Schizophrenia is a debilitating and costly mental illness. Many patients do not respond well to currently available treatments, and adverse side effects are common. Cannabidiol (CBD), a natural component of the Cannabis Sativa plant, has been shown to have a number of therapeutic qualities, including potential as a new antipsychotic. Although CBD has been used in several different models of schizophrenia, previous research has failed to consider possible sex differences in responsiveness to the compound. The present research therefore used both male and female rats in the widely used ketamine model of schizophrenia. PVG/C Hooded rats were randomly assigned to one of four experimental conditions: a saline only control group (saline injection followed by second saline injection; N = 6M, 6F); ketamine only group (ketamine injection followed by saline injection; N = 6M, 6F); cannabidiol low dose group (ketamine injection followed by a cannabidiol injection of 10mg/kg; N = 6M, 6F); and a cannabidiol high dose group (ketamine injection followed by a cannabidiol injection of 20mg/kg; N = 6M, 6F). Behavioural testing occurred in a Y-maze and open-field, where both normal and stereotyped behaviours were recorded, as well as locomotor activity and spatial memory. Ketamine successfully induced stereotypy but failed to induce hyperlocomotion. Findings support the potential antipsychotic effects of CBD, particularly for reducing stereotypic behaviour in females. Results found data trends that suggest sex differences in responsiveness to CBD when administered with ketamine, although further research is needed due to lack of statistical significance.

Dopamine (DA) neurons are implicated in the hyperlocomotion of neonatal 6-hydroxydopamine (6-OHDA)-lesioned rats, an animal model of attention deficit hyperactivity disorder (ADHD). Because serotonin (5-HT) neurons mediate some DA agonist effects, we investigated the possible role of 5-HT neurons on locomotor activity. Rats were treated at 3 days after birth with vehicle or 6-OHDA (134 μg ICV; desipramine pretreatment, 20 mg/kg IP, 1 h), and at 10 weeks with vehicle or 5,7-dihydroxytryptamine (5,7-DHT; 75 μg ICV; pretreatment with desipramine and pargyline, 75 mg/kg IP, 30 min), to destroy DA and/or 5-HT fibers. Intense spontaneous hyperlocomotor activity was produced in rats lesioned with both 6-OHDA and 5,7-DHT. Locomotor time in this group was 550 ± 17 s in a 600 s session, vs. 127 ± 13 s in the 6-OHDA group and <75 s in 5,7-DHT and intact control groups (p < 0.001). Oral activity dose-effect curves established that 5,7-DHT attenuated DA D1 receptor supersensitivity and further sensitized 5-HT2c receptors. Acute treatment with dextroamphetamine (0.25 mg/kg SC) reduced locomotor time in 6-OHDA+5,7-DHT-lesioned rats to 76 ± 37 s (p < 0.001). Striatal DA was reduced by 99% and 5-HT was reduced by 30% (vs. 6-OHDA group). Because combined 6-OHDA (to neonates) and 5,7-DHT (to adults) lesions produce intense hyperlocomotion that is attenuated by amphetamine, we propose this as a new animal model of ADHD. The findings suggest that hyperactivity in ADHD may be due to injury or impairment of both DA and 5-HT neurons.

Animal models have proven to be useful tools for modeling human neurochemical and behavioral responses to drugs of abuse, including cocaine. Cocaine is a psychomotor stimulant that facilitates monoaminergic neurotransmission by binding to transporters and inhibiting the reuptake of dopamine, serotonin and norepinephrine into presynaptic neurons. Many of the behavioral effects of cocaine, including its locomotor-activating and reinforcing properties, have been attributed to the ability of cocaine to enhance dopaminergic activity. In addition to its direct effects on monoamine neurotransmitters, cocaine impacts other neurotransmitter systems including the endogenous opioid system. The effects of selectively antagonizing mu opioid receptors on cocaine-induced behaviors were evaluated during this research. This research also evaluated the effect of selectively antagonizing dopamine D1 or D2 receptors on cocaine-induced mu opioid receptor occupancy by endogenous opioid ligands. This research furthered our understanding of how the endogenous opioid and dopaminergic systems interact to mediate cocaine-induced behaviors. Although data support the role of mu opioid receptors in modulating cocaine-mediated locomotion and reward, the location of the mu opioid receptors involved has not been established. An evaluation of the effects of a selective mu opioid receptor antagonist administered directly into specific brain regions on cocaine-induced behaviors is important for understanding how the endogenous opioid and dopaminergic systems interact to mediate cocaine-induced behaviors. The studies outlined herein sought to determine the contribution of mu opioid receptors in specific regions of the mesocorticolimbic system to the rewarding and locomotor-activating effects of cocaine in the rat. In addition, to further understand the role of mu opioid receptors in cocaine reward, neuronal activation was studied via cFos activation following the expression of cocaine-induced place preference. Results of the research outlined herein demonstrate the importance of mu opioid receptors in cocaine-induced reward and activity, and demonstrate the anatomical selectivity of mu receptors within the nucleus accumbens, VTA and caudate putamen in this regard. These data suggest that cocaine causes the release of endogenous opioid peptides and that these peptides contribute to the rewarding and locomotor-stimulating effects of cocaine. Further, these data also suggest that opioid peptides are released in the nucleus accumbens shell during the expression of cocaine place preferences and that mu opioid receptors in this region are critical for the manifestation of this behavior. Although data demonstrate that extracellular levels of endogenous opioid peptides are increased following cocaine administration, the time- and dose-dependent occupancy of mu opioid receptors within specific brain regions had not been established in previous studies. The present research sought to determine the time- and dose-dependent occupancy of mu opioid receptors, measured indirectly by displacement of 3H-DAMGO binding, within specific brain regions. 3H-DAMGO binding was measured by in vitro autoradiography. In addition, the contribution of dopamine D1 and D2 receptors in cocaine-induced 3H-DAMGO displacement was evaluated. Results demonstrate that cocaine administration caused a dose- and time-dependent displacement of 3H-DAMGO binding to mu opioid receptors within the nucleus accumbens core and shell. This displacement was attenuated by pretreatment with a selective D2 dopamine receptor antagonist, demonstrating that cocaine, acting via D2 dopamine receptors, can cause the release of an endogenous opioid peptide that binds to mu opioid receptors within the nucleus accumbens core and shell. Previous studies have demonstrated that chronic administration of non-selective mu opioid receptor antagonists has profound effects on mu opioid receptor density and signaling. The research presented herein sought to determine whether chronic treatment with the selective mu opioid receptor antagonist, CTAP, would increase mu opioid receptor density and agonist-stimulated G-protein activation. In addition, this research sought to determine whether chronic CTAP administration would sensitize animals to the locomotor stimulating effects of cocaine. Results outlined herein demonstrate that chronic CTAP treatment sensitized animals to the locomotor effects of cocaine and that this sensitization occurred in conjunction with an increase in mu opioid receptor density within the nucleus accumbens core and shell. / Pharmacology

Hyperactivity is thought to be associated with an alteration of dopamine (DA) neurochemistry in brain. This conventional view became solidified on the basis of observed hyperactivity in DA-lesioned animals and effectiveness of the dopaminomimetics such as amphetamine (AMP) in abating hyperactivity in humans and in animal models of hyperactivity. However, because AMPreleases serotonin (5-HT) as well as DA, we investigated the potential role of 5-HT in an animal model of hyperactivity. We found that a greater intensity of hyperactivity was produced in rats when both DA and 5-HT neurons were damaged at appropriate times in ontogeny. Therefore, previously we proposed this as an animal model of attention deficit hyperactivity disorder (ADHD) - induced by destruction of dopaminergic neurons with 6-hydroxydopamine (6-OHDA (neonatally) and serotoninergic neurons with 5,7-dihydroxytryptamine (5,7-DHT) (in adulthood). In this model effects similar to that of AMP(attenuation of hyperlocomotion) were produced by m-chlorophenylpiperazine (m-CPP) but not by 1-phenylbiguanide (1-PG), respective 5-HT2 and 5-HT3 agonists. The effect of m-CPP was shown to be replicated by desipramine, and was largely attenuated by the 5-HT2 antagonist mianserin. These findings implicate 5-HT neurochemistry as potentially important therapeutic targets for treating human hyperactivity and possibly childhood ADHD.

The basal ganglia are the key circuitry controlling movement and reward behavior. Both locomotion and reward-related behavior are also modified by dopaminergic input from the substantia nigra and the ventral tegmental area (VTA). If the basal ganglia are severed by lesion or in disease, such as in Parkinson’s disease, the affected individuals suffer from severe motor impairments and often of affective and reward-related symptoms. The subthalamic nucleus (STN) is a glutamatergic key area of the basal ganglia and a common target for deep brain stimulation in Parkinson’s disease to alleviate motor symptoms. The STN serves not only motoric, but also limbic and cognitive functions, which is often attributed to a tripartite anatomical subdivision. However, the functional output of both VTA and STN may rely more on intermingled subpopulations than on a strictly anatomical subdivision. In this doctoral thesis, the role of subpopulations within and associated with the basal ganglia is addressed from both a genetic and a behavioral angle. The identification of a genetically defined subpopulation within the STN, co-expressing Paired-like homeodomain transcription factor 2 (Pitx2) and Vesicular glutamate transport 2 (Vglut2), made it possible to conditionally reduce glutamatergic transmission from this subgroup of neurons and to investigate its influence on locomotion and motivational behavior, giving interesting insights into the mechanisms possibly underlying deep brain stimulation therapy and its side-effects. We address the strong influence of the Pitx2-Vglut2 subpopulation on movement, as well as the more subtle changes in reward-related behavior and the impact of the alterations on the reward-related dopaminergic circuitry. We also further elucidate the genetic composition of the STN by finding new markers for putative STN subpopulations, thereby opening up new possibilities to target those cells genetically and optogenetically. This will help in future to examine both STN development, function in the adult central nervous system and defects caused by specific deletion. Eventually identifying and characterizing subpopulations of the STN can contribute to the optimization of deep brain stimulation and help to reduce its side-effects, or even open up possibilities for genetic or optogenetic therapy approaches.