulation of CB1 receptor transmission bidirectionally controls the motivational valence of opiate-related behavioral conditioning

We report that intra-PLC modulation of CB1 receptor transmission bidirectionally controls the motivational valence of opiate-related behavioral conditioning. (PLC) division of the mPFC bidirectionally regulates the motivational valence of opiates; whereas CB1 activation switched morphine reward signaling into an aversive stimulus, blockade of CB1 transmission potentiated the rewarding properties of normally sub-reward threshold conditioning doses of morphine. Both of these effects were dependent upon DA transmission as systemic blockade of DAergic transmission prevented CB1-dependent modulation of morphine reward and aversion behaviors. We further report that CB1-mediated intra-PLC opiate motivational signaling is usually mediated through a -opiate receptor-dependent reward Ubenimex pathway, or a -opiate receptor-dependent aversion pathway, directly within the ventral tegmental area. Our results provide evidence for a novel CB1-mediated motivational valence switching mechanism within the PLC, controlling dissociable subcortical reward and aversion pathways. Introduction In the mammalian brain, cannabinoid CB1 receptor and mesolimbic dopamine (DA) transmission functionally interact with opiate-receptor substrates during the processing of motivationally salient learning and memory (Tanda et al., 1997; Rodrguez De Fonseca et al., 2001). The interconnected ventral tegmental area (VTA) and medial prefrontal cortex (mPFC) contain high levels of CB1 receptors. CB1 receptor transmission within these regions can potently modulate rewarding and aversive motivational behaviors and memory formation (Laviolette and Grace, 2006; Zangen et al., 2006; Tan et al., 2010). For example, modulation of CB1 transmission within the prelimbic cortical (PLC) division of the mPFC, increases the emotional salience of fear-related stimuli (Laviolette and Grace, 2006; Tan et al., 2010). In addition, considerable evidence demonstrates functional interactions between CB1 transmission and subcortical DAergic signaling. For example, -9-tetrahydrocannabinol (THC) increases glutamate levels within the mPFC and activates downstream DAergic neuronal activity in the mesolimbic pathway (Diana et al., 1998; Pistis et al., 2001, 2002). Furthermore, extracellular recording studies within the VTA have exhibited that Ubenimex CB1 receptor Ubenimex activation increases the spontaneous activity of subcortical DA neuronal populations (French et al., 1997). Although the euphorigenic effects of opiate-class drugs are well established, similar to many other drugs of abuse, opiates also possess aversive stimulus properties (Bechara and van der Kooy, 1987). The VTA serves as a critical neural region for the processing of opiate-related motivational information (Bozarth and Wise, 1981; Laviolette et al., 2004). Within the VTA, opiate-related motivational processing is usually mediated via heterogeneous opiate-receptor populations. Thus, whereas opiates primarily produce rewarding Ubenimex effects via functional interactions with -opiate receptor (MOR) substrates (Gysling and Wang, 1983; Johnson and North, 1992), activation of -opiate receptor (KOR) subtypes is usually linked to the aversive stimulus effects of opioids (Bechara and van der Kooy, 1987; Shippenberg and Elmer, 1998; Davis et al., 2009). Anatomically, MOR-sensitive substrates in the VTA predominantly project to the basolateral nucleus of the amygdala (BLA) whereas KOR-sensitive neuronal substrates predominantly project to the nucleus accumbens (NAc; Ford et al., 2006), suggesting a functional segregation within opiate-dependent motivational signaling originating from the VTA. Furthermore, efferents from the mPFC to VTA neuronal populations modulate subcortical DA transmission within FLJ14936 the mesolimbic pathway, including via direct inputs to DAergic neurons within the VTA (Carr and Sesack, 2000a). Nevertheless, how CB1 transmission within the mPFC may modulate opiate-related motivational information through interactions with subcortical DA substrates is not currently known. Using an unbiased conditioned place preference (CPP) procedure, we examined how pharmacological modulation of CB1 transmission specifically within the PLC division of the mPFC may influence opiate-related reward learning and memory processing. We report that intra-PLC modulation of CB1 receptor transmission bidirectionally controls the motivational valence of opiate-related behavioral conditioning. Whereas CB1 receptor activation switched the motivational valence of morphine from rewarding to strongly aversive, pharmacological blockade of intra-PLC CB1 receptor transmission strongly increased the reward salience of normally sub-reward threshold conditioning doses of morphine. Furthermore, we demonstrate that intra-PLC CB1 transmission bidirectionally controls opiate motivational valence through dissociable MOR versus KOR-dependent substrates, directly within the VTA. Materials and Methods Animals and surgery. All experimental procedures were.